Tissue Homeostasis and Cancer: Alejandro Rodrı Guez-Molinero, Marı A Lo Pez-Die Guez, Jose R. Banegas
Tissue Homeostasis and Cancer: Alejandro Rodrı Guez-Molinero, Marı A Lo Pez-Die Guez, Jose R. Banegas
Tissue Homeostasis and Cancer: Alejandro Rodrı Guez-Molinero, Marı A Lo Pez-Die Guez, Jose R. Banegas
http://intl.elsevierhealth.com/journals/mehy
a
Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid,
Arzobispo Morcillo 2, 28029, Madrid, Spain
b
Clinical Research Unit, Fundación Hospital Comarcal San Antonio Abad, Vilanova i la Geltrú, Barcelona,
Spain
Summary Epithelial cells are known to release an important amount of cytokines capable to modulate immune
system functions. On the other hand, immune system cells can release cytokines, which play an important role in the
control of the growth of epithelial cells. In this paper, we stand the hypothesis that a mutual (reciprocal) growth
regulation exists between epithelial cells and immune system. We propose a model describing plausible cytokine
circuits that may regulate (inhibit) both epithelial growth and epithelial inflammation. In addition, we describe how
dysfunction of these circuits could lead to tumoral growth, excessive inflammation or both. A failure in the regulation
of epithelial growth by the immune system could give rise to a neoplasm, and a failure in the regulation of the immune
system by the epithelium could give rise to inflammatory or autoimmune diseases. This model may satisfactorily
explain the link between inflammation and cancer.
c 2006 Elsevier Ltd. All rights reserved.
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2006.10.033
1334 Rodrı́guez-Molinero et al.
Many of the cells with a known capacity to syn- preservation of the tissue structure that enables
thesize substances that regulate the growth of organs to perform their function.
other cells, belong to the immune system [6]. In- Invasion of the body frequently takes place due
deed, many immunosuppressive substances, such to a defect in tissue continuity, and generally cul-
as corticoids or methotrexate, can markedly alter minates in damaging the affected tissue. This calls
tissue repair and formation processes, including for the immune system to synchronize two clearly
embryogenesis. related processes, namely: defense against the
Immune system disorders, such as immunodefi- noxa; and repair of tissue damage [23]. When an
ciencies, have been widely related with cancer epithelial barrier is disrupted and exogenous sub-
[7,8]. Some noxae capable of producing tumors stances pass into the internal milieu, this triggers
(alcohol) are linked to dysfunction of the immune an inflammatory response mediated by the innate
system and to alterations to tissue repair or forma- immune system and the TCD4 + Th1 lymphocytes
tion (cirrhosis) [9,10]. Indeed, many new or re- of the adaptive immune system. In tandem with
paired tissues are considered precancerous the inflammatory response, growth factors are se-
lesions, and growth regulatory substances have fre- creted which tend to repair the epithelial defect.
quently been implicated in oncogenesis. Once the tissue repair is complete, the inflamma-
Abundant evidence suggests that the tissue re- tion is also resolved, with the tissue returning to
pair and formation system plays a fundamental role a state of homeostasis [23,24].
in the genesis and growth of neoplasms (gr. néos Yet when, in this state of homeostasis, the
new + gr. plasma formation). Recently, Helicobac- integrity of the epithelial barrier is intact, the in-
ter pilori-related stomach cancer has been discov- nate immune system and TCD4 + Th1 lymphocytes
ered to derive from cells that migrate from bone are not active because the integrity of the barrier
marrow to repair the damage caused [11]. Cells, prevents invasion by exogenous substances and
such as macrophages and their derivatives, impli- there is thus no need for phagocytic and cytotoxic
cated in both immunity and repair, have been function. In such a homeostatic situation, a humor-
found in reduced numbers in tumors, such as hepa- al defense predominates, via secretion of antibod-
tocarcinoma and skin cancers [12,13]. Moreover, ies, such as IgA, which are secreted by the mucosa
oncogenic noxae, such as tobacco, alcohol or radi- and neither activate the complement nor stimulate
ation, cause major alterations in these growth reg- phagocytosis, but instead facilitate the elimination
ulatory cells [14,15]. of the injurious agent at the exterior of the organ-
It is interesting to note that many antineoplastic ism. This humoral response is mediated by
agents, such as methotrexate or corticoids, are TCD4 + Th2 lymphocytes, which secrete a series
really immunosuppressors and thus interfere in of so-called anti-inflammatory cytokines, owing to
the process of tissue growth [16,17]. Others, such their capacity to antagonize interferon and macro-
as Tamoxifen, directly alter the balance between phage actions [25,26], and down-regulate the
inhibitory and stimulatory factors of tissue growth. growth of TCD4 + Th1 lymphocytes [27,28].
