Curr Pathobiol Rep (2016) 4:135–145

DOI 10.1007/s40139-016-0106-6

LEAKY JUNCTIONS IN CANCER (CHRIS CAPALDO, SECTION EDITOR)

Tight Junctions and the Tumor Microenvironment

Ellaine Salvador1 • Malgorzata Burek1 • Carola Y. Förster1

Published online: 1 July 2016

 The Author(s) 2016. This article is published with open access at Springerlink.com

Abstract Introduction
Purpose of review Tight junctions (TJs) are specialized
differentiations of epithelial and endothelial cell mem- Since epithelial cells line hollow organs, they are prone to
branes. TJs play an important role in the adhesion of cells damage and are much exposed to carcinogens in the
and their interaction with each other. Most cancers origi- environment. For this reason, they demand high renewal
nate from epithelial cells. Thus, it is of significance to rate. Due to their vulnerability, about 90 % of human
examine the role of TJs in the tumor microenvironment cancers originate from the epithelial tissues [1•].
(TME) and how they affect cancer metastasis. Constant remodeling of cell-to-cell contacts takes place
Recent findings In epithelium-derived cancers, intactness for renewal and replacement of old or damaged cells. In
of the primary tumor mass is influenced by intercellular addition, this process helps to incorporate newly differen-
structures as well as cell-to-cell adhesion. Irregularities of tiated cells without compromising the integrity of the
these factors may lead to tumor dissociation and subse- barrier [2]. In epithelium-derived cancers, intactness of the
quent metastasis. Low expression of TJs is observed among primary tumor mass is influenced by intercellular structures
highly metastatic cancer cells. as well as cell-to-cell adhesion [3]. These factors should be
Summary In this review, we summarized findings from maintained since irregularities may lead to tumor dissoci-
current literature in consideration of the role of TJs in ation and subsequent metastasis [4]. Tight junctions (TJs)
relation to the TME and cancer. Deeper understanding of are among those that preserve cell adhesiveness in this
the mechanisms leading to TJ dysregulation is needed to tumor mass. Therefore, alterations in the TJs present could
facilitate the design and conceptualization of new and result to split of the tumor mass [5]. In addition, TJs also
better therapeutic strategies for cancer. suppress cell proliferation [6].
Owing to these facts, research has focused greatly in
Keywords Tight junctions
Intercellular permeability
drawing the link between TJs and the tumor microenvi-
Tumor microenvironment
Metastasis
Cancer ronment (TME). In this review, we surveyed current lit-
erature in consideration of the role of TJs in relation to the
TME and cancer.

This article is part of the Topical collection on Leaky Junctions in

Characteristics of Tight Junctions
Cancer.

& Carola Y. Förster Tight junctions (TJs) are specialized differentiations of

Foerster_C@ukw.de epithelial cell membranes [5]. They form a continuous
1 intercellular barrier between epithelial cells and separate
Department of Anesthesia and Critical Care, University of
Wurzburg, Oberdürrbacher Straße 6, 97080 Würzburg, tissue spaces which regulate selective transport across the
Germany epithelium [7•].

