Biochimica et Biophysica Acta 1826 (2012) 312–330
Contents lists available at SciVerse ScienceDirect
Biochimica et Biophysica Acta
journal homepage: www.elsevier.com/locate/bbacan
Review
Using mice to unveil the genetics of cancer resistance
Louise van der Weyden ⁎, David J. Adams
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
a r t i c l e
i n f o
Article history:
Received 6 March 2012
Received in revised form 10 May 2012
Accepted 13 May 2012
Available online 19 May 2012
Keywords:
Cancer
Resistance
Tumorigenesis
Mouse
a b s t r a c t
In the UK, four in ten people will develop some form of cancer during their lifetime, with an individual's relative risk depending on many factors, including age, lifestyle and genetic make-up. Much research has gone
into identifying the genes that are mutated in tumorigenesis with the over-whelming majority of geneticallymodified (GM) mice in cancer research showing accelerated tumorigenesis or recapitulating key aspects of
the tumorigenic process. Yet if six out of ten people will not develop some form of cancer during their lifetime, together with the fact that some cancer patients experience spontaneous regression/remission, it suggests there are ways of ‘resisting’ cancer. Indeed, there are wildtype, spontaneously-arising mutants and GM
mice that show some form of ‘resistance’ to cancer. Identification of mice with increased resistance to cancer
is a novel aspect of cancer research that is important in terms of providing both chemopreventative and therapeutic options. In this review we describe the different mouse lines that display a ‘cancer resistance’ phenotype and discuss the molecular basis of their resistance.
© 2012 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cancer resistance in wildtype mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Wildtype mouse strains show differential susceptibility/resistance to cancer . . . . . .
2.2.
Exploiting genetic diversity between wildtype mouse strains to identify ‘resistance’ genes
2.3.
Heterocephalus glaber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cancer resistance in spontaneously-arising mutant mice . . . . . . . . . . . . . . . . . . .
3.1.
Dm1 mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
S-27, S-31 and S-87/2 mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
SR/CR mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cancer resistance in genetically-modified (GM) mice . . . . . . . . . . . . . . . . . . . . .
4.1.
T-cell signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.1.
Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.2.
Tumor necrosis factors . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.3.
CTLA-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.
Phospholipase A2 enzymes . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2.
Cyclooxygenase enzymes . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: AC, adenocarcinoma; AOM, azoxymethane; APC, antigen-presenting cells; BH, BCL2 homology; CCl4, carbon tetrachloride; cM, centimorgan; COX, cyclo-oxygenase;
CTLA-4, cytotoxic T-lymphocyte antigen 4; DC, dendritic cells; DEN, diethylnitrosamine; DMBA, 7,12-dimethylbenz[α]anthracene; DSB, DNA-strand break; DSS, dextran sodium sulfate;
G5, five generations of inter-crossing (late generations); GM, genetically modified; IFN-γ, interferon-gamma; IκB, IkappaB; IKK, IκB kinase; IL, interleukin; Mb, megabase; MCP-1, monocyte chemoattractant protein-1; MEF, mouse embryonic fibroblasts; MHC, major histocompatibility; MMTV, mouse mammary tumor virus; MNNG, N-methyl-N′-nitro-Nnitrosoguanidine; MNU, N-Nitroso-N-methylurea; Mom, modifier of Min; NER, nucleotide excision repair; NF-κB, nuclear factor kappa B; NMR, naked mole-rat; NO, nitric oxide; NOS,
nitric oxide synthase; PA, pulmonary adenomas; Par1, pulmonary adenoma resistance 1; PI3K, phosphoinositide 3-kinase; PI3P, phosphatidylinositol 3-phosphate; PLA2, phospholipase
A2; PUFA, polyunsaturated fatty acids; RASSF, Ras association family; RBD, Ras binding domain; R-Smads, receptor-activated Smads; SAC, selective for apoptosis of cancer cells; SCC, small
cell carcinoma; SCID, severe combined immunodeficiency; SQ, squamous cell carcinoma; SR/CR, spontaneous regression/complete resistance; TAg, T antigen; TERT, telomerase reverse
transcriptase; TGF, transforming growth factor; Th cell, T helper cell; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TPA, 12-O-tetradecanoylphorbol-13-acetate; TR,
telomerase RNA; UC, ulcerative colitis; UTR, untranslated region; UVB, ultraviolet B
⁎ Corresponding author. Tel.: + 44 1223 834 244; fax: +44 1223 496 802.
E-mail address: lvdw@sanger.ac.uk (L. van der Weyden).
0304-419X/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbcan.2012.05.003
313
L. van der Weyden, D.J. Adams / Biochimica et Biophysica Acta 1826 (2012) 312–330
4.2.3.
Nitric oxide synthases . . . . . . . . .
4.2.4.
IkappaB kinase complex . . . . . . . .
4.2.5.
Polyunsaturated fatty acids . . . . . . .
4.3.
Cell growth/death . . . . . . . . . . . . . . .
4.3.1.
p53 . . . . . . . . . . . . . . . . . .
4.3.2.
INK4a/ARF/INK4b locus . . . . . . . . .
4.3.3.
Phosphatase and tensin homologue . . .
4.3.4.
Activator protein 1 . . . . . . . . . . .
4.3.5.
Transforming growth factor-β . . . . . .
4.3.6.
Smad3 . . . . . . . . . . . . . . . .
4.3.7.
Bone morphogenetic proteins . . . . . .
4.3.8.
B-cell lymphoma 2 family . . . . . . .
4.3.9.
Protein tyrosine phosphatase 1B . . . .
4.3.10. Rassf3 . . . . . . . . . . . . . . . . .
4.3.11. Serine/threonine protein kinases . . . .
4.3.12. GATA factors . . . . . . . . . . . . . .
4.3.13. Prostate apoptosis response-4 . . . . . .
4.4.
Maintaining genomic stability/integrity . . . . .
4.4.1.
PPM1D . . . . . . . . . . . . . . . .
4.4.2.
Poly(ADP-ribose) polymerase-1 . . . . .
4.4.3.
O 6-methylguanine-DNA methyltransferase
4.4.4.
DNA methyltransferase 1 . . . . . . . .
4.4.5.
Terc . . . . . . . . . . . . . . . . . .
4.5.
Miscellaneous . . . . . . . . . . . . . . . . .
4.5.1.
Eph receptor A2 . . . . . . . . . . . .
4.5.2.
Fibroblast factor binding protein . . . .
5.
Conclusions . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Cancer resistance in wildtype mice
There is no doubt that cancer is a devastating disease, with four
out of every ten people being struck by cancer at some point in
their life. However, the flip-side of this fact is less emphasized, specifically that six in every ten people will not develop cancer. When
taken together with the fact that many heavy smokers remain cancer free (~ 10% smokers develop lung cancer, depending upon how
much they have smoked) and some cancer patients experience
spontaneous regression/remission of their tumor [1], this suggests
that ‘cancer resistance’ is possible. The germline transmission of a
defective allele at the tumor suppressor locus greatly increases
the risk of developing certain forms of cancer, however, the majority of cancers are sporadic, and epidemiological data suggest that
there are likely to be multiple low-penetrance genes that segregate
in the human population and confer strong resistance or susceptibility to environmentally-induced cancers [2]. It has been proposed
that individual cancer risk is determined by combinations of resistance or susceptibility alleles inherited through the germline, and
while most humans will be at average risk, some might inherit
more than their fair share of susceptibility alleles, and be highly
cancer prone, while others will inherit a predominance of resistance alleles and be very resistant [3].
Animal models of cancer are commonly used to study tumor biology and develop new approaches to conquering human cancer. Mice
are widely used as the preeminent animal models in cancer research,
due to their small size, inbred nature, and underlying similarities in
the biology of tumorigenesis with humans, implying that genes that
control susceptibility/resistance to tumor development in mice will
also be relevant to the human situation. Thus the development
and characterization of mice models displaying a cancer resistant
phenotype are crucial for the identification of genes involved in
cancer resistance and offer invaluable tools for determining potential
chemopreventive strategies.
2.1. Wildtype mouse strains show differential susceptibility/resistance to
cancer
An important feature of mouse tumorigenesis is strain-dependent
tumor susceptibility/resistance. Wildtype mouse strains show differential susceptibility/resistance to a variety of both spontaneous and
chemically-induced tumor types. For example, compared to the essentially lung tumor resistant C57BL/6J strain, A/J mice exhibit high
susceptibility to spontaneous and chemically-induced lung tumors
[4]. Similarly, C57BL/6J mice are also resistant to chemically-induced
liver tumors [5]. For the organotropic colon carcinogen azoxymethane
(AOM), A/J and SWR/J strains are susceptible, whereas the AKR/J
strain is resistant [6]. For viral-induced oncogenesis in mice, several
host genes are known to play a major role in determining the level
of resistance/susceptibility including the complex genetic locus coding for the major histocompatibility (MHC) antigens of the mouse
(the H-2 locus) (reviewed in Ref. [7]). For example, in infections
with Gross leukemia virus [8,9], Tennant leukemia virus (B/T-L) [10],
some strains of mammary tumor virus [11], and Friend leukemia
virus [12], H-2 b/b is strongly associated with resistance to oncogenesis,
whereas H-2 a/a, H-2 d/d, and H-2 k/k are associated with susceptibility to
oncogenesis.
The X/Gf strain has a very low incidence of spontaneous and induced (chemical, radiation) tumors, believed to be due to their highly
endogenous immune competence, and an absence (or very low presence) of any leukemia or mammary tumor viruses [13]. Similarly,
wild-derived mouse strains (such as Musculus spretus and Musculus
castaneous), derived primarily from captured wild mice that have
been bred to homozygosity through sibling matings, and are thus
from populations with much greater diversity than found in the classical laboratory strains [14], are often more resistant to carcinogens
and pathogens than the commonly used laboratory-derived strains.
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Table 1
Major tumor resistance loci identified from crosses between ‘susceptible’ and ‘resistant’ mouse strains. AC, adenocarcinomas; PA, pulmonary adenomas; Par-1, pulmonary adenoma
resistance-1; SCC, small cell carcinoma; SQ, squamous cell carcinoma.
Resistance locus
F1 mice
(back-crossed to perform the linkage analysis)
Details of the locus
Chromosomes 5 and 7: skin cancer
NIH × M. spretus
(NIH mice are very sensitive to DMBA/TPA-induced
skin papillomas and carcinomas, whereas
M. spretus are resistant)
A/J × M. spretus
(A/J mice are very sensitive to urethane-induced PA,
whereas M. spretus are resistant)
A/J × SM/J
(SM/J mice are resistant to urethane-induced PA)
A single locus on chromosome 5 affecting both early and late stages
of malignancy, and two independent loci on chromosome 7 primarily
affecting benign tumor development (not progression) [236].
Chromosome 11: lung cancer
Chromosome 18: lung cancer
Chromosome 12: lung cancer
A/J × BALB/cByJ
(BALB/cByJ mice are 14 times more resistant to
urethane-induction of PA than A/J mice)
A/J × SM/J
2.2. Exploiting genetic diversity between wildtype mouse strains to identify ‘resistance’ genes
An approach to identify these resistance loci has been to exploit
the genetic diversity between the ‘resistant’ and ‘susceptible’ mouse
strains. For example, crosses between M. spretus and inbred laboratory strains showed that M. spretus/M. musculus F1 hybrids were extremely resistant to most chemical carcinogenesis protocols, failing
to develop appreciable numbers of tumors of a wide range of tissues
[15]. Such interspecific crosses have led to the detection of multiple
loci affecting tumor development, such as the mapping of several
loci that control resistance to different stages of skin tumor development and resistance genes for lung tumor development (see Table 1).
Although undeniably such breeding strategies have been predominantly used to identify tumor ‘susceptibility’ loci (summarized in Ref.
[3]), it is important to remember that genes classified as conferring
‘resistance’ in a particular mouse strain can also reveal themselves
as susceptibility loci in subsequent crosses into other genetic backgrounds (and presumably vise versa) [16]. Thus individual loci
might only be revealed as resistance or susceptibility loci after crossing to a genetic background that allows gene–gene interactions
resulting in the expression of the trait, as inter-locus interactions
have been shown to be an important component of tumor susceptibility [17,18].