Until now, cancer has been regarded as anoma- When the epithelial barrier is present, besides a
lous tissue that falls outside normal growth regu- physical defense in terms of this barrier and the
latory mechanisms. Yet, in the light of the possibility of a humoral defense coordinated by
above, doubts as to the ‘‘autonomy’’ of such tis- TCD4 + Th2 lymphocytes, the immune system per-
sue that ‘‘ignores’’ the orders of the system, ap- forms a task of immunosurveillance toward what-
pear to be well-founded. There seems to be ever may be seen as foreign or injurious, and
increasing soundness in the notion that cancer is tolerance toward self or substances seen as innoc-
due to an anomaly in the regulation of tissue uous. Indeed, in this task of tolerance toward
growth rather than to resistance to normal growth innocuous substances, immature dendritic cells as
regulation [18,19]. well as regulatory T lymphocytes (Treg) and Th2
lymphocytes themselves have been implicated,
inasmuch as all are capable of secreting anti-
The hypothesis inflammatory cytokines (Il-10, Il-4, TGF-beta,
etc.) that block the immune system’s response
The immune system is tasked with defending the against innocuous substances [29–33].
body against invasion by exogenous agents, but it The epithelial barrier itself is considered by
also has a primordial role in the maintenance of tis- some authors to form part of the innate immune
sue homeostasis [20–22]. This means that the im- system, in view of its evident protective function
mune system is in charge of maintaining cell and active participation in many immune responses
growth and death within suitable limits, to ensure through secretion of multiple cytokines. In certain
Tissue homeostasis and cancer 1335
cases, such as the intestinal epithelium, cells may of each of its elements. Accordingly, we propose a
even act as antigen-presenters [34,35]. plausible interaction model below, even though
With barrier integrity intact, entry of pathogenic there may be other means of interaction and feed-
agents is prevented and the tolerance process is back, and –conceivably– different forms of inter-
implemented [36,37]. It is therefore likely that action in the various tissues.
the epithelial cells themselves directly contribute
to the anti-inflammatory environment of the epi-
thelia that are intact. This is at least what one A model of homeostasis
would tend to infer from observation of the capac-
ity of epithelial cells at numerous sites to secrete Immature dendritic cells performing tasks of immu-
anti-inflammatory interleukins (Il-13, TGF-beta or nologic surveillance in healthy epithelia [43] have
Il-10) [38–40]. Such is the epithelium’s cytokine the capacity to stimulate secretion of anti-inflam-
secretion capacity that skin keratinocytes have, matory interleukins (Il 4 Il10) by Th2 lymphocytes
in certain circumstances, come to be identified as [44], favor the generation by the latter of Treg-lym-
the greatest local source of Il-10 [41]. phocytes as well as secretion of TGF-beta by them
Hence, the epithelia have an important immuno- [45–50]. In turn, cytokines that secrete Th2 lym-
logic function, through direct protection of and phocytes also favor Treg-lymphocyte generation
participation in the triggering of inflammatory pro- [51] (Fig. 1).
cesses, and possibly also in the tolerance mecha- In brief, immature dendritic cells favor the pres-
nism toward innocuous substances [27,36]. ence and activity of regulatory Th2 and Treg-lym-
No less interesting is the fact that the immune phocytes, which secrete anti-inflammatory and
system itself can control epithelial growth, not antiproliferative cytokines. It is known that TGF-
only, as explained above, by facilitating secretion beta, which secretes Treg-lymphocytes, inhibits
of growth factors if necessary, but also by possibly the growth of epithelial cells [52] and that epithe-
preventing their excessive proliferation. This is de- lial cells, for their part, secrete Il-10 [41], which
duced from the fact that the same anti-inflamma- acts by way of feedback on the dendritic cells,
tory cytokines that secrete immune cells in a maintaining them in an immature state [53–56].
state of homeostasis, generally also have an anti-
proliferative effect on epithelial cells [42]. This ef-
fect is especially noteworthy in the case of Inflammation
Transforming Growth Factor beta (TGF-beta),
which is arguably the endogenous substance with When the epithelial barrier is breached, the den-
the greatest known antiproliferative potential for dritic cell is activated and stimulates the
many cells [42]. TCD4 + Th1 lymphocytes to trigger inflammation
The above leads us to conclude that the epithe- and subsequent growth of the epithelial barrier (re-
lium may influence inflammation and this in turn pair) [57,58]. Th2-lymphocyte growth is inhibited
may influence epithelial growth, and what is more by the cytokines secreted by the Th1 lymphocytes,
important and less well known, that the epithelium and Treg-lymphocyte stimulation ceases seeing as
may possibly inhibit inflammation, and that the im- the dendritic cells are not immature and Th2 lym-
mune system may inhibit epithelial growth. phocytes are not in abundance.