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TJs serve various functions. Foremost, they seal inter- forming TJ structures which shows that occludin is not
cellular spaces and separate the apical and basolateral fluid indispensable for TJ structural assembly. To demonstrate
compartments of epithelia and endothelia. They regulate this, occludin null mice were born without any signs of
epithelial and endothelial cell permeability and act as abnormal phenotype but later showed growth retardation.
points of contact between the plasma membranes of The TJs appear morphologically unaltered but histological
neighboring cells, occluding the extracellular space. They abnormalities were observed in several tissues [14]. In
also act as cell-to-cell adhesion molecules. They play a role addition, occludin knock-out mice manifest atrophic gas-
in cell adhesion and paracellular barrier functions and form tritis, testicular atrophy, male infertility, salivary gland
an intercellular barrier and an intramembrane diffusion dysfunction, osteoporosis, and brain calcifications [14, 15].
fence [5]. The diffusion of solutes is regulated by TJs Apical-basal polarity is used to sense cell–cell contacts
through size and charge selectivity and differs depending on epithelial surfaces. It has been observed that hippo
on epithelial cell type. TJs are impermeable to most pathway elements co-localize with occludin, creating a
macromolecules but are permeable to inorganic ions. As possible sensor system in pancreatic epithelial cells which
such, TJs, together with adherens junctions and desmo- may regulate their proliferation [16•]. It has been reported
somes, maintain the integrity of the epithelial cell layer and that epigenetic silencing of occludin could promote
protect multicellular organisms from the external envi- tumorigenic and metastatic properties of cancer cells [17].
ronment [5]. In addition, they play a role in cell polarity, For example, occludin was shown to inhibit Raf-1 signal-
differentiation, growth and proliferation through their ing which induces tumor growth [18]. A low level of
involvement in cell signaling processes. They are sug- occludin expression results to an increased progression and
gested to be involved in the regulation of cell proliferation metastatic potential in breast, ovarian, endometrial, and
by controlling epithelial cell microenvironment [8]. Due to liver carcinoma [19–22]. The increased metastatic poten-
this, they are able to suppress malignant phenotype of cells tial, however, might not be due to occludin downregulation
during tumorigenesis. Furthermore, they function as cell but the activation of epithelial to mesenchymal transition
migration barrier. Their functions are shown to be regu- (EMT) which leads to downregulation of adhesion-asso-
lated by phosphorylation. A link between barrier disruption ciated proteins [23].
due to TJ dysfunction and disease has long been estab-
lished [9]. Claudins
The main cause of lethality among cancer patients is
metastasis [10]. Metastasis takes place with various pre- Of the various proteins classified as TJs, the claudin family
requisites. Primarily, cancer cells need to be able to sur- made up of transmembrane proteins appears to be of major
mount the barriers, mostly epithelial and endothelial tissues significance for TJ selectivity. Expression of many types of
consisting of cells bound together by tight junctions (TJs). claudins is altered in cancer cells [5]. The expression of
Dissociated cells provide easy access to metastasizing one particular claudin may be upregulated or downregu-
cancer cells. Therefore, the intactness of TJs helps prevent lated depending on the type of cancer. Among the various
cell dissociation [11, 12]. members of the claudin family, claudin-1, -3, -4, and -7 are
among the most frequently dysregulated both at the tran-
scriptional and post-transcriptional levels [24]. Physiologic
Tight Junctional Components plasticity of the TJ involves claudin switching which is the
adaptability of claudin expression and gene-specific
Transmembrane proteins occludin, claudins, junctional retention in the TJ [25•].
adhesion molecules (JAMs), and tricellulin as well as Claudins are found to be involved in tumor progression
intracellular scaffold proteins like zonula occludens (ZO) and play a role in epithelial to mesenchymal transition. The
and cingulin comprise the molecular make-up of tight expression pattern of claudins influences tumor behavior in
junctions (TJs). various types of epithelial neoplasia. For example,
decreased expression of claudin-1, -2, and -7 coincides
Transmembrane Proteins with more intrusive breast carcinoma [26–29]. Meanwhile,
overexpression of claudin-3 and -4 is found in several
Occludin neoplasias such as in ovarian, breast, pancreatic, and
prostate cancers [24]. Also, in order to clarify its role in
The first discovered molecular component of the TJs is tumor progression, the role of claudin-7 in esophageal
occludin [13]. Although it was first suggested to form the squamous cell carcinoma was analyzed. Results proposed
structural unit of the TJs, it has later been found out that that the reduced expression of claudin-7 could lead to
embryonic stem cells lacking occludin are still capable of tumor progression and subsequent metastatic events [30].