2.3. Heterocephalus glaber
A rodent that has been shown to possess natural resistance to cancer is the naked mole-rat (NMR; Heterocephalus glaber). In a colony of
1500 animals in captivity, the oldest individuals are more than
30 years of age, and although animals over 24 years show evidence
of frailty and die of age-related causes, death because of cancer has
never been observed, and necropsies have not revealed incidental tumors [19]. Thus, the NMR appears to be a cancer-resistant mammal.
In vitro studies on NMR fibroblast cells found that they react to signals in the culture environment that cause them to express unusually
high levels of the tumor suppressor p16 INK4A, and expression of
the combination of the oncogenes SV40 large T antigen (TAg) and
Ras G12V reduced the level of p16 INK4A, thereby permitting the cells
to grow well in culture but did not confer the ability to grow as colonies in soft agarose (a surrogate assay for tumorigenicity) [20]. More
recently, NMR cells expressing SV40 TAg and Ras oncogenes were
shown to rapidly enter crisis when transplanted into SCID mice and
thus unable to form tumors [21]. Thus understanding the basis for
Par-1 maps to a 2 cM (2.2 Mb) region between D11Mit70 and Hoxb9.
Candidate gene is Tob1 [237,238].
Par-1 corresponds to human 17q11–23. LOH at 17q was found in 53% of AC
(but only at low levels in the other lung cancer subtypes, suggesting that the
gene is selective for AC, probably at the level of the target cell) [239,240].
Par-2 maps to a 0.5 cM region between D18Mit103 and D18Mit188 [241–243].
Par-3 candidate gene is protein kinase C eta (nPKCη), which is expressed
exclusively in skin and lung and down-regulated in PA. Par1 and Par3 act
synergistically. Par-3 corresponds to human 14q11–24. LOH at 14q was found
in 30–42% of AC, SQ and SCC (affecting all 3 subtypes of lung cancer suggests
that it is related to the progression of lung tumors in general) [239,240].
cancer resistance in the NMR will provide important clues for mechanisms defining the causes of cancer susceptibility and resistance in
mammals.
3. Cancer resistance in spontaneously-arising mutant mice
Most inbred strains of mice succumb to growing malignant
tumors, including both endogenously-arising ones (autochthonous
tumors) and transplantable tumors (non-autochthonous tumors)
that originated in a mouse of the same strain. However, as with any
biological function, this phenotype can change through a mutation,
and although spontaneous gene mutations for resistance (or increased
susceptibility) to a malignant tumor are rare events, they provide
valuable information about the biological function of the gene involved. Mouse mutations for resistance to transplantation of a malignant tumor or its metastases are discussed in more detail below.
3.1. Dm1 mice
Studies to identify spontaneous mutants of the mouse MHC locus
(H-2 mutations) were initiated in the early 1960s using skin graft survival or rejection as a screening tool for mutants [22,23]. For example,
H-2 dm1 is a spontaneous MHC class I mutation first identified in a
mouse of the B10.D2 strain (MHC haplotype H-2 d) because it rejected
parental B10.D2 skin grafts [22]. Later studies showed that this mutation was due to a hybrid gene containing the 5′ part of the D d gene
and the 3′ part of the L d gene, resulting in a deletion of the segment
between these genes that contains three other MHC class I genes
[24]. Subsequently, the heterozygous carriers of the dm1 mutation
(H-2 dm1/H-2 b) were found to recover from Friend retrovirusinduced leukemia, whereas normal heterozygous mice (H-2 d/H-2 b)
die from the disease [25]. Unfortunately, the immunological mechanism of spontaneous regression of these tumors in H-2 dm1/H-2 b
mice has not been characterized in full detail.
3.2. S-27, S-31 and S-87/2 mice
In screens designed to expose host genes for resistance, mice were
analysed for their ability to survive transplantable metastatic tumors
[26,27]. In a screen of over 70,000 mice, three spontaneous mutations
affecting the incidence of survival and metastases were identified.
One survivor of the C57BL/10Sn strain, designated S-27, survived an
intraperitoneal injection of EL4 lymphoma cells (H-2 b), which normally kills C57BL/10Sn mice (H-2 b). When the mutant gene was
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crossed onto the C57BL/6J background (H-2 b), the S-27 mutants were
able to resist moderate (but not high) doses of transplantable B6
tumor, and resist metastasis to a variety of cell lines (including
radiation-induced lymphoma BB, chemically-induced lymphoma
EL4, and rhabdomyosarcoma MCA/77-23, which typically result in
metastasis and death in wildtype C57BL/6J mice), 1 indicating that S27 mice carry a gene for resistance to metastasis [27,28]. In contrast,
the S-31 mutant identified in the same screen resists the initial EL4
innoculum but is highly susceptible to its metastasis. Similarly, the
S-87/2 mutant was identified in a screen using the C57BL/6J strain
for susceptibility to sarcoma MCA/77-23 cells, and although it is resistant to the original tumor transplant, it shows increased susceptibility
to metastasis.
Genes for resistance or susceptibility to the tumor and its metastasis in these three S-mutants were found to be in novel single exon
genes Aβ4–7 comprising the Aβ6 gene family, whose protein coding
region is very similar to the classical H-2-Ab cDNA encoding the β
chain of MHC class II molecules, found on the surface of antigen presenting cells (APC). However, these mutant Aβ4–6 genes have been
shown to be molecularly unstable in somatic cells of mice carrying
them, including the mutant strains S-27 (genes Aβ4 b, Aβ6 w302), S31 (hybrid between Aβ5 s5 and Aβ4 b genes) and S-87/2 (gene not
yet identified), and this instability results in somatic mosaicism of
these nontrivial MHC class II molecules in their APC [29]. Thus these
genes controlling susceptibility/resistance to the spread of metastatic
tumors are remarkably different from the classical MHC gene system.
315
sentinels of the immune response and T cells as effectors of adaptive
anti-tumor immunity, with a variety of cytotoxic molecules mediating the critical role of host prevention of malignancy. Conversely,
while acute inflammation is a part of the defense response, chronic
inflammation can lead to a wide variety of diseases, including cancer,
and in the last decade a growing body of epidemiological and clinical
data has emerged to support the concept that longstanding inflammation potentiates or promotes tumor development, growth and
progression.
The balance between cell proliferation and apoptosis is influenced
by genes that contribute to the development of cancer (oncogenes)
and those that encode proteins that normally suppress tumor formation (tumor suppressor genes), and virtually all cancer cells contain
mutations that enable evasion of apoptosis through dynamic interplays between activated oncogenes and/or mutated tumor suppressor genes. Genetic stability tumor suppressor genes preserve
genome integrity, and activate the numerous multiple-step DNA repair pathways that exist, depending on the nature of the DNA lesion.
Thus genes that augment the host immune system; and/or dampen down the inflammatory response; and/or halt proliferation and
promote apoptosis of the tumor cells; and/or maintain the integrity
of the genome all play important roles in cancer resistance. Examples
of such genes and their modifications in mouse models of cancer are
discussed in more detail below and summarized in Table 2. Unfortunately, some of these GM ‘cancer resistant’ mice also show associated
phenotypes such as reduced lifespan, susceptibility to pathogens and
nephropathy (reviewed in Ref. [35]).
3.3. SR/CR mice
4.1. T-cell signaling
In 2003, Cui and colleagues discovered a single mouse in their
BALB/c colony that displayed resistance to intraperitoneal injection
of murine sarcoma S180 cells (H-2 q), 2 which typically results in
ascites accumulation and death within 3–4 weeks [30]. When this
mouse was bred with wildtype S180-sensitive mice, of a variety of
different genetic backgrounds, 30–40% of the F1 progeny was also resistant, and this dominant trait was termed ‘spontaneous regression/
complete resistance’ (SR/CR) [30,31]. Interestingly, the response does
vary according to age, with SR/CR mice that are 6 weeks old on first
exposure to S180 cells showing complete resistance to ascites formation, whereas mice that are 22 weeks old on first exposure showing
development of ascites accumulation over the first 2 weeks, which
then disappears within 24 h [30,31]. In addition to resistance to
S180 cells, SR/CR mice either on a BALB/c or C57BL/6J congenic background show significantly higher levels of resistance to a wide variety
of cancer cell lines in comparison to wildtype mice (including MethA
sarcoma, B16 melanoma, LL/2 lung carcinoma and J774 and EL-4 lymphoma cells) [32].
The SR/CR trait of cancer resistance is mediated primarily by leukocytes of the innate immune system [33,34] and is based on two
separate processes: leukocyte migration/infiltration to the site of the
cancer cells and recognition of common surface properties on cancer
cells (Fig. 1) [32]. The identity of the chromosomal region responsible
for this genetic trait is as yet unknown.
4. Cancer resistance in genetically-modified (GM) mice
The idea that the immune system might help protect humans
against cancer was first suggested by Paul Ehrlich over a century
ago, and much research has focused upon dendritic cells (DCs) as
1
Spontaneous metastasis assay is when intradermally growing tumors are surgically
removed and mice scored for metastases that occur afterwards. In susceptible C57BL/6J
mice, surgery does not prevent the metastases, which grow in various organs and inevitably kill the mouse.
2
Mouse S180 sarcoma cells do not show detectable levels of MHC protein on their
cell surface and thus can form highly aggressive cancers in all strains of laboratory
mouse and rats.
4.1.1. Cytokines
Cytokines are hormonal messengers responsible for most of the
biological effects in the immune system, and can be functionally divided into two groups: pro-inflammatory and anti-inflammatory
(but promote allergic responses). T lymphocytes are a major source
of cytokines, the most prolific of which are those expressing CD4
(also known as helper T cells; Th), and this subset can be further subdivided into Th1 and Th2. Th1-type cytokines (particularly IFN-γ)
tend to produce pro-inflammatory responses, whereas Th2-type
cytokines (such as IL-4, 5, 10 and 13) tend to produce more of an
anti-inflammatory response. Despite the fact that excessive proinflammatory responses can lead to uncontrolled tissue damage, cytokines released from Th1 cells are in particularly effective in shifting
immune systems into a Th1-dominant state, which enhances cellmediated immunity [36]. The Th1 branch of the immune system,
which employs T cells, NK cells and macrophages, plays major role
in combating cancer but growing cancers actively suppress immune
responses and disregulate the activity of these effector cells [37].
Chemokines are a family of small cytokines that have the ability to
induce directed chemotaxis in nearby responsive cells (‘chemotactic
cytokines’). Members of the chemokine family are divided into four
groups depending on the spacing of their first two cysteines: CC (or
β-chemokine), CXC (or α-chemokines), C (or γ chemokines), and
CX3C (or δ-chemokines). Some chemokines are pro-inflammatory
and can be induced during an immune response to recruit cells of
the immune system to a site of infection, while others are homeostatic and involved in controlling the migration of cells during normal
processes of tissue maintenance or development.
A number of studies transplant/xenograft models in mice have
demonstrated that secretion of cytokines and chemokines from tumors can produce anti-tumor effects (some examples of which are
shown in Table 3). Although further investigation is required to elucidate the precise mechanisms involved in the anti-tumor activity of
these Th1 cytokines/chemokines, studies using mouse models have
helped determine that in some cases it can be NK-dependent. For example, depletion of NK cells from nude mice with anti-asialo GM1
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A
B
C
Fig. 1. SR/CR leukocyte migration and destruction of cancer cells. Leukocyte infiltration is an important part of the SR/CR resistance mechanism [32]. (A) S180 sarcoma cells (large
orange circles) secrete chemotactic factors (small orange circles) that attract SR/CR leukocytes (large blue circles), allowing tight contact between the leukocytes and cancer cells,
which facilitates their destruction. (B) In contrast, other cancer cell lines, such as LL/2 and MethA (large yellow circles) produce little or no chemoattractant and are therefore not
efficiently killed by SR/CR leukocytes. (C) However, co-injection of MethA or LL/2 cells with S180 cells results in attraction of SR/CR leukocytes and efficient destruction of these
cancer cells.
antibody diminishes the growth retardation of IL-27-transfected
colon cancer (Colon 26/IL-27) tumors and IL-21-transfected pancreatic cancer (AsPC-1/IL-21) tumors [38]. Furthermore, the use of immunodeficient mouse lines (such as nude and SCID mice) has
helped to determine that there is also involvement of specific T-cell
subsets in this process. For example, while the growth of AsPC-1/IL21 and AsPC-1/IL-23 tumors in nude mice was retarded compared
with that of parental (untransfected AsPC-1) tumors, the growth of
AsPC-1/IL-23 tumors in SCID mice was not different from that of parental tumors [39].