Hence, a negative feedback is established be- When the epithelial barrier is repaired and the
tween the two systems, which makes biological inflammation disappears, Il-10 increases, the den-
sense because, when the epithelium is present, dritic cells return to a state of immaturity, and epi-
its cytokines collaborate in inhibiting any unneces- thelial homeostasis is restored.
sary inflammation. Furthermore, absence of
inflammation is evidence of the fact that there is Oncogenesis
a protective epithelium acting as a barrier, and
that no further growth of such epithelium is If dendritic cells steadily die or mature for a reason
required. unconnected with the disruption of the epithelial
To our knowledge, this double regulation has barrier, stimulation of Th2 and Treg-lymphocytes
never been defined as such, despite the fact that will cease and, with this, inhibition of epithelial
each of its constituent elements and their func- growth by TGF-beta will be reduced.
tions are independently known. The existence of Since TGF-beta is a powerful epithelial growth
this negative feedback between the epithelium inhibitor, it will come as no surprise that it is our
and the immune system is postulated as a hypoth- contention that any decline in its concentration
esis, since we have evidence to prove the existence can be translated as a rise in cell growth rate.
1336 Rodrı́guez-Molinero et al.
Figure 1 Homeostasis. If the epithelial barrier is intact, there is an abundance of IL-10 secreted by the epithelial
cells, which maintains the dendritic cell in an immature state. The immature dendritic cell, in turn, stimulates
TCD4 + Th2 lymphocytes to secrete Th2 interleukins (IL-4, IL-10), and regulatory lymphocytes to secrete TGF-beta. The
TGF-beta produced by these cells inhibits the growth of the epithelial cells, which provide feedback and so contribute
to the immature state of the dendritic cells by secreting IL-10.
Growing epithelial cells can secrete Il-10 seeking epithelial growth, which ultimately is what consti-
negative feedback by dendritic cells, but if there tutes 95% of all neoplasms. Indeed, most neo-
are no dendritic cells or if these are in a mature plasms are infiltrated or surrounded by a greater-
phase, TGF-beta will not increase in order to cur- than-expected number of cells belonging to these
tail local growth. This succession of events may types, a phenomenon that until now has seemed
generate or facilitate the appearance of a paradoxical [59–63]. Hence, if our hypothesis were
neoplasm. accurate, inflammation could facilitate rather than
impede tumor growth; indeed, this fact has been
repeatedly demonstrated in the literature, though
Evaluation of the hypothesis only recently has attention been paid to its impor-
tance [23,64–67]. We feel that we have put
Given that TCD8 + and natural killer lymphocytes forward a plausible mechanism whereby inflamma-
are capable of destroying tumor cells, and perform tion facilitates tumor growth.
better when appropriately stimulated by cytokines We have proposed that TGF-beta is the cytokine
that release TCD4 + Th1 lymphocytes, it was via which the immune system slows epithelial
thought until now that inflammatory state and growth, and that the defect in this cytokine must
Th1 response were the immune system’s best be assumed to be implicated in oncogenesis
means of combating tumor mass. We, on the other [68,69]. In this regard, it has been shown that for
hand, think – and have indeed said as much – that the TGF-beta receptor KO mice, have a greater
tumor growth should be studied in terms of exces- incidence of epithelial neoplasms [70,71], and it
sive growth rather than in terms of tissue invasion. is known that in many neoplasms the intracellular
This means that attention should be paid to which TGF-response pathway is altered and is resistant
cytokines synthesized by the immune system facil- to its inhibitory activity, but if our hypothesis is
itate cell reproduction and which cytokines inhibit correct, then, even without alterations in the
it. From this point of view, it is clear that the transduction pathway, the mere reduction in
immune system coordinated by Th2 and Treg-lym- TGF-beta in the tumor mass could be a cause of
phocytes and dendritic cells or immature macro- growth [72]. It has recently been reported, at least
phages, has an enhanced capacity to curtail in the case of colon and endometrial cancers, that
Tissue homeostasis and cancer 1337
a reduction in TGF-beta is more frequently seen in growth. As seen above, these facts, poorly under-
tumors than are alterations in their transduction stood until now, could be explained by a paracrine
pathway [69,73–76]. growth-control system such as that outlined here.