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Junctional Adhesion Molecules extracellular matrix (ECM) as a first step. The breakdown
could then lead to invasion of neighboring tissue par-
Junctional adhesion molecules (JAMs) are located in cell- enchyma [41]. However, since the TME has ways by
to-cell contacts such as tight junctions. They are expressed which to maintain its normal conditions, this could only
by leukocytes and platelets as well as by epithelial and be possible once the TME is altered. In this case, deviant
endothelial cells [31]. They regulate cell interactions in the immune responses and altered homeostasis facilitate and
immune system and tight junction formation in epithelial modulate tumorigenesis. For instance, when the tumor
and endothelial cells during the acquisition of cell polarity acquires the capacity to bypass the means by which the
[32]. JAMs are involved in the EMT, a process that plays a TME signals it to normalcy, intercellular interactions are
vital role in the invasiveness and metastasis of various disrupted, forcing the TME to adapt to the growing tumor
cancers. It has been shown that JAM-A upregulation could [42•].
induce EMT and when JAM-A expression is silenced, Cancer cells are not the only ones responsible for the
EMT is reversed [33•]. manifestation of disease. Instead, normal cell types both
resident and recruited to the TME contribute to the per-
Plaque Proteins sistence of cancer and cancer-related symptoms. For
instance, alterations in both tumor and endothelial cells are
Zonula Occludens essential for cancer cells to grow and metastasize. The
dysregulation of significant TJ proteins leads to the loss of
Zonula occludens (ZO) are scaffold-forming intracellular cell-to-cell association, cell contact inhibition that results
plaque proteins located between the transmembrane pro- to uncontrolled growth, and loss of adhesion to the base-
teins and the actin cytoskeleton [34]. They regulate the ment as well as its degradation [43].
assembly of cellular junctions. They bind actin, occludin, Low expression of TJs is observed among highly
and claudins [35]. metastatic cancer cells. On the other hand, weakly
Several ZO are involved in cell proliferation. For metastatic tumor cells demonstrate increased TJ expres-
instance, ZO-1 is demonstrated to interact with so-called sion. Control of cellular proliferation involves various TJ-
ZO-1-associated nucleic acid binding (ZONAB) proteins, a associated proteins such as transmembrane, adaptor and
Y-box transcription factor. This implies that ZO-1 is signaling proteins as well as transcription factors. When
involved in gene expression regulation, cell proliferation, the expression levels of these proteins are changed,
and morphogenesis of epithelial tissue [36]. intercellular permeability is increased, polarity and con-
Decreased expression of ZO-1 was shown to correlate tact inhibition are lost and expression of growth-stimu-
with increased invasiveness in breast, colorectal, and latory genes in the nucleus increases. According to
digestive tract cancers [37]. It is also found to be involved research conducted on human tumors, there is a correla-
in tumor invasion-associated EMT implicating its role in tion of the loss of functional TJs in cancer progression
tumor growth process [38]. and metastasis. In addition, it has also been shown that
some proteins associated with TJs suppress tumors and
regulate signal transduction which suggests the partici-
Tumor Microenvironment pation of TJ disruption in early carcinogenesis. It has
been observed that mutant mice that lack specific TJ
The tumor microenvironment (TME) is composed of all the proteins develop hyperproliferative disorders [44]. The
normal cells, blood vessels, signaling molecules, and location of epithelial cells allows their direct exposure to
extracellular matrix (ECM) surrounding the tumor cells. It the external environment making them prone to injury or
is made up of malignant and nontransformed cells that attack by toxins, microbes, and viruses. Damage in the
interact with each other such as endothelial cells, pericytes, epithelial cells brings about loss of TJ integrity. This
fibroblasts, adipocytes, and also contains cells of the becomes a cue for the cells to launch a repair program
immune system, the tumor vasculature, and lymphatics involving cellular proliferative and migratory activities in
(Fig. 1) [39•]. the damaged area. This is accompanied by TJ reassembly
The TME has the ability to influence tissue function as in order to reform the epithelial layer. The loss of
well as the development of malignancies [40]. The adherence between epithelial cells during the process of
interaction as well as the penetration of both the EMT allows them to become more motile and acquire
endothelium and mesothelium by a tumor cell is a sig- mesenchymal characteristics. Studies show that this
nificant step for tumor metastasis. In order for carcinoma mechanism relates to a functional loss of E-cadherin [45].
to invade, tumor cells need to be able to degrade the Other events associated with EMT are loss of polarity
underlying basement membrane as well as the which takes place together with the loss of TJs [46].