In addition to the transplant/xenograft models as mentioned
above, one cytokine in particular, IL-12, has been shown to demonstrate in vivo anti-tumor activity in a wide variety of murine tumor
models. For example, mice treated intraperitoneally with IL-12 were
found to exhibit anti-tumor and anti-metastatic activity against a variety of different mouse tumors (including melanomas, hepatic tumors and sarcomas) [40–42]. Conversely, IL-12 deficiency has been
shown to promote photocarcinogenesis in mouse skin [43]. Interestingly the same group found that IL-12 deficiency was also associated
with an enhanced resistance to the development of TPA-induced skin
tumors in DMBA-initiated mouse skin, due to a reduction in the
DMBA/TPA-induced inflammatory responses in the skin and tumors
of these mice (possibly due to their lower expression levels of COX2 and pro-inflammatory cytokines) [44]. Thus the role of IL-12 in
chemical carcinogenesis is not so clear.
4.1.2. Tumor necrosis factors
Tumor necrosis factors (or the TNF-family) are a group of cytokine
family members that can cause apoptosis. Nineteen cytokines have
been identified as part of the TNF family, however, monocytederived tumor necrosis factor-alpha (TNF-α) is the best-known
member of this class, and sometimes referred to when the term
“tumor necrosis factor” is used. TNF-α is a major mediator of inflammation, however its role in tumor growth and dissemination is
context-dependent, as although TNF-α was originally identified by
its ability to induce the necrosis of transplanted tumors in mice
[45], subsequent clinical trials have shown that local administration
of TNF-α at high concentrations produces a powerful anti-cancer activity by causing selective damage and obliteration of intratumoral
blood vessels, yet there is also evidence that TNF-α possesses
mitogenic activity and can enhance the ability of tumor cells to
metastasize (reviewed in Ref. [46]). For example, mice deficient in
TNF-α show a dramatic reduction (up to 90%) and delayed onset of
chemical-induced skin tumors [47–49] and mice transplanted with
a breast carcinoma cell line showed reduced tumor growth when
dosed weekly with an anti-murine TNF-α antibody (cV1q), compared
to transplanted mice dosed with vehicle alone [49]. Thus it has been
proposed that the effects of TNF-α on tumor development are context
dependent: high-dose local delivery of TNF-α can cause tumor regression, yet sustained production of endogenous TNF-α in the
tumor microenvironment can enhance cancer development and metastasis (reviewed in Ref. [50]). Interestingly, the tumor resistance
phenotype associated with loss of TNF-α can be partially recapitulated by loss of one of its major down-stream targets, monocyte chemoattractant protein-1 (MCP-1), as mice carrying a knockout allele of
Mcf1 showed a ~50% reduction in chemical-induced skin tumors
compared with wildtype mice [48].
In addition to being a key mediator of inflammation, TNF-α elicits
pleiotropic effects in a wide range of cells by binding and activating
two cell-surface receptors, specifically TNF receptors 1 and 2
(TNFR1 and R2). Similar to the conflicting reports of TNF-α in cancer
resistance, the role of TNFR1 in cancer resistance is context dependent. For example, one study found that mice carrying a knockout
Tnfr1 allele showed a reduced incidence of carcinogenic dietinduced liver tumorigenesis (interestingly the same protective effect
was not achieved in Tnfr2 null mice) [51]. In contrast, in colitisassociated carcinogenesis TNFR1 functions as a tumor suppressor,
with histological inflammation scores being higher and neoplastic lesions occurring more frequently and earlier in Tnfr1 null mice subjected to chemical-induced colitis, compared to controls [52].
Nevertheless, taken together, these studies confirm that ablation of
the TNF signaling pathway can confer a cancer resistant phenotype.
4.1.3. CTLA-4
Activation of T lymphocytes is thought to require at least two signals, one delivered by the T-cell receptor (TCR) complex after antigen
recognition, and one provided on the engagement of co-stimulatory
receptors, such as CD28 (which binds CD80 and CD86 on APCs). However, other molecules can bind CD80/86, such as cytotoxic Tlymphocyte antigen 4 (CTLA-4; CD152). In contrast to co-ligation of
the TCR and CD28, which results in T-cell activation, cytokine production, proliferation and differentiation, co-ligation of the TCR and
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Table 2
Genetically engineered mice displaying cancer resistance phenotypes. The type of resistance includes the development of spontaneous or carcinogen-induced tumors
(such as those arising naturally or after exposure to chemicals or irradiation), the
development of genetically-induced tumors (by breeding to mice that carry genetic
mutations predisposing them to the development of tumors) or the development of
non-autochthonous tumors after transplantation (either intravenously, subcutaneously,
intradermally, intracranially or intraperitoneally) with human or mouse tumor cell lines
(with the resistance to tumor formation arising from over-expression or knock-down of
a specific gene in the tumor cells or administration of a specific inhibitor).
Genetic manipulation
T-cell signaling
Loss of IL-12
Loss of Tnfα
Loss of Mcp-1
Loss of Tnfr1
Expression of CTLA4-Ig
Inflammation
Expression of Pla2g2a
Loss of Pla2g4
Loss of Ptgs-2
Loss of Ptgs-1
Loss of Nos-2
Loss of Ikkβ
Expression of Ikkα
Expression of fat-1
Cell proliferation and death
Expression of p53
Expression of Ink4a/Arf
Expression of Pten
Loss of c-Jun
Loss of c-Fos
Expression of Tgfβ
Loss of Smad3
Expression of Bmp-4
Expression of Bmp-6
Expression of Bcl2
Loss of Bcl-xL
Loss of Ptp1b
Expression of Rassf3
Expression of PKCδ
Expression of Gata4
Expression of Gata6
Expression of Par-4
Genomic stability/integrity
Loss of Ppm1d
Loss of Parp-1
Loss of Dnmt1
Loss of Terc
Expression of Mgmt
Resistance to
spontaneous or
carcinogeninduced tumors
Resistance to
geneticallyinduced tumors
[44]
[47,48]
[48]
[51]
[55]
[68]
[77]
[77]
[49]
[62,63,67]
[69,70]
[74,75]
[75]
[86,87]
[91]
[93]
[97,98]
[76,78]
[99]
[104–106]
[110,111]
[115]
[118]
[120]
[124,127]
[129]
[134]
[133]
[139,140]
[137]
[119]
[125]
[126]
[138]
[148]
[152]
[155]
[166]
[166]
[174]
[181]
[170]
[182]
[62,208–211]
[214–219]
[202–205,244]
[213,214]
[193–201]
Angiogenesis
Loss of Fgfbp
Adhesion
Loss of EphA2
Resistance to
transplanted
tumor cell lines
[161]
[159]
[164,165,167]
[175]
[182,188]
[220–223]
[232,233]
[228,229]
[226,227]
CTLA-4 results in cell-cycle arrest and termination of T-cell activation
(reviewed in Ref. [53]). A soluble recombinant form of CTLA-4,
CTLA41g, has been used as a competitive inhibitor of CD28 activation
and can inhibit T cell-dependent immune responses, including induction of anti-tumoral immune responses, rejection of transplanted organs, and autoimmune responses [54]. In agreement with this, a
CTLA-4Ig transgenic mouse model (K14-CTLA-4Ig), that expressed
high amounts of CTLA-4Ig in the skin and systemic circulation,
exhibited significant suppression of skin tumor formation after
being chronically irradiated with UV [55]. Blockade of CD80/CD86CD28-CTLA-4 interactions in these mice significantly altered the
Th1/Th2 balance in favor of Th1-mediated immune responses, and
317
thus reversed the chronic UV radiation-induced tendency to generate
Th2 rather than Th1 immune responses [56].
4.2. Inflammation
4.2.1. Phospholipase A2 enzymes
Phospholipase A2 (PLA2) enzymes hydrolyze the fatty acid from
the sn-2 position of membrane phospholipids. The released polyunsaturated fatty acids can be subsequently metabolized into eicosanoids (such as prostaglandins and leukotrienes) that are involved in
numerous homeostatic biological functions [57]. The PLA2 superfamily comprises four main types including the secreted (s)PLA2, cytosolic (c)PLA2, calcium-independent (i)PLA2, and lipoprotein-associated
(Lp)PLA2 (reviewed in Ref. [58]).
The mouse sPLA2 group IIA gene Pla2g2a has been proposed to
play a role in anti-bacterial defense, inflammation and eicosanoid
generation, clearance of apoptotic cells, and the Wnt signaling pathway (reviewed in Ref. [59]). The evidence for Pla2g2a being involved
in cancer resistance is linked to the ‘Min’ mouse strain. Min (Apc +/Min)
mice carry a point mutation that disrupts the mouse homolog of the
human familial polyposis gene (APC) and they develop intestinal neoplasms [60]. Multiplicity of these neoplasms is affected by genetic
background, and a strong modifier locus, Mom1 (‘modifier of Min-1’)
that suppressed Min-induced tumorigenesis was found in the AKR
strain [61]. The Mom-1 region was subsequently mapped to mouse
chromosome 4 and found to contain Pla2g2a and a locus distal to
D4Mit64 [62], and Pla2g2a transgenic mice show a reduction in Mininduced intestinal tumors [62,63]. Interestingly, a second modifier
of the Min phenotype, Mom-2, was serendipitously detected while
further investigating Mom-1 in additional inbred strains [64] and
this spontaneously arising mutation, specifically a 4 base-pair duplication in the coding sequence of Atp5a1 (an ATP synthase component), conferred a dominant, resistant phenotype with reduced
polyp multiplicity [65]. Dove and co-workers were able to refine the
locus of an additional modifier of the Min phenotype, Mom-7, to within the first 7.4 Mb of chromosome 18, and there are possibly five segregating alleles that likely to act by modulating net tumor growth or
initiation [66]. However, the mechanism by which Pla2g2 performs
its role in tumor resistance is still unclear. There is evidence for it
being an Apc-independent role as expression of a Pla2g2a transgene
reduced tumorigenesis 90–100% in the large intestine of mice carrying a knockout Muc2 allele (Muc2 −/− mice develop of adenocarcinomas in the small and large intestine) [67] and provided
protection against carcinogen-induced duodenal and colon tumors
(the tumors demonstrated upregulation of β-catenin which is indicative of involvement of the Wnt signaling pathway) [68]. Indeed, several models have been proposed to illustrate its putative biological
effects on tumor development (reviewed in Ref. [59]).
The cPLA2 group IV family member PLA2G4 catalyzes the hydrolysis of membrane phospholipids to release arachidonic acid, which is
subsequently metabolized into prostaglandins, which in turn regulate
many key intracellular pathways, in particular the inflammatory response. Thus inhibition of PLA2G4 would decrease the amount of arachidonic acid available to be metabolized into prostaglandins and as
a result impair tumorigenesis. In agreement with this, Hong and colleagues found that Min mice carrying a knockout allele of Pla2g4
showed decreased prostaglandin production and an 83% reduction
in tumors of the small intestine compared with littermates
(Pla2g4 +/− and Pla2g4 +/+ mice on a Min background) [69]. Similarly,
mice carrying a truncated Apc allele (Apc +/Δ716 mice) and a knockout
allele of Pla2g4 showed a significantly reduced size of small intestinal
polyps (although the number of polyps remained unchanged) [70].