Treg-lymphocytes are anti-inflammatory and hin- Tumors could therefore be caused by a defect in
der the antitumoral action of TCD8 + and natural the regulation of epithelial growth, whether be-
killer lymphocytes, with the result that the pres- cause of damage to the immune cells tasked with
ence of these cells has always been regarded as such regulation, or because these cells are im-
facilitating tumor growth [77,78]. This is inconsis- mersed in a chronic inflammatory state, which pre-
tent with the repeatedly proved observation that, vents them from performing their function. Were
rather than impeding tumor genesis and growth, this to be the case, the noxae that cause cancer
inflammation actually facilitates it. From our point would have to do so via one of these two mecha-
of view, the presence of Treg-lymphocytes in the nisms. The truth is that numerous cancer-related
tumor mass is positive, because they are the great- noxae, such as asbestos for instance, are known
est source of TGF-beta in the entire immune sys- to cause chronic inflammation. Others have been
tem and are thus able to inhibit the growth of associated with damage to the immune system,
epithelial cells. This prediction is supported by such as alcohol which causes ‘‘immunosuppres-
some studies, which, seeking to prove the con- sion’’, tobacco which damages the alveolar macro-
trary, have instead concluded that infiltration by phage, or radiation which reduces the number of
tumor regulatory cells does not worsen and, in- dendritic skin cells, also known as Langerhans cells
deed, may improve disease prognosis [79,80]. It [94].
has even been observed that Treg-lymphocytes Hence, some carcinogenic substances damage
may produce tumor remissions [81–83]. the cells proposed by us as controllers of epithelial
However, the presence of Treg-lymphocytes in growth. Given that there are a number of such cells
neoplasms might not suffice to inhibit their growth and that they can be regenerated, sporadic expo-
if there no dendritic cells that stimulate them to sure to one of these substances would not be ex-
secrete antiproliferative cytokines. Thus, accord- pected to produce uncontrolled growth. Chronic
ing to our model, an absence of dendritic cells or exposure, on the other hand, might reduce the
a defect in their function, could give rise to a neo- population of local regulatory cells to the point
plasm. In support of this hypothesis, we have the where there is excessive secondary epithelial
very telling evidence that dendritic cells are found growth, and if such exposure continues, this may
to be reduced in number or damaged in almost all then degenerate into neoplasia. This is in line with
types of tumors [12,13,15]. Surprisingly, moreover, the fact that, before neoplasms appear, exposure
the presence of these cells is inversely correlated to carcinogenic noxae must generally be chronic,
with disease stage [84–87], in that the more den- and there is therefore nothing undue in the fact
dritic cells, the less advanced the disease. that these should be preceded by disorderly cell
According to our hypothesis, the cells of healthy growth, such as that caused by alcohol in the liver,
epithelials secrete anti-inflammatory cytokines, i.e., cirrhosis.
such as Il-10. Among other things, this maintains At the same time, if uncontrolled growth is
the dendritic cells in an immature state caused by damage to the regulatory cells, or by
[84,88,89], which ultimately favors TGF-beta chronic inflammatory state, drugs that have shown
secretion by regulatory lymphocytes. Hence, in some efficacy in the treatment of neoplasms,
the event of there being a lack of dendritic cells, would have to act by preventing inflammation, or
there would be Il-10 secretion by the epithelium replacing the population of immune cells tasked
but it would not achieve an adequate TGF-beta re- with curtailing growth. Insofar as the former is con-
sponse. Most tumors are made up of epithelial cells cerned, it is evident that the vast majority of che-
that grow uncontrollably and, as our model pre- motherapeutic drugs used in cancer are powerful
dicts, secrete substantial amounts of interleukin anti-inflammatories or immunosuppressors, start-
10 [56,90–93], though, as has been seen, the ing with corticoids, which in addition maintain
TGF-beta response is defective. There is thus the dendritic cells in a state of immaturity [95]. Even
possibility that tumor cells may well be sending analgesic and anti-inflammatory non-steroids,
out the appropriate signal and it is the immune sys- which block prostaglandin-mediated maturation
tem that is inadequately inhibiting growth. of dendritic cells [96] but are not directly antipro-
In brief, many tumors secrete Il-10 but lack TGF- liferative, have shown themselves to be useful in
beta. Their dendritic cells are reduced in number the prevention of several neoplasms [97]. With
or damaged, and infiltration by Treg-lymphocytes, respect to the possibility of repopulating damaged
unlike inflammation, does not accelerate their immune cells [98–100], it is noteworthy that
1338 Rodrı́guez-Molinero et al.
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