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Fig. 1 The tumor microenvironment (TME) and tight junctions cells. Both malignant and nontransformed cells interacting with each
(TJs). The TME is composed of normal cells, blood vessels, signaling other are present. Vital to this interaction are the TJs which regulate
molecules, and extracellular matrix (ECM) surrounding the tumor selective transport across the cells

Tight Junctions in Different Tumorigenic Tissues changes in endothelial cells of the BBB resulting in
enhanced permeability and brain edema [47]. Damaged
Tight junctions (TJs) are important in the regulation of cerebrovascular endothelial cells cEND cultured in the
selective transport across the epithelium [7•]. For this presence or absence of astrocytic factors, for example,
reason, their involvement in cell proliferation through induced mRNA expression of inflammatory markers, alter
control of the epithelial cell microenvironment is impli- calcium ion levels and decreased tight junction proteins
cated [8]. They are thus suggested to affect metastasis of claudin-5 and occludin expression [48]. Severe cerebral
tumorigenic cells. Expression of TJ-associated proteins is edema is observed in most patients with glioma and it is a
shown to be dysregulated in various tumorigenic tissues main cause of mortality in glioma patients. Vasogenic
(Table 1). edema is caused by the disturbance of the BBB either by
the destruction of TJs or by the increase of endothelial
Glioma and Glioblastoma fenestrations and pinocytosis [49].
Glucocorticoids (GCs) are the most common molecules
Gliomas are the most frequent tumors of the central ner- used to treat tumor-associated cerebral edema [50]. GCs
vous system. They are associated with a poor prognosis and regulate the BBB and target occludin, claudins and VE-
high lethality. The blood–brain barrier (BBB) restricts the cadherin. Transactivation of certain target genes leads to
delivery of therapeutics into the brain making most of the improved barrier properties of endothelial cells [51]. For
systemically administered drugs ineffective in the brain instance, at the cellular level, GCs have been shown to
tumor treatment. Progression of glioma leads to structural strengthen the BBB properties by increasing the

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Table 1 Regulation of tight junctional (TJ) proteins expression in various tumorigenic tissues
Tumor type Tight junctions References Tight junctions References
downregulated upregulated

Mammary gland adenocarcinoma Claudin 1 [63, 72•] Claudin 3 [24, 29, 75•]
Claudin 2 [27] Claudin 4 [24, 29]
Claudin 3 [72•]
Claudin 4 [72•]
Claudin 7 [28, 29, 73, 74]
Claudin 12 [72•]
ZO-1 [70, 76, 77, 78]
ZO-2 [70, 76, 77, 78]
Glioma/Glioblastoma Claudin 1 [64, 65]
Claudin 5 [64, 65]
Colorectal carcinoma Claudin 1 [86•] Claudin 2 [88]
Claudin 4 [86•]
Claudin 7 [86•]
ZO-1 [37]
Hepatocellular carcinoma Claudin 1 [81]
Pulmonary carcinoma Claudin 6 [94]
Prostatic carcinoma Claudin 3 [24]
Claudin 4 [24]
Cutaneous squamous carcinoma Claudin 1 [68, 69] Claudin 2 [68]
Claudin 4 [69, 70]
Occludin [69]
ZO-1 [7•, 69]