4.2.2. Cyclooxygenase enzymes
Cyclooxygenase (COX) enzymes are responsible for the conversion of arachidonic acid to prostaglandins, which in turn can play a
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Table 3
Transplant and xenograft mouse models have demonstrated that secretion of Th1-type cytokines or chemokines from tumors produces anti-tumor effects.
Cytokine/
chemokine
Immune system role
Transduced cells
Phenotype of the recipient mice
IL-12
Stimulates production of IFN-γ in Th cells,
thereby promoting the Th1 profile.
Murine colon carcinoma
cell line (colon 26)
BALB/c mice showed an initial tumor take followed by a complete
tumor regression and subsequent acquired tumor-specific
protective immunity [249].
Nude or SCID mice produced tumors, however they survived
longer than those injected with parental cells [250].
BALB/c mice showed an initial tumor take followed by complete
regression and subsequent acquired tumor-specific protective
immunity. Nude or SCID mice produced tumors but their
overall survival was significantly longer than mice inoculated
with parental cells [251].
Nude and SCID mice produced tumors, however nude mice
survived longer than those injected with parental cells,
unlike SCID mice [250].
BALB/c mice showed a significantly inhibited tumor growth
(and in other experiments, direct injection of recombinant
IL-18 into established tumors also inhibited tumor growth) [252].
IL-15
Secreted by mononuclear phagocytes
(and some other cells) following viral infection
and regulates T and NK cell activation and
proliferation.
Human pancreatic cancer
cell line (AsPC-1)
Murine colon carcinoma
cell line (colon 26)
Human pancreatic cancer
cell line (AsPC-1)
IL-18
IL-21
IL-23
IL-27
Produced by many cell types, it is a potent
inducer of IFN-γ by T cells and NK cells and
is synergistic in this function with IL-12. It can
drive differentiation of CD4+ T cells to the Th1
phenotype (and can also promote Th2 responses
under some conditions).
Secreted primarily from CD4+ T cells, it induces
proliferation of NK and activated T cells and
increases the lytic functions of NK and cytotoxic
T cells.
Secreted from activated DC, and enhances
proliferation of memory T cells and production
of IFN-γ from activated T cells. It is structurally
related to IL-12, thus shares its biological
activities in facilitating Th1 responses.
Produced primarily from activated DC, it is
involved in an early phase of Th1 differentiation.
It also synergizes with IL-12 in IFN-γ production
from naive T and NK cells.
Murine prostate
carcinoma cell line (RM1)
Human oesophageal
tumor cell line (T.Tn)
Human pancreatic cancer
cell line (AsPC-1)
Murine colon carcinoma
cell line (colon 26)
Human oesophageal
tumor cell line (T.Tn)
Murine melanoma
cell line (B16-F1)
Murine colon carcinoma
cell line (colon 26)
Murine neuroblastoma
cell line (TBJ)
CCL19
CCL21
CXCL4 (PF-4)
Produced by a subset of DC and possibly by other
non-lymphoid cells, in T-cell areas of lymphoid
tissue. Its ability to chemoattract T cells, B cells,
DC, macrophage progenitor cells and NK cells, is
mediated through the CCR7 receptor.
Constitutively expressed by high endothelial
venules in lymph nodes and Peyer's patches,
lymphatic vessels and stromal cells in spleen and
appendix. It binds to the CCR7 receptor and is
chemotactic for mature DC, naive and memory
T cells. Along with CCL19, it is required for normal
lymphoid tissue organization that is essential for
effective T cell-DC interactions.
Released from alpha-granules of activated
platelets during platelet aggregation. It interacts
with the CXCR3B receptor and is chemotactic for
neutrophils, fibroblasts and monocytes.
Murine breast cancer
cell line (C3L5)
Murine DC cells
Human head and neck
squamous carcinoma
cell line (KB)
Murine Lewis lung
carcinoma cell line (LLH)
Human myeloma cell lines
(LP-1, U266, RPMI8226)
Nude mice developed small tumors that regressed spontaneously
thereafter, in contrast to parental cells [253].
Nude mice developed tumors, but at a retarded growth rate
relative to parental cells [39].
BALB/c mice developed tumors, followed by a complete
tumor regression and subsequent acquired tumor-specific
protective immunity. BALB/c mice given tail vein injection
showed significantly reduced number of lung metastasis
relative to parental cells. Nude mice developed tumors,
but at a retarded growth rate relative to parental cells [254,255].
Nude mice developed small tumors which regressed
spontaneously thereafter, in contrast to parental cells [253].
C57BL/6J mice given tail vein injection showed significantly
reduced number of lung metastasis relative to parental cells [255].
BALB/c mice rejected the tumors and subsequently acquired
tumor-specific protective immunity. Nude mice developed tumors,
but the growth was retarded compared to that of parental cells,
however the survival of SCID mice was not different from that of
the nude mice inoculated with parental cells [38].
A/J mice developed small tumors, followed by a complete tumor
regression, with most showing subsequent acquired tumor-specific
protective immunity. Tail vein injection showed significantly
reduced number of liver metastasis relative to parental cells [256].
Only 10% of C3H/HeN mice injected developed tumors
(compared with 100% of mice injected with a transduced control)
and subsequently acquired partial tumor-specific protective
immunity [257].
BALB/c mice subcutaneously administered the murine lung
tumor cell line, L1C2, and 5-days later received an intratumoral
injection DC transduced with CCL21, showed complete tumor
eradication (60% of mice compared to 12% of mice that received
unmodified DC cells) [258].
Transgenic mice (CC-10 TAg) that develop pulmonary
adenocarcinomas by 4 months, showed a marked reduction
in tumor burden with extensive mononuclear cell infiltration of
the tumors after a single intra-tracheal administration of CCL21
gene-modified DC [259].
Nude mice showed an inhibition of solid tumors through an
anti-angiogenic action [260].
Nude mice given tail vein injection showed significantly
reduced number of lung metastasis [261].
SCID mice showed significant reduction in microvessel densities
in human myeloma xenografts and markedly reduced the tumor
volume, which significantly extended their overall survival [262].
Data in this table are derived from cancer cell lines that are retrovirally transduced with specific a cytokine or chemokine gene and then transplanted (intraperitoneally or
subcutaneously, unless stated otherwise) into recipient mice. However, it should be noted that many of these cytokines and chemokines have also been shown to have an antitumoral effect when administered as a recombinant protein. For example, administration of recombinant CXCL4 effectively suppressed the growth and lung metastases of a murine melanoma cell line (B16-F10) in syngeneic C57BL/6J hosts and prevented the growth of primary tumors of B16-F10 and a human colon carcinoma cell line (HCT-116) in semi-syngeneic
CByB6F1/J mice [245,246]. In addition, BALB/c mice subcutaneously administered a murine lung tumor cell line (L1C2), and 5-days later receiving an intra-tumoral injection of recombinant CCL19, showed significant systemic reduction in tumor volumes [247], and transgenic mice that develop pulmonary adenocarcinomas by 4 months, showed a marked reduction
in tumor burden with extensive mononuclear cell infiltration of the tumors after a single intra-nodal administration of recombinant CCL21 [248]. A/J, BALB/c, C3H/HeN and C57BL/6J are
immunocompetent mice, whereas nude and SCID mice are immunocompromised. Abbreviations: DC, dendritic cells, DC; IFN-γ, interferon-γ; IL, interleukin; SCID, severe combined immunodeficient; Th, helper T cell.
L. van der Weyden, D.J. Adams / Biochimica et Biophysica Acta 1826 (2012) 312–330
role in the inflammatory response. COX exists in two main isoforms,
COX-1, which is constitutive and responsible for generation of eicosanoids for “housekeeping functions”, and COX-2, the inducible isoform, which contributes eicosanoids involved in a variety of growth
and inflammatory events [71,72]. Many malignant cells (particularly
in breast and colorectal cancers) show over-expression of COX-2,
while COX-1 expression remains unaltered [72], and non-steroidal
anti-inflammatory drugs, which are known to inhibit COX enzymes,
have shown to lower the mortality rate from cancers in the gastrointestinal tract [73]. Studies in the mouse have confirmed the approach
of ablating COX-2 as an approach to protect against cancer. For example, mice carrying a knockout allele of Cox-2 (Ptgs-2 −/−) on a mutant
Apc background (either Min or Δ716 mice) showed a dramatically
reduced number and size of intestinal polyps [74,75]. Loss of COX-2
has also been shown to provide a protective effect in other tumor
types, with Ptgs2 −/− embryonic stem cells showing a dramatic
reduction in ability to form teratocarcinomas when injected into
syngeneic mice [76], and Ptgs2 −/− mice showing a 75% reduction
in chemically-induced skin papilloma formation [77]. Nude mice
that received Celecoxib (a COX-2 inhibitor) showed reduced growth
and lymphangiogenesis of human mammary cancer xenografts as
compared with controls [78]. Conversely, transgenic COX-2 overexpression sensitizes mouse skin for carcinogenesis, with keratin 5
promoter-driven overexpression of COX-2 in basal keratinocytes contributing to skin-tumor promotion and progression by establishing an
“auto-promoted” skin phenotype, i.e., the initiating dose of DMBA
was sufficient to induce skin carcinogenesis in COX-2 transgenic
mice [79]. However, in contrast to these reports, one study found
that over-expression of COX-2 provided a protective effect against
chemically-induced skin papilloma formation with transgenic mice
over-expressing COX-2 under the control of the human keratin-14
promoter (K14.COX-2 mice) developing skin tumors at a much
lower frequency than wildtype littermates [80]. Further analysis of
this model to reconcile these findings revealed that the effect of
COX-2 over-expression on skin carcinogenesis is context dependent,
with the mechanism of this resistance restricted to TPA promotion,
as K14.COX-2 mice developed more tumors than wildtype mice
when anthralin was used as the tumor promoter or when they were
treated only with DMBA [81].
Although the role of the COX enzymes in tumorigenesis has predominantly headlined COX-2, there is some evidence that COX-1
also has a role to play. For example, studies using mice carrying a
knockout allele of Cox-1 (Ptgs-1 −/−) found a 75% reduction in
DMBA/TPA-induced skin papilloma formation [77] and ~ 80% reduction in polyp formation on a Min background [75]. Interestingly, the
COX-1 and −2 inhibitor, piroxicam, reduced the growth of canine
mammary cancer xenografts in nude mice unlike mice treated with
vehicle or the selective inhibitor of COX-2, deracoxib [82]. Thus at
least in some tumor types, there are comparable contributions of
both COX isoforms in the development of cancer.
4.2.3. Nitric oxide synthases
Nitric oxide (NO) is a short-life molecule produced by the nitric
oxide synthase (NOS) enzyme, in a reaction that converts arginine
and oxygen into citrulline and NO. There are three isoforms of the
enzyme: neuronal NOS (nNOS/NOS-1), inducible NOS (iNOS/NOS2), and endothelial NOS (eNOS/NOS-3). NO plays a role in a multitude
of diseases, including cancer, myocardial and central nervous system
pathologies, and inflammation (reviewed in Ref. [83]). NOS-2 is
cytokine-inducible, calcium/calmodulin-independent, expressed in
essentially every cell type and can locally generate high quantities
of NO at micromolar range for prolonged periods of time [84]. Numerous reports suggest that NO can have tumor-promoting effects, and as
such NOS-2 expression has been reported as having tumor-promoting
effects (reviewed in Ref. [85]). In agreement with this, mice carrying
knockout Nos-2 alleles on a Min background show significantly
319
reduced intestinal adenoma formation [86,87]. In contrast, several
clinical and experimental studies indicate that the presence of NO in
tumor microenvironment is detrimental to tumor cell survival and
metastasis, and that NOS-2 expression can have anti-tumor effects
(reviewed in Ref. [85]). For example, one study found that mice carrying a knockout Nos-2 allele on a Min background developed significantly more intestinal adenomas than Apc Min/+, Nos2 +/+ littermates
[88]. Interestingly, another study found no difference in ulcerative
colitis (UC)-associated colo-rectal cancer development in wildtype
and Nos-2 −/− mice, and suggests that in the absence of NOS-2,
other factors such as NOS-3, may play a role in nitrosative stress
and UC-associated carcinogenesis [89]. It has been suggested that
the dichotomy of NOS-2 expression in cancer can be reconciled by
consideration of the concentrations of NO involved, the temporalspatial mode of NO action, intracellular targets, cellular redox state
and the timing of an apoptotic stimulus (reviewed in Ref. [85]). However, for now, the cancer resistant phenotype of the Nos-2 null mice
needs further investigation.