transendothelial electrical resistance (TEER) of endothelial in brain endothelial cells contributing in this way to the
monolayer and decreasing the paracellular permeability for stabilization of the BBB [63]. Downregulation of claudin-1
small and large molecules [52, 53]. TJs proteins occludin, and claudin-5 has been detected in human glioma and has
claudin-5, and ZO-1 have been identified as GC targets at been associated with tumor progression [64, 65]. However,
the BBB [52–56]. GC treatment leads to direct binding of the BBB in peripheral glioma remains essentially intact and
glucocorticoid receptor to glucocorticoid response ele- this is one of the reasons for the poor treatment efficacy of
ments in the occludin promoter or to activation and binding this tumor [66].
of other transcription factors such as p54 [57, 58]. GC-
mediated claudin-5 increase was observed in brain Cutaneous Squamous Carcinoma
endothelial cells from different species and the induction of
claudin-5 was observed at the promoter, mRNA, and pro- TJs in epidermis form a barrier to prevent diffusion of
tein levels [53, 54, 58]. In addition, induction of other molecules from and into the body. Claudin-1 knock-out
BBB-associated claudins, claudin-1 and -12, was observed mice showed fetal dehydration from skin due to impaired
in brain endothelial cells after GC treatment [59, 60]. VE- barrier function in the epidermis [67]. During the pro-
cadherin, a component of adherens junctions, plays a role gression of skin tumorigenesis, changes in the expression
in the formation and regulation of TJs and is also induced and distribution pattern of TJ-proteins have been observed.
by GC-treatment [61]. Human cutaneous squamous carcinoma (SCC), its precur-
Glioma cells express high amounts of vascular sor tumors and sun-exposed skin models showed broader
endothelial growth factor (VEGF). VEGF is induced by localization of ZO-1 and claudin-4 as well as downregu-
hypoxia, promotes angiogenesis and increases BBB per- lation of claudin-1 in deeper epidermal layers at the TJs in
meability. Increased levels of VEGF lead to down-regu- comparison to healthy skin [68–70]. In addition, SCC
lation of TJ proteins claudin-5 and occludin [62]. GCs also showed complete loss of occludin at the TJ. This feature
modulate the expression of VEGF in brain tumor cells and seems to be common for different types of tumors.