4.2.4. IkappaB kinase complex
The IkappaB (IκB) kinase (IKK) complex includes the catalytic subunits IKKα and IKKβ and the scaffold protein NEMO (also known as
IKKγ). The IKK has a crucial role in the activation of the transcription
factor nuclear factor kappa B (NF-κB) by phosphorylating the inhibitory molecule IκBα, which triggers the subsequent polyubiquitylation
and degradation of IκBα through the proteasome, allowing the derepressed NF-κB to bind target genes involved in cell proliferation,
survival and immunity. More recently, the IKK has also been identified as having key roles in other processes ranging from allergy to
cancer through NF-κB-independent pathways (reviewed in Ref.
[90]). Although IKKα and IKKβ share considerable sequence identity,
it is IKKβ that usually serves the more critical function in the activation of classical NF-κB signaling. Mice that specifically lack IKKβ in
their intestinal epithelial cells (villin-Cre/Ikkβ F/Δ mice) show a dramatic decrease of AOM-DSS-induced 75% in tumor incidence, and
mice that specifically lack IKKβ in the myeloid lineage (LysM-Cre/
Ikkβ F/F mice) show an almost 50% reduction in tumor counts, relative
to the Ikkβ F/Δ controls [91]. Thus IKKβ acts both within enterocytes,
which eventually give rise to the transformed component of the
tumor, and within myeloid cells, which influence tumor growth; in
each cell type IKKβ contributes to tumor promotion through a different mechanism, specifically by suppressing apoptosis in epithelial
cells and regulating expression of inflammatory mediators in myeloid
cells [91].
In contrast, IKKα has been shown to function as a molecular
switch that controls epidermal differentiation, and a reduction of
IKKα expression promotes skin tumor development, with IKKα hemizygote (IKKα +/−) mice developing 2- and 11-times more papillomas
and carcinomas, respectively, than wildtype mice 3 [92]. The same
group also showed that mice over-expressing human IKKα in the
suprabasal compartment of the epidermis, which results in increased
epidermal differentiation and reduced keratinocyte proliferation, developed significantly fewer chemically-induced squamous cell carcinomas and metastases than wildtype mice [93].
4.2.5. Polyunsaturated fatty acids
Polyunsaturated fatty acids (PUFA) belong to two families: n-6
and n-3 PUFAs. Mammals cannot naturally produce n-3 PUFA from
the more abundant n-6 PUFA, so they must rely on a dietary supply.
n-3 PUFA have been implicated in inflammation dampening and
there is evidence to suggest that they are potentially protective
3
IKKα-deficient (Ikkα−/−) mice could not be used as they show impaired formation
of the skin, resulting in death soon after birth.
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L. van der Weyden, D.J. Adams / Biochimica et Biophysica Acta 1826 (2012) 312–330
against several cancers, such as colon or breast cancers, mainly on the
promotion and progression stages, whereas n-6 PUFA tend to favor
cancer development [94]. The fat-1 gene of Caenorhabditis elegans encodes an n-3 fatty-acid desaturase enzyme that converts n-6 to n-3
PUFA and transgenic mice carrying fat-1 gene can convert n-6 to n-3
PUFA, resulting in an abundance of n-3 and a reduction in n-6 PUFA
in these mice [95]. The increased levels of n-3 PUFA in these mice confer protection to acute DSS-induced colitis [96] and the same group
showed that these mice have a lower incidence and growth rate of
DSS/AOM-induced colon tumors, via an n-3 PUFA-mediated dampening of inflammation and NF-κB activity [97]. More recently, the group
found that these mice were also more resistant to liver cancer, with
the development of fewer DEN-induced liver tumors relative to controls, due to an n-3 PUFA-derived 18-HEPE and 17-HDHA-mediated
down-regulation of TNF-α [98]. Transgenic fat-1 mice implanted
with mouse melanoma B16 cells also show a reduced incidence of
tumor formation and growth rate relative to controls, mediated by
the n-3 PUFA metabolite prostaglandin E3-induced activation of
PTEN pathway [99].
[104] (Fig. 2). Similarly, p44 mice showed a very low incidence of spontaneous tumors, and showed signs of premature aging [105] (Fig. 2). Interestingly, one p53 mouse model was able to uncouple the cancer
resistance phenotype from the premature aging phenotype by proper
regulation of full-length p53 expression. “Super-p53” mice showed significantly increased resistance to the development of spontaneous and
chemically-induced tumors compared to wildtype mice, and did not
show any signs of premature aging — presumably as the p53 is
not constitutively active, but rather activated only in response to
the appropriate stimuli, where it can respond in an enhanced manner (Fig. 2) [106]. Paradoxically, one study found a tumor inhibitory
effect of p53 loss in transgenic mice expressing epidermal-targeted
Ras, Fos, or human TGF-α [107]. The authors proposed that the paradoxic block in papillomatogenesis in the p53 −/− background may
occur by mechanisms that attempt to maintain epidermal homeostasis and could result from upregulation of additional p53 homologs, such as p73 and p63 (which exhibit some functions similar
to p53 and are able to bind to consensus p53-binding sites of
known transcriptional targets) [107].
4.3. Cell growth/death
4.3.2. INK4a/ARF/INK4b locus
The INK4a/ARF/INK4b locus (also known as CDKN2a and CDKN2b)
is a small 35 kb region on human chromosome 9p21 that contains
three related genes: ARF (also known as p19 ARF or p14 ARF), p15 INK4b,
and p16 INK4a, that each encode distinct tumor suppressor proteins
(reviewed in Ref. [108]). The tumor suppressor activities of p15 INK4b
or p16 INK4a are related to their ability to inhibit the cell cycle, specifically maintaining Rb-family proteins in a hypophosphorylated state,
which promotes binding E2F to effect a G1 cell-cycle arrest, whereas
the tumor suppressor activity of ARF is largely ascribed to its ability
to regulate p53 in response to aberrant growth or oncogenic stresses
such as c-MYC activation (reviewed in Ref. [109]). Knockout studies
of mice deficient for either of these genes have revealed that all
three strains are more prone to spontaneous cancers than wildtype
littermates whereas overexpression of the Ink4a/Arf/Ink4b locus confers a degree of cancer resistance (reviewed in Ref. [109]). From
the same group that generated the "super-p53" mice (see above),
mice that carry an allele of the Ink4a/Arf/Ink4b locus on a bacterial artificial chromosome and display modest overexpression of p16 INK4a,
p15 INK4b, and Arf were generated (“super-Ink4/Arf” mice)[110].
“Super-Ink4a/Arf” mice treated with carcinogens (to induce skin
papillomas, fibrosarcomas, plasmacytomas, and lung adenomas) are
4.3.1. p53
The tumor suppressor gene p53 is a major genome guardian molecule and responds to a diverse array of stresses that include DNA
damage and aberrant oncogene signaling. Upon activation, p53 prevents the emergence of cancer cells by initiating cell cycle arrest, senescence, or apoptosis [100]. The fact that half of all human cancers
display loss-of-function mutations or deletions in the p53 gene is a
strong argument for the importance of p53 anti-cancer function
[101]. Although early attempts to generate genetically engineered
mouse models over-expressing p53 (either globally or in a tissuespecific manner) have not always been successful due to issues of
embryonic lethality or premature degeneration of the targeted tissue
(reviewed in Ref. [102]), models using only moderately elevated (or
correctly regulated) levels of p53 expression have had success in
showing that boosting p53 levels confers cancer resistance (reviewed
in Ref. [103]). Heterozygous p53 mice expressing the ‘m’ allele (p53+/m)
displayed a phenotype consistent with ‘activated p53’, showing enhanced resistance to the generation of spontaneous tumors compared
with control littermates (p53+/+ and p53+/−), although they also displayed a multitude of phenotypes consistent with premature aging
p53+/m mouse
p44 mouse
Super-p53 mouse
p53
p53
p53
p53 m
p53
p53
p44
p53
Viable
More resistant to cancer
Premature aging
Viable
More resistant to cancer
Premature aging
Viable
More resistant to cancer
No change in aging
Fig. 2. Examples of genetically engineered p53 mutant mice showing cancer resistance phenotypes. Wildtype (endogenous) p53 alleles are shown in gray, and modified or exogenous (transgenic) p53 alleles are shown in red. p53m mice carry one p53 allele that contains a deletion of the 5′ UTR and exons 1–6 (constituting two-thirds of the protein), so
produces only a C-terminal fragment that marginally enhances the transactivation and DNA binding activity of the wildtype protein [104]. Transgenic p44 mice carry a stably integrated copy of the p44 gene (a ‘short form’ of the p53 allele in which translation initiates at codon 41 in exon 4 and produces a 44 kDa protein that is unable to transactivate target
genes such as Mdm2 and p21/Cip1/Waf1 [105]). Transgenic Super-p53 mice carry a stably integrated copy of the p53 gene in the form of a large genomic transgene (contained in a
bacterial artificial chromosome) that contains > 100 kb of the surrounding genomic sequence of the gene [106].
L. van der Weyden, D.J. Adams / Biochimica et Biophysica Acta 1826 (2012) 312–330
more resistant to tumor development than their wildtype littermates,
and also display a lower incidence of spontaneous tumors [110].
In addition, when compared with “super p53” or “super Ink4a/Arf”
mice, “super Arf/p53” double transgenic mice showed a delay in the
latency of chemically-induced fibrosarcomas and papillomas, as well
as a significantly diminished incidence of sporadic cancer in aged
mice [111].
4.3.3. Phosphatase and tensin homologue
The tumor suppressor gene product of the phosphatase and tensin
homolog (PTEN) gene is a lipid phosphatase, which reduces the cellular levels of phosphatidylinositol-3-phosphate (PI3P) by antagonizing
the activity of phosphoinositol-3 kinase (PI3K). Loss of PTEN activity
leads to the accumulation of cytosolic PI3P and activation of the AKT
pathway, which results in increased cell growth, survival, invasiveness, and metabolism, whereas over-expression of PTEN in cell culture down-regulates cyclin D1 expression and results in cell cycle
arrest [112]. PTEN was the first phosphatase identified to be frequently mutated or to show somatic deletions in various human cancers
and Pten-deficient (Pten +/−) mice develop hyperplastic or neoplastic
changes in many organs at an early age [113]. Over-expression of
PTEN specifically in the mammary gland of mice results in a marked
decrease in mammary epithelial cell proliferation and an increase in
epithelial cell apoptosis [114], and was later found to confer a resistance to mammary tumors. Specifically, over-expression of the
proto-oncogene Wnt-1 in mammary epithelium leads to mammary
hyperplasia and subsequently focal mammary tumors, however,
mice that ectopically express PTEN and Wnt-1 in mammary epithelium showed a reduction in the onset (5.9 to 7.7 months), growth
rate (time to grow from 0.5 to 1 cm was 8.4 to 17.7 days) and number
(11% reduction) of Wnt-1-induced tumors within a 12-month period
[115]. Earlier this year, a “Super-PTEN” mouse was generated (similar
to the generation of “Super-p53” and “Super-Ink4a/Arf” mice above)
which carries a large genomic fragment encompassing the entire
Pten locus and shows a cancer resistance phenotype, specifically reduced susceptibility to chemically-induced fibrosarcomas [116].
4.3.4. Activator protein 1
Activator protein 1 (AP1) functions in almost all areas of cellular
behavior and is activated in response to a variety of extracellular signals from cytokines and growth factors to stress and inflammation.
The expansive transcriptional repertoire mediated by AP1 complexes
is propagated by the diverse array of homo- or hetero-dimeric combinations formed by members of the Jun, Atf, Fos, Fra and Maf transcription factor families which are often deregulated by oncoprotein
signaling in malignant cellular transformation (reviewed in Ref.
[117]). c-Jun levels and N-terminal phosphorylation (which is crucial
for its activation) are cell cycle regulated, and over-expression of Jun
promotes cell growth in many cell lines whereas mouse fibroblasts
lacking c-Jun exhibit severely impaired proliferation (reviewed in
Ref. [117]). This inhibition of proliferation leads to a cancer resistance
phenotype as transgenic mice expressing TAM67 (a dominantnegative form of c-Jun that lacks the N-terminal transactivation domain) under control of the human keratin-14 promoter show a dramatic inhibition of DMBA/TPA-induced skin papillomas [118]. In
addition, expression of TAM67 in non-small cell lung cancer NCIH1299 cells reduced the growth of established xenograft tumors
from these cells in nude mice [119]. A similar benefit was seen with
loss of functional expression of the AP1 subunit c-fos, as c-fos −/−
mice carrying a v-H-ras transgene developed TPA-induced skin papillomas with similar kinetics and incidence to wildtype mice, however,
whereas wildtype papillomas progressed to malignant tumors, c-fosdeficient tumors failed to undergo malignant conversion [120]. In addition, the life span of 60% of BALB/c mice dosed with a DNA vaccine
against murine transcription factor Fos-related antigen 1 (Fra-1), was
321
tripled in the absence of detectable tumor growth after lethal administration of murine breast carcinoma D2F2 cells [121].
4.3.5. Transforming growth factor-β
Transforming growth factor-β (TGF-β) initiates downstream signaling events by activation of transmembrane serine-threonine kinase receptors, TGF-β type I and II receptors (TGF-βRI and TGFβRII) and intracellular Smad effectors, regulating numerous epithelial
cell processes. TGF-β plays a crucial role in cancer initiation and progression through tumor cell autonomous signaling and interactions
with tumor microenvironment. The complexity associated with
TGF-β regulation of cell behavior was evident in early experiments
that demonstrated TGF-β-mediated growth inhibition in culture conditions that previously stimulated progressive anchorage independent growth, and primary keratinocytes responding to TGF-β
stimulation with arrest of the cell cycle in G1 while a number of
other cancer cell lines were able to evade this response. Thus TGF-β
can both induce growth inhibition and support anchorage independent growth, however the responses are cell type and context dependent (reviewed in Ref. [122]). More recently, it has been found that
TGF-β signaling acts as a suppressor of epithelial cell tumorigenesis
at early stages, but promotes tumor progression by enhancing migration, invasion, and survival of the tumor cells during the later stages
(reviewed in Ref. [123]). Consistent with a growth inhibitory effect
arising from TGF-β expression, studies in mice have shown that
transgenic mice over-expressing TGF-β in certain cell types can result
in a cancer resistance phenotype. For example, transgenics overexpressing TGF-β in mammary tissue do not develop mammary tumors, are resistant to DMBA-induced mammary tumor formation
[124], and show reduced MMTV-induced mammary tumor formation
[125]. Highly malignant K-ras-transformed thyroid cells showed a decrease in tumorigenicity in nude mice in vivo when they were transfected with the human TGF-βRII gene [126]. Interestingly, transgenic
mice with keratinocyte-targeted TGF-β expression are more resistant
than controls to DMBA/TPA-induced benign skin tumors, however,
the malignant conversion rate was vastly increased in the transgenic
mice compared to control mice [127]. Thus, the diversities of TGF-β
signaling in tumors imply a need for caution to TGF-β-targeted strategies of tumor prevention and/or therapeutics.
4.3.6. Smad3
Smads are the central mediators converting signals from receptors
for TGF-β superfamily members to the nucleus. Catalytically active
TGF-β type I receptor (TGF-βRI) phosphorylates the C-terminal serine
residues of receptor-activated Smads (R-Smads), which include
Smad2 and Smad3. TGF-βRI and Ras-associated kinases differentially
phosphorylate Smad2 and Smad3 to create three phosphorylated
forms, and phosphorylated Smad2 and Smad3 rapidly oligomerize
with Smad4 and translocate to the nucleus to regulate transcription
of target genes. Reversible shifting of Smad3-mediated signaling between tumor suppression and oncogenesis in hyperactive Rasexpressing epithelial cells indicates that the TGF-βRI-dependent
phosphorylated form of Smad3 transmits a tumor-suppressive TGFβ signal, whereas oncogenic features such as cell growth and invasion
are promoted through the JNK-dependent phosphorylated Smad3
pathway (reviewed in Ref. [128]). Since Smad3 has been shown to
exert both tumor-suppressive and -promoting roles in a contextdependent manner, the role of Smad3 in skin carcinogenesis was examined. Homozygous knockout Smad3 (Smad3 −/−) mice are resistant
to TPA-induced epidermal hyperproliferation, show reduced DMBA/
TPA-induced papilloma formation comparison with wildtype mice,
and do not develop squamous cell carcinomas [129]. TPA-induced
Smad3−/− papillomas showed reduced expression levels of AP-1 family members and reduced leukocyte infiltration, particularly macrophages, in comparison with wildtype papillomas [129]. Interestingly
a previous study found that Smad3 −/− mice showed accelerated
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cutaneous wound healing compared with wildtype mice, characterized by an increased rate of re-epithelialization and reduced local
infiltration of monocytes [130]. Thus loss of Smad3 may be beneficial
for tumor resistance as it eliminates the ability of TGF-β to exert its
potent chemotactic effect on macrophages and thus impairs the
local inflammatory response.
4.3.7. Bone morphogenetic proteins
The bone morphogenetic protein (BMP) family is part of the TGF-β
superfamily. Engaging of BMPs to their cell surface receptors leads to
activation of the receptor kinase activity, which phosphorylates
Smad-1, -5 or ‐8, allowing formation of complexes with Smad4 and
subsequent nuclear translocation and regulation of transcription of
BMP target genes. BMP-Smad signaling regulates stem cell renewal,
cell proliferation, differentiation, migration, and apoptosis. In addition, BMP-Smad signaling has been shown to play an important role
in tumorigenesis, with increasing evidence indicating that in many
tissues, BMP-Smad signaling has a tumor-suppressing activity and
that BMPs can repress tumor growth (reviewed in Ref. [131]). For example, although transgenic mouse strains epidermally-expressing
BMP-6 (under control of the keratin 10 promoter) show keratinocyte
hyperproliferation as well as inflammation [132], they are resistant to
DMBA/TPA-induced skin tumor formation [133]. The authors postulated that this was due to the increased apoptotic frequencies and
downregulation of AP-1 constituents observed in the keratinocytes
of these mice [133]. Similarly, transgenic mice epidermallyexpressing BMP-4 (under control of the cytokeratin 4 promoter) do
not develop skin tumors after treatment with MNNG/TPA, compared
to papillomas and SCCs developing in 50% of control mice [134]. The
epidermis of these mice showed reduced mitotic indices and only
minimal hyperproliferation, and inflammation in response to TPA
[134].
4.3.8. B-cell lymphoma 2 family
B-cell lymphoma 2 (BCL2) proteins are important cell death regulators, whose main function is to control the release of cytochrome c
from mitochondria in the intrinsic apoptotic pathway. The BCL2 protein family consists of both pro- and anti-apoptotic members, which
all share sequence homology in their BCL2 homology (BH) domains.
The pro-apoptotic proteins comprise the multidomain proteins BAX
and BAK, and anti-apoptotic BCL2 proteins include BCL2, BCL-xL,
BCL-w, MCL1, BCL-B and BCL2A1. Many of these proteins have been
identified as important cellular oncogenes that not only promote tumorigenesis but also contribute to the resistance to chemotherapeutic drugs (reviewed in Ref. [135]). In addition, the importance of
BCL2 proteins in cancer progression has recently been highlighted
in a genome-wide screen identifying BCL-xL and MCL1 as highly amplified in cancer cells [136]. Bcl-xL is one of several anti-apoptotic proteins regulated by signal transducer and activator of transcription 3
(Stat3), which is required for chemically- and UVB-induced skin carcinogenesis. To investigate the functional role of Bcl-xL in skin carcinogenesis, skin-specific Bcl-xL-deficient mice were generated in
which Bcl-xL expression was disrupted in the basal compartment of
mouse epidermis using the bovine keratin 5 promoter to drive expression of Cre recombinase (K5.Cre x Bcl-xLfl/fl mice). These mice were
more resistant than wildtype controls to skin tumor development
with delayed onset and reduced number of tumors using either UVB
or DMBA/TPA [137]. Bcl-2, Mcl-1, and survivin protein levels were increased in unstimulated Bcl-xL-deficient epidermis and carcinogenesisinduced skin tumors, suggesting that Bcl-xL plays a role early in skin
carcinogenesis through its anti-apoptotic functions to enhance survival
of keratinocytes following DNA damage [137].
In agreement with this, studies using transgenic mice overexpressing Bcl-2 showed that they were protected against c-mycinduced liver tumors (by inhibiting a pre-tumoral phase characterized by increased proliferation and apoptosis) [138], DEN-induced
liver carcinogenesis (by delaying the growth of proliferative foci at
the early stages of carcinogenesis and inhibiting cell proliferation in
these foci) [139] and chronic UVB-induced tumors (as they developed
tumors much later and at a significantly lower frequency than controls) [140]. However, these findings are in conflict with studies
which have reported Bcl-2 knockout (Bcl-2 −/−) mice show retarded
oncogene-induced tumor development (transgenic mice carrying
lung targeted expression of Raf oncogenes take longer to develop tumors when on a Bcl-2 −/− background) [141], and transfection of
human gastric cancer SGC-7901 cells with Bcl-2 siRNA significantly
suppresses their ability to grow when injected subcutaneously into
nude mice (these cells resulted in smaller tumors compared to cells
transfected with non-silencing siRNA) [142]. Thus it may be that
Bcl-2 can play different roles in different tissues and contexts. Indeed,
opposing findings have reported for BCL-2 expression in tumors, for
example, loss of BCL-2 expression correlates with tumor recurrence
in colorectal cancer [143], whereas BCL-2 expression correlates with
metastatic potential in pancreatic cancer cell lines [144].
4.3.9. Protein tyrosine phosphatase 1B
Protein-tyrosine phosphatase 1B (PTP1B) is a non-transmembrane
protein tyrosine phosphatase that has long been studied as a negative
regulator of insulin and leptin signaling (reviewed in Ref. [145]).
Ptp1b-null mice are lean, resistant to weight gain on a high-fat diet
hypersensitive to insulin and show increased insulin sensitivity
[146]. PTP1B is also a negative regulator of cell growth [145] and loss
of Ptp1b in a p53-null background (Ptp1b −/−, Trp53 −/− mice) leads
to an increased incidence of B-cell lymphoma through the regulation
of B-cell development [147]. However, it has also long been known
that expression levels of PTP1B are elevated in a number of human
cancers, particularly breast and ovarian cancer [145]. More recently,
PTP1B has been shown to be a positive regulator of the ErbB2induced mammary tumorigenesis in mice, as Ptp1b-deficient mice
crossed with transgenic mice over-expressing activated mutants of
ErbB2 in mammary epithelial cells (MMTV/neu mice) showed a significantly delayed onset of breast cancer, and treatment of MMTV/neu
mice with a specific PTP1B inhibitor resulted in significant mammary
tumor latency and resistance to lung metastasis, whereas transgenic
over-expression of PTP1B induced breast tumors in the absence of exogenous ErbB2 [148,149]. However, it is important to note that Ptp1b
deficiency does not offer universal protection against breast cancer,
as breast tumors driven by the polyoma middle TAg were not affected
by loss of Ptp1b [149]. Thus, PTP1B appears to have a selective, positive
role in oncogenic signaling from ErbB2, however, it is not known if
this will apply in other oncogenic or tissue settings. Thus more investigation of PTP1B in tumorigenesis is needed, specifically to ensure
that there are no possible cancer-promoting effects of chronic PTP1B
inhibition.