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Occludin downregulation is associated with decreased invasive ductal carcinomas of the breast compared to normal
epithelial adhesion and susceptibility to apoptosis [69]. breast epithelium [29]. In addition, reduced expression of
Claudin-2 upregulation accompanied by claudin-1 down- claudin-7 corresponds to a higher tumor grade as well as
regulation was associated with tumor progression [68]. metastatic disease [73]. Using immunohistochemistry and
tissue microarray, it was observed that claudin-7 is strongly
Mammary Gland Adenocarcinoma expressed in normal luminal epithelial cells of the breast
lobule compared to ductal carcinoma and invasive breast
Cell-to-cell contacts in the epithelium are not just static carcinoma. Claudin-7 was significantly lower or absent in the
points that hold the cells together since they consistently carcinomas [74]. Still in another study conducted using two
undergo remodeling and incorporation of newly differen- breast cancer cell lines of metastatic origin (MCF-7 and
tiated cells. Although this does not lead to loss of barrier MDA-MB-415), a marked overexpression of claudin-3
function, alterations in TJs could impact breast cancer protein was shown. When protein levels of claudin-3 were
progression due to modified cell polarity, cell fate, and cell suppressed, the rate of cellular motility decreased. These
migration. The major characteristic of cancer is abnormal results could indicate that claudin-3 overexpression may
proliferation. However, progression of cancer is not only play an important role in the disruption of TJ integrity
determined by rapid proliferation in tumor cells. It is also leading to enhanced cell motility which is a key determinant
due to other factors such as apoptosis resistance as well as of tumor progression [75•].
the ability to bypass senescence pathways. In addition, Meanwhile, low ZO-1 and ZO-2 expression were observed
individual TJ proteins may also play a role in modulating to correlate with poor prognosis in breast cancer [70, 71,
breast cancer progression. 76–78].
Impairment of functional control over polarity and cell
fate determination, or cell motility characteristics, may Prostatic Carcinoma
result from alterations in the TJ complex at the onset of
breast cancer. Dysregulation of these cellular processes Like in many organs and tissues such as the brain, the
could lead to breast cancer progression and metastasis. The enteric epithelium or the testis where TJs abound due to the
differentiation of the mammary gland is significant in the presence of a barrier where they help to regulate barrier
reduction of the risk reduction for breast cancer. In one function, it has been shown that TJs also exist in prostate
study, a role for the estrogen receptor b (ERb-/-) in the tissue due to the blood-prostate barrier [72•]. In one study,
organization and adhesion of epithelial cells as well as for the effect of hepatocyte growth factor (HGF) on TJ func-
differentiated tissue morphology was suggested. Findings tion in human prostate epithelial, prostate stem cell-like
implicated that by facilitating terminal differentiation of and prostate cancer cell lines was evaluated. It has been
the mammary gland ERb could contribute to the risk demonstrated that HGF could impact the metastasis of
reduction for breast cancer [71]. prostate cancer. During this process, TJs play a vital role
In another study, functional regions of occludin in human and they are found to be regulated by HGF. TJ function
tissues and breast cancer cell lines were amplified. It has regulation by HGF was found to be dependent on cell
been observed that tumor tissues have truncated or variant tumorigenicity [79•]. In another study, the overexpression
signals of occludin. Moreover, expression of occludin in of claudins is implicated in the invasive potential of human
the human breast cancer cell lines tested also varied. This prostate cancer. The effects of flavonoids have been studied
demonstrates the significance of occludin in TJ integrity and it was observed that they subdue claudin expression
maintenance in breast tissues [22]. which leads to suppression of cancer migration and inva-
One study showed a link between the expression of sion [80].
interleukin (IL)-18, reported to have a pro-tumor effect in
various cancers, and claudins in breast cancer migration. Hepatocellular Carcinoma
This study showed that exogenous IL-18 could enhance
breast cancer cell migration and inhibit the expression of Loss of TJs in the liver has been associated with malignant
claudin-1, 3, 4, and 12 in human breast cancer cell line MCF- transformation. Nonetheless, a growing body of evidence
7. Upon knocking down these claudins, all except claudin-1 reveals the upregulation of TJ protein expression in cancer
increased breast cancer cell migration with claudin-12 gen- tissue and their role in cell invasion and metastatic pro-
erating the most effects. The results suggest that IL-18 is gression. In hepatocellular carcinoma (HCC), overexpres-
important for the induction of breast cancer cell migration by sion of claudin-1 led to increased expression of
down-regulating claudin-12 and activating the p38 mitogen- transcription factors regulating epithelial-mesenchymal
activated protein kinase (MAPK) pathway [72•]. Another transition (EMT) of human liver cells [81]. However,
study showed that expression of claudin-7 is lower in another study showed correlation of claudin-1

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downregulation and a poor prognosis in HCC. Claudin-7 small or large cell carcinomas [91]. Meanwhile, claudins
mRNA overexpression was also detected in HCC. In this show variable patterns of expression in tumor cells.
case, overexpression of claudin-7 correlated with a better Squamous cell carcinomas express claudin 1 but not
prognosis among patients [82]. Downregulation of claudin- claudin 5 while adenocarcinomas express claudin 5 but not
5 expression in sinusoidal endothelial cells of HCC patients claudin 1 [20]. Epithelial metastases of lung tumors
was correlated with a poor prognosis [83]. showed a 50–70 % expression of claudins 1, 2, 3, 4, and 5
and a 90 % expression of claudin 7 [92]. TJ proteins are
Gastric/Colorectal Adenocarcinoma usually overexpressed in lung tumors. Besides TJ protein
overexpression, matrix metalloproteinases are also
Claudins are vital for the absorption of nutrients in the small increased which leads to spread of the tumor [93]. On the
intestine [84]. In the same way, they are vital in cell prolif- other hand, immunohistochemical study of tissue from
eration and transformation during cancer. For instance, in patients with nonsmall cell lung cancer revealed low
colon cancer, claudin-1 was shown to promote transforma- claudin-6 expression indicative of a worse prognosis [94].
tion as well as metastatic behavior [85]. Expression of Nonetheless, permeability of pulmonary epithelium can be
claudin-1, -4, and -7 was found to decrease in colorectal governed by various factors. For example, in using human
cancer. This implies critical effects on cell proliferation, alveolar epithelium cell line H441, it has been shown that
motility, invasion, and immune response against the tumor soluble factors obtained from human lung endothelial cell
[86•]. One study did an analysis of the allele frequencies on line HPMEC-ST1.6R could influence the barrier properties
three common single nucleotide polymorphisms (SNPs) in of the former [95]. Thus, in the TME where there is
the genes for claudin-1 and 7 in colon cancer patients. It was interplay of different cell types, the possible effects that the
observed that polymorphisms in both claudins investigated different interactions among these cells bring about need to
are related to differentiation and tumor state in colon cancer be further explored.
[87•]. On the other hand, deficiency in claudin-15 results to
megaintestine and a decreased paracellular ion permeability
of the intestinal epithelium. Nonetheless, no tumorigenesis Cytokines, Tight Junctions, and the Tumor
was detected among those exhibiting the phenotype [8]. Microenvironment
Also, in colorectal cancer, it has been demonstrated that
resveratrol, a naturally occurring polyphenol, upregulates Dysfunction in the TME as well as the epithelium can be
intercellular junctions such as desmosomes, gap- and tight crucial for carcinogenesis [96]. It is suggested that cancer
junctions (claudin-2), and adhesion molecules (E-cadherin). cases are triggered by mutation and inflammation, although
On the other hand, it downregulates the NF-jB pathway. most cases have unknown origin [97]. Chronic inflamma-
These processes lead to inhibition of the EMT phenotype tion could lead to cellular events that promote cell trans-
[88]. In another study, CITED4, a transcriptional cofactor formation resulting to cancer formation. Inflammation
deregulated in colorectal cancer, was knocked down via activates cytokine production within the TME [98]. There
shRNA-mediation in the colorectal cancer cell line SW480. is greater oxidative stress in the microenvironment sur-
Changes in proliferation, apoptosis/cell cycle, migration, rounding inflammation compared to normal. Inflammation
invasion, colony formation, and adhesion were analyzed. leads to expression of cytokines which in turn activates the
Decreased cellular proliferation and modulation of actin- inflammatory cascade [97]. Moreover, cytokines contribute
associated adherens junctions/TJs expression have been to the promotion of cell tumor proliferation as well as
observed [89]. apoptosis inhibition and anti-tumor immunity suppression.
Meanwhile, the function of junctional adhesion mole- When epithelium surrounding the stroma is altered, it also
cules (JAMs) which comprise the integral parts of TJs in the alters the stroma along with the mediators leading to TME
gastric epithelium and in gastric cancer cell proliferation, formation [99]. In the same manner, when TJs within the
invasion, and apoptosis was investigated. It has been shown TME are disrupted, cytokine-mediated perturbation of TJs
that JAM-A promotes the proliferation but inhibits apoptosis occurs which in turn leads to increased paracellular per-
of gastric cancer [90]. On the other hand, decreased ZO-1 meability [100] and promotes TJ remodeling [101].
expression was noted in the human digestive tract.

Pulmonary Carcinoma Conclusions

The expression of TJ proteins such as claudins in different The tumor microenvironment (TME) engages a complex
lung tumors varies. For instance, occludin was found in interaction among the component cells that comprise it.
adenocarcinomas but not in squamous cell carcinomas, Communication and cross-talk in the TME are maintained

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by the tight junctions (TJs). Dysregulation of TJs at the 10. Eccles SA, Welch DR (2007) Metastasis: recent discoveries and
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