4.3.10. Rassf3
RAS proteins belong to a large superfamily of small GTPases and
are signal transduction proteins that can interact with a wide array
of effectors through the RAS binding domain (RBD) to stimulate diverse cytoplasmic signaling pathways. Although typically associated
with loss of growth control and tumorigenic transformation
(reviewed in Ref. [150]), there is increasing that RAS proteins have
the ability to activate a variety of growth-inhibiting pathways including apoptosis and cell cycle arrest. For example, four members of the
Ras association domain family (RASSF), RASSF1, RASSF2, RASSF4 and
RASSF5 have been identified as RAS effectors and tumor suppressors
involved in the pathways mediating RAS growth-inhibitory effects
(reviewed in Ref. [151]). In a search of the gene(s) responsible for
naturally acquired resistance to breast cancer tumorigenesis found
in a small percentage of MMTV/neu transgenic mouse, comparative
genetic profiling was used to screen alterations in gene expression
in the mammary gland between resistant and susceptible mice from
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this strain [Jacquemart et al., 2009]. One of the genes identified as
being over-expressed in mammary glands of tumor-resistant MMTV/
neu mice was Rassf3, and a MMTV/neu-Rassf3 bi-transgenic mouse
line showed delayed mammary tumor incidence compared to
MMTV/neu littermates [152]. Thus Rassf3 influences mammary tumor
incidence in MMTV/neu transgenic mice, although the molecular mechanism of growth-inhibition of Rassf3 and its particular role in MMTV/
neu tumor initiation and progression needs further investigation.
4.3.11. Serine/threonine protein kinases
The serine/threonine protein kinase C (PKC) family was first identified as intracellular receptor(s) for the tumor promoting agent
phorbol esters. At present ten PKC isozymes have been discovered
and are classified in three subfamilies according to the functional domain composition: classic/conventional (PKC-α, PKC-βI, PKC-βII and
PKC-γ), novel (PKC-δ, PKC-ε, PKC-η and PKC-θ) and atypical (PKC-ζ
and PKC-τ). PKC isozymes can redistribute inside the cell in response
to apoptotic stimuli through intrinsic localization sequences or
specific-scaffolding protein binding, and this spatial regulation
seems to be functional to the phosphorylation of substrates present
only in specific subcellular districts. PKC isozymes are involved in
tumor progression and metastasis, with each isoform being unique
in its contribution to cancer development and progression (reviewed
in Ref. [153]). Of the novel PKC isoforms, PKC-ε confers a tumorigenic
and metastatic invasiveness phenotype in nude mice [154], whereas
PKC-δ seems to have possible tumor-inhibitory characteristics. For
example, transgenic mice epidermally over-expressing PKC-δ (from
the human keratin 14 promoter) showed a suppression of DMBA/
TPA-induced skin tumor formation (papillomas and carcinomas) relative to wildtype mice [155]. However, the tumor resistance phenotype associated with PKC-δ expression is tissue specific and does not
extend to brain and pancreatic cancer, where it seems to have a
more pro-oncogenic role. For example, human ductal carcinoma
PANC1 cells over-expressing PKC-δ were more tumorigenic than control cells when subcutaneously administered to nude mice, and the
mice also developed lung metastasis [156].
4.3.12. GATA factors
The GATA family of transcription factors consists of six members
that have two highly conserved zinc-finger domains and recognize a
consensus DNA-binding motif of (A/T)/GATA/(A/G). They regulate biological functions, including organogenesis, differentiation, proliferation and apoptosis, by activating or repressing transcription [157].
Thus GATA factors coordinate cellular maturation with proliferation
arrest and cell survival, so a role in human cancers is not surprising
(reviewed in Ref. [158]). Genetic alterations in GATA-6 have been
found in human malignant astrocytoma specimens, and knockdown of Gata6 expression in transformed astrocytes leads to acceleration of tumorgenesis [159]. Conversely, re-expression of GATA6 in
human glioblastoma U87 and U373 cells lacking GATA-6 expression
reduced their tumorgenic growth in NOD-SCID mice, concomitant
with inhibition of VEGF expression [159]. The same group identified
GATA4 as being expressed in the embryonic and adult central nervous
system and acting as a negative regulator of astrocyte proliferation
and growth, via transcriptional induction of p15 INK4B, leading to attenuation of cyclin D1 [160]. Recently they showed that inducible
re-expression of GATA4 in U87 cells suppresses their ability to form
astrocytomas after intracranial injection in NOD-SCID mice [161].
4.3.13. Prostate apoptosis response-4
The prostate apoptosis response-4 (par-4) gene was first identified by differential hybridization as an immediate early apoptotic
gene upregulated in response to elevated intracellular Ca 2+ concentration in ionomycin-treated rat prostate cancer AT-3 cells [162].
Human Par-4 protein shares significant sequence similarity with its
rat counterpart, and ubiquitous expression has also been observed
323
in nearly all tissues of mice, horses, pigs and cows. Par-4 is a cancer
cell-selective proapoptotic protein that inhibits NF-κB-mediated cell
survival mechanisms and is down-regulated in many cancers
(reviewed in Ref. [163]). The apoptotic effect of Par-4 is evident in
vivo as injection of a Par-4-expressing adenoviral construct into tumors generated by transplanted murine prostate PC-3 cells in SCID
mice resulted in a drastic reduction in tumor volume within
3 weeks, due to an increase in apoptosis [164], and over-expression
of Par-4 in tumors generated by xeno-transplanted human melanoma
A375-C6 cells in SCID mice correlated with decreased tumor development and increased apoptosis [165]. Analysis of deletion mutants of
Par-4 led to the identification of a unique core domain (spanning
amino acids 137–195), which when over-expressed, induces apoptosis specifically in cancer cells, and therefore is called the ‘selective for
apoptosis of cancer cells’ (SAC) domain. Consistent with the cancerselective apoptotic action of the SAC domain, GFP-tagged SAC transgenic mice show remarkable resistance toward the formation of
spontaneous and oncogene-induced tumors [166], as well as nonautochthonous tumors (after transplant of mouse lung carcinoma
LLC1 cells into their flanks) [167]. Recent findings indicate that Par4 is also secreted by cells and extracellular Par-4 induces cancer
cell-specific apoptosis by interaction with the cell-surface receptor
GRP78 [168]. In agreement with this, recombinant Par-4 or SAC protein intravenously administered to immunocompetent C57BL/6
mice significantly inhibited lung metastasis of LLC1 cells [167]. Thus
both systemic (extracellular) and intracellular Par-4 may contribute
to tumor resistance in SAC- and Par-4-transgenic mice.
4.4. Maintaining genomic stability/integrity
4.4.1. PPM1D
p53-induced Ser/Thr protein phosphatase PPM1D (also known as
‘wild-type p53-inducible phosphatase 1’, Wip1) is a member of the
PPM1 family. One of the functions of PPM1D is to negatively regulate
the DNA damage response through the dephosphorylation and inactivation of p53, ATM, p38 and Chk1/2 [169–171]. PPM1D overexpression has been observed in many different types of human
cancers (reviewed in Ref. [172]) and attenuates the effects of chemotherapy in patients with breast and ovarian carcinomas [173]. Thus it
is likely that the over-expression of PPM1D participates in oncogenic
transformation and cancer development. Furthermore, the decreased
expression of PPM1D results in the enhancement of the DNA damage
response [171]. In agreement with this, it has been shown that Ppm1d
knockout mice show a tumor resistant phenotype. Specifically, Ppm1d
knockout (Ppm1d −/−) mice are resistant to the development of spontaneous tumors over their entire lifespan [174], and show impaired
mammary carcinogenesis relative to controls [170]. In addition,
whereas transformation can be induced with a single oncogene in
mouse embryonic fibroblasts (MEFs) from p53 knockout (Trp53 −/−)
mice, injecting nude mice with Ppm1d −/−, Trp53 −/− MEFs expressing
Hras1, Myc or Erbb2 did not result in tumor formation [170]. Following on from these findings, administration of Ppm1d inhibitors has
shown to decrease the proliferation of xenograft tumors and tumors
developed in MMTV/neu transgenic mice [175], suggesting that
PPM1D is a potential target protein for cancer therapy. Indeed,
much effort has gone into validating PPM1D as a therapeutic target
and identifying specific inhibitors.
4.4.2. Poly(ADP-ribose) polymerase-1
Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 belong to a
family of enzymes that use β-NAD + as a substrate to catalyze poly
(ADP-ribosyl)ation of proteins. Their catalytic activity is stimulated
by DNA-strand breaks (DSB) and thus they play a role in the DNA
damage response, which has important consequences for genomic
stability and tumor development (reviewed in Ref. [176]). Treatment
of Parp-1 knockout (Parp-1 −/−) mice with alkylating agents reveals
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extreme sensitivity and genomic instability as alkylating agents produce DNA damage repaired mainly through base excision repair
(NER) and DSB repair pathways [177,178]. Conversely, Parp-1 −/−
mice do not show elevated tumorigenesis to carcinogens which give
rise to bulky DNA lesions [179] as they are repaired mainly through
the NER pathway in which Parp-1 is not involved. Chemicallyinduced models of skin cancer have shown that development of
DMBA/TPA-induced papilloma-like premalignant lesions is strongly
delayed in Parp-1−/− mice with the final number of tumor-bearing
mice and total tumor number being significantly reduced, relative to
treated wildtype mice [180]. In agreement with this, pharmacologic
inhibition of PARP-1 (using 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]1(2 H)-isoquinolinone) results in a strong delay in tumor formation
and dramatic reduction in tumor size and multiplicity during DMBA/
TPA-induced skin carcinogenesis [181]. The authors proposed that
PARP inhibition or genetic deletion of PARP-1 prevents tumor promotion through its ability to co-operate with the activation AP-1, NF-κB,
and HIF-1α [181]. Interestingly, the same group found a gain in
tumor-free survival in Parp-1 −/− mice on a p53-deficient background,
which was confirmed by a significant delay in tumor formation in
nude mice injected with Ras-transformed fibroblasts from Parp-1 −/−,
p53−/− mice, and suggested that this was due to the abrogation of
the oxydated status of p53 −/− cells (as iNOS expression and nitrite
release were dramatically reduced in the Parp-1 −/−, p53 −/− mice)
[182].
However, it needs to be mentioned that some studies have found
an increased incidence of tumorigenesis in Parp-1 −/− mice in a DNA
repair-deficient background. For example, in p53 heterozygous and
homozygous backgrounds, Parp-1 −/− mice develop a variety of tumors, including mammary gland carcinoma, lung cancer, brain tumor
and lymphoma, faster than Parp-1−/−, p53+/+ mice [183–185], and
on a background of haploinsufficiency of non-homologous end-joining
molecule Ku80 (Ku80+/− mice), a high frequency of liver cancer was
observed in Parp-1 −/− mice relative to Parp-1 +/+ mice [186]. In
addition, Parp-1 co-operated with Werner syndrome protein in the
maintenance of chromosomal integrity and suppressing tumorigenesis [187]. Thus further studies are needed to examine the benefits
of loss of PARP-1 in the context of a deficiency in certain types of
DNA repair mechanisms and in specific tissues. Nevertheless it cannot be ignored that PARP-1 is over-expressed in many types of
human tumors, frequently correlating with poor outcome (reviewed
in Ref. [176]). Studies in mice have shown that genetic elimination
of PARP-1 in malignant melanoma (RNAi-mediated depletion of
Parp-1 in murine melanoma B16 cells) reduces tumor progression
and chemoresistance in vivo [188], and PARP inhibition is particularly toxic in cancer cell lines and human tumors that lack BRCA1 or
BRCA2 and are defective in homologous recombination [189,190].
Thus, PARP inhibitors that compete with β-NAD + have two therapeutic applications in cancer: (i) as chemo/radio-potentiators and
(ii) as a stand-alone therapy for tumor types that are already deficient in certain types of DNA repair mechanisms (reviewed in
Ref. [191]).
4.4.3. O 6-methylguanine-DNA methyltransferase
Several environmental carcinogens and chemotherapeutic drugs
alkylate DNA, and the most mutagenic lesion is the alkylation at
the O 6-position of the DNA base guanine (O 6MeG). This class of
mutagenic DNA adducts is repaired by the ‘suicide’ enzyme O 6methylguanine-DNA methyltransferase (MGMT), which transfers
the alkyl group to a cysteine residue in its active site, after which
the protein becomes inactive and targeted for proteasomal degradation. Thus MGMT is a key node in the defense against commonly
found carcinogens, and a marker of resistance of normal and cancer
cells exposed to alkylating therapeutics. MGMT also likely protects
against therapy-related tumor formation caused by these highly mutagenic drugs (reviewed in Ref. [192]). The functional importance of
MGMT in cancer prevention/resistance has been demonstrated by
transgenic over-expression of human MGMT in mice. Numerous studies have shown that MGMT-CD2 transgenic mice, predominantly expressing MGMT not only in the thymus, were significantly more
protected from developing tumors after being exposed to Nalkylated nitrosamines and their derivatives, specifically MNUinduced thymic lymphomas [193–196], AOM-induced colonic aberrant crypt foci [197], and NNK-induced lung tumors [198], compared
with non-transgenic mice. Similarly, transgenic mice over-expressing
MGMT under control of the cytokeratin promoter (Ck.MGMT mice)
showed significantly lower numbers of malignant carcinomas than
control mice after treatment of DMBA/TPA-induced benign skin papillomas with MNU [199]. Transgenic mice over-expressing an inducible form of the Escherichia coli MGMT gene, ada, showed a
statistically significant reduction of liver tumor formation after treatment with hepatocarcinogen DEN [200], and a degree of protection
against malignant progression of spontaneously developing liver tumors (as although there was no significant difference in tumor incidence compared to controls, ada-transgenic mice had fewer
malignant tumors and survived longer) [201]. Further work from
the same group has shown that the MGMT transgene partially rescues
the cancer-prone phenotype of MNU-treated mice either deficient in
the DNA mismatch repair gene Pms2 [202], heterozygous for p53
[203], or over-expressing LMO1 [204]. In addition, the spontaneous
development of hepatocellular carcinoma in C3HeB/FeJ male mice
was significantly reduced in those expressing human MGMT compared with non-transgenics [205].
4.4.4. DNA methyltransferase 1
DNA methylation is the reversible addition of a methyl group to
cytosine in CpG dinucleotides and is essential for normal embryonic
development. However, global genomic hypomethylation and aberrant hypermethylation of regulatory regions of tumor suppressor
genes have been associated with chromosomal instability and transcription repression, respectively, providing cancer cells with a selective advantage (reviewed in Ref. [206]). DNA methyltransferases
are the enzymes responsible for the addition of methyl groups to
CpG dinucleotides, which, together with histone modifiers, initiate
the events necessary for transcription repression to occur. The methylation of genomic DNA in cancer cells is catalyzed by DNA methyltransferases DNMT1 and DNMT3B, revealing significantly elevated
expression in different types of cancers. In the case of colo-rectal
cancer, mouse models have demonstrated a strong link between
hypthermethylation-induced silencing of tumor suppressor genes and
tumorigenesis. For example, mice heterozygous for a targeted Dnmt1
allele (Dnmt1 +/−) showed a retarded net growth rate of intestinal
adenomas and reduced tumor multiplicity by approximately 50% in
ApcMin/+ mice [207], and Dnmt1+/−, Apc+/Min mice given a weekly
dose of the DNA methyltransferase inhibitor 5-aza-deoxycytidine,
show reduced average numbers of intestinal adenomas [208]. Mouse
models carrying hypomorphic alleles of Dnmt1 showed a variety of
tumor resistance phenotypes, including complete suppression of polyp
formation in ApcMin/+ mice [209], reduced intestinal tumor formation
in Mlh1−/− mice [210] and reduced tumor burden (acinar cell pancreatic
cancer) in ApcMin/+, p53−/− mice [211]. However, it must be noted that
Dnmt1−/−, Mlh1−/− mice developed invasive T- and B-cell lymphomas
earlier and at a much higher frequency than Dnmt+/+, Mlh1−/− littermates [210]. Thus, the reduction of Dnmt1 activity has significant but
opposing outcomes in the development of two different tumor types:
DNA hypomethylation and mismatch repair deficiency interact to exacerbate lymphomagenesis, while hypomethylation protects against intestinal tumors.
4.4.5. Terc
Telomerase is a ribonucleoprotein enzyme complex that adds
telomeric repeats to the ends of chromosomes. The core telomerase
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components are the telomerase reverse transcriptase (TERT) catalytic
subunit, encoded by the TERT gene on chromosome 5p15, and the telomerase RNA (TR) template subunit, encoded by the TERC gene on
chromosome 3q26. Telomerase is frequently over-expressed in
many cancers, a consequence of which is maintenance of telomere
length, and thus evasion of the steady decrease in telomere length
that accompanies proliferation of normal cells, although it has also
been suggested that telomerase up-regulation confers other advantages on cancer cells independent of its enzymatic activity (reviewed
in Ref. [212]). Late-generation (G5) Terc −/− mice, which have short
telomeres and are telomerase-deficient, show defects in proliferative
tissues and a moderate increase in the incidence of spontaneous
tumors in highly proliferative cell types (lymphomas, teratocarcinomas), presumably as a consequence of chromosomal instability
[213]. However, different cell types vary in their sensitivity to the
chromosomal instability produced by telomere loss or to the activation of telomere-rescue mechanisms as evidenced by the fact that
G5 Terc −/− mice are resistant to tumor development in chemicalinduced carcinogenesis in the skin (DMBA/TPA-induced skin papillomas regressed within one week after termination of TPA treatment)
[213] and liver (significantly decreased number and size of CCl4 or
DEN-induced surface liver nodules) [214]. Similarly, Terc −/− mice
were found to be relatively resistant to spontaneous tumorigenesis
in cancer-prone mice, including Ink4a −/− mice [215], Apc Min/+ mice
[216], Alb-uPA transgenic mice [214], Atm −/− mice [217], p53 R172P/
R172P
mice [218], and MMT transgenic mice (expressing the MUC1
(Mucin 1) and polyomavirus middle T (PyMT) oncogene) [219]. In
addition, transplant and xenograft studies have demonstrated that reduction of Terc expression, via the use of double-stranded oligodeoxynucleotides, ribozymes, or antisense vectors, can reduce the in
vivo tumorigenicity of liver and gastric cancer cell lines [220,221]
and metastatic potential of melanoma cell lines [222,223]. However,
it needs to be noted that G5 Terc −/− mice show defects in proliferative tissues and a moderate increase in the incidence of spontaneous
tumors in highly proliferative cell types (lymphomas, teratocarcinomas), presumably as a consequence of chromosomal instability in
these mice [213]. Other studies have found that G5 Terc −/− mice
also show an orally-dosed DMBA-induced metastatic tumor burden
similar to that of wildtype mice [224].
4.5. Miscellaneous
4.5.1. Eph receptor A2
The Eph receptor tyrosine kinase (RTK) family is composed of
14 members that are subdivided into two subclasses based upon
their complementary Ephrin ligands (there are nine Ephrin ligands
classified as either Ephrin A or Ephrin B). The Eph RTK and their
cell-surface bound ligands are involved in a variety of cell-to-cell
inter-communications that affect processes such as cell patterning,
guidance, migration and adhesion. High expression levels of one
member of the Eph receptors, EphA2 on human chromosome 1p36.1,
are correlated with tumor metastasis and poor prognosis [225]. Confirming the role of EphA2 in malignant invasion, human gastric cancer
SGC-7901 cell xenografts in nude mice given intratumoral injections
of EphA2 siRNA plasmid showed suppressed growth (the tumors also
showed reduced expression of matrix metalloproteinase-9) [226].
Expression of EphA2 mutants (that lack the cytoplasmic domain or
carry a point mutation that inhibits its kinase activity) in breast cancer
cells resulted in decreased tumor volume, increased tumor apoptosis
in primary tumors, and significantly reduced lung metastases in both
experimental and spontaneous metastasis models, suggesting that
receptor phosphorylation and kinase activity of the EphA2 receptor, at
least in part, contribute to tumor malignancy [227]. In addition, there
is data to suggest that EphA2 co-operates with ErbB2 to promote
tumor progression in mice, and importantly that EphA2 function in
tumor progression depends on oncogene context, as tumors from
325
MMTV/neu (which overexpress neu, the rat homolog of ErbB2, in the
mammary epithelium) but not MMTV/PyV-mT mice (which overexpress
the polyomavirus middle TAg in mammary epithelium) were sensitive
to therapeutic inhibition of EphA2 [228]. Mouse models of GI cancer
have demonstrated that EphA2 plays an oncogenic role in the intestine
as ApcMin/+ mice carrying a knockout allele of EphA2 gene develop significantly fewer intestinal tumors [229], yet there is evidence that
EphA2 may function as a tumor suppressor, as mice that are homozygous for a gene trap allele of EphA2 (EphA2−/−) demonstrate increased
susceptibility to skin carcinogenesis [230]. Thus whether EphA2 acts as
an oncogene or tumor suppressor may depend on a multitude of complex factors, such as the tissue type, normal versus malignant cells, presence/absence of ligands or endogenous receptor tyrosine kinases, and
co-operation with other specific oncogenic mutations.
4.5.2. Fibroblast factor binding protein
The fibroblast growth factor (FGF) family consists of at least 23
structurally related polypeptide growth factors that are important
regulators of angiogenesis, embryonic development, cell migration,
proliferation and differentiation, and are particularly important in
tumor growth. One mechanism that determines their biological activities in tumor growth is based on their mobilization from the extracellular matrix, which can occur via heparanase-mediated cleavage
of heparansulphate proteoglycans or the action of the fibroblast
growth factor-binding protein (FGF-BP) serving as a carrier protein.
FGF-BP expression is highly tissue specific and strictly regulated
through different promoter elements. Besides its role in embryogenesis and wound healing, FGF-BP is upregulated in several tumors
and it is associated especially with early stages of tumor formation,
where angiogenesis plays a critical role (reviewed in Ref. [231]). In
agreement with this, several mouse tumor models have shown
that targeting of FGF-BP abolishes or reduces tumor growth and angiogenesis. For example, human squamous cell carcinoma ME-180
and colon cancer LS174T cell lines depleted of FGF-BP by targeting
with specific ribozymes exhibited reduced growth and angiogenesis
when administered to nude mice [232]. Similarly, administration of
FGF-BP-specific siRNA duplexes to tumor xenograft-bearing mice
lead to an ~ 40% reduced tumor growth relative to controls [233]. In
addition, it was found that adenoviral vector‐mediated wildtype p53
transduction resulted in growth inhibition of squamous cell carcinoma of the head and neck tumor cells in a xenograft mouse model,
that was due, at least in part, to anti-angiogenesis mediated by the
down-modulation of FGF-BP [234]. Finally, in vivo all-trans retinoic
acid treatment of squamous cell carcinoma xenografts in nude mice
reduced FGF-BP expression in parallel with decreased tumor growth
and angiogenesis and induction of apoptosis [235]. This indicates
that FGF-BP can be rate-limiting for tumor growth and serves as an
angiogenic switch molecule.
5. Conclusions
The mouse has proved itself to be a most invaluable tool to researchers in understanding the genetics of cancer susceptibility and
resistance. The availability of different strains of wildtype mice, spontaneously occurring mutants and GM mice have shown that there are
many genes involved in the cancer resistance phenotype. In general,
genes that augment the host immune system; and/or dampen down
the inflammatory response; and/or halt proliferation and promote
apoptosis of the tumor cells; and/or maintain the integrity of the genome all play important roles in cancer resistance. However, investigation of these genes using mouse models has revealed a subtlety to
the situation with some genes being involved in both tumor resistance and susceptibility, depending on their context, such as tissue
type, relative concentration of the protein or genetic background of
the mouse. In addition, some genes only confer resistance to specific
types of tumors, such as carcinogen-induced tumors but not oncogene-
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induced tumors. Thus the mouse has played a crucial role in highlighting
the complexities of identifying genes responsible for cancer resistance, as
well as identifying potential targets for chemoprevention.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
D.J.A was supported by Cancer Research UK and the Wellcome
Trust.
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