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Epithelial-Mesenchymal Transition in Gastrointestinal Cancer: From a... 51
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downregulation of the nuclear yes-associated protein 1 (YAP1). Inhibition of
HIPPO signaling induces tumor cell motility, angiogenesis, and metastasis
(Chang et al. 2022; Liao et al. 2021; Liu et al. 2021).
• EMT and metastasis – leader vs. follower cells – If EMT is characteristic of
primary tumors, carcinoma cells from metastatic sites can undergo the reverse
process of MET (Dardare et al. 2021; Liu et al. 2021; Luu 2021). Tumor cells can
migrate individually (single-cell migration; EMT phenomenon) or as a group
(collective migration). During collective cell migration, two groups of cells were
identified: leader (pathfinder or tip cells) and follower (trailing) cells. The leader
cells are localized to the leading edge and have the role of exploring and
modulating the microenvironment and ECM. They interact with ECM growth
factors and chemokines. The collective leader cells are guided by catenins, Rho
GTP-ases, Arp 2/2, or filopodia or lamellipodia, which are proteins from the
enabled/vasodilator stimulated phosphoprotein (Ena/VASP) family and are
responsible for maintaining the integrity of the cytoskeleton (Gurzu et al. 2008,
2013; Khalil and Friedl 2010). Leader cells can remain in the leading position for
hours but can also be linked to the followers by adhesion molecules. To keep
cell-cell junctions and collective movement, “chain-like cooperative behavior” is
necessary for the follower cells. If the junctions are not maintained, they can still
move as packs of cells through a “pushing elongation” mechanism, which is more
common in tumors undergoing expansive growth (Khalil and Friedl 2010; Liao
et al. 2021; Zoeller et al. 2019). The genetic profile of the 2 groups is not similar,
and at least 14 different gene mutations were identified between the 2 groups
(Liao et al. 2021; Zoeller et al. 2019).
4 Esophageal Squamous Cell Carcinoma
Esophageal cancer ranks seventh in cancer inci dence and sixth for mortality globally
(Dong et al. 2022; Zhai et al. 2022). Most of the carcinomas of the upper and middle
esophagus are squamous cell carcinomas (SCC), whereas adenocarcinomas usually
develop in the middle part and gastroesophageal junction. Little is known about the
EMT of esophageal SCCs. ZEB1/2, SLUG, Twist, and SOX2 are the most obvious
modified EMT-TFs, as are miRNAs and long non-coding RNAs (Liao et al. 2021;
Wang et al. 2022).
• Transcriptional EMT from early and late-partial EMT to mesenchymal
phenotype – In SCCs of the esophagus, the expression of TFs depends on the
EMT stage. In this process, ZEB1/2, Twist, and SNAIL proved to be activated
from early or partial EMT to late or complete EMT and maintain positivity of
tumor cells for vimentin and N-cadherin. SMAD2 seems to be upregulated in the
late stages of partial EMT. While in adenocarcinomas, stemness is more charac-
teristic for poorly differentiated, mesenchymal-type tumors, in SCCs stemness
properties are exhibited in tumor cells durin g early and late-partial EMT and
downregulated in SCCs with the mesenchymal phenotype (Liao et al. 2021; Wen
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et al. 2016). ZEB1 and ZEB2 can be modulated by TGF-β1, which downregulates
the tumor suppressor gene LINC00886 located at 3q25.31, or by ELF3, which
binds to the promoter region of miR-144-3p and suppresses its transcriptional role
in SCCs (Dong et al. 2022). Another hypothesis refers to Twist-induced expres-
sion of ZEB1, vimentin, and podoplanin. Podoplanin (D2-40) is a marker of
lymphatic vessels and cancer stem cells (CSCs). Its activity is independent of
E-cadherin (Liao et al. 2021).
• EMT and FAT Atypical Cadherin 1 (FAT1) – Downregulation of the adhesion
molecule FAT1 stimulates EMT by conferring stemness properties to cancer
cells and promoting β-catenin nuclear translocation (Zhai et al. 2022). FAT1
downregulation can also inhibit HIPPO pathway signaling through further
upregulation of the nuclear expression of YAP1/TAZ protein complexes, increas-
ing tumor cell motility and metastasis (Liao et al. 2021; Liu et al. 2021).
• EMT-driven metabolomics – The metabolic alterations that frame the EMT
process are targeted by TGF-β (Rajagopal et al. 2021). Its activation can be
induced by acidosis, which is the result of lactate synthesized by tumor cells.
TGF-β-related EMT is accompanied by the promotion of fatty acid metabolism
and the phosphorylation of SMAD 2/3 (Liao et al. 2021).
• EMT and chemoresistance – EMT-induced cisplatin resistance of esophageal
SCCs mainly occurs through increased drug efflux. One such mechanism is
FAT1 knockdown, which induces the upregulation of the drug resistance-related
gene ABCC3 (Zhai et al. 2022).
5 Gastric and Gastroesophageal Cancer
Data from 2020 (GLOBOCAN) shows that gastric cancer (GC) ranks fifth for
incidence and fourth for cancer global mortality (He et al. 2022), although
molecular-targeted drugs have already been synthesized for the molecular groups
established by the Cancer Genome Atlas (TCGA) Consortium, World Health Organization (WHO), and the Asian Cancer Research Group (ACRG). GC incidence is
higher in Asia and East Europe, and geographic differences were reported in
molecular profile and evolution (Kadar et al. 2015). Individualized therapy is
based on the following molecular groups: Epstein-Barr (EBV)-positive, cases with
genomic stability, the chromosomal instability (CIN) group, microsatellite instable
(MSI) carcinomas, microsatellite stable tumors displaying EMT (MSS/EMT),
MSS/TP53+, and MSS/TP53- carcinomas (Satala et al. 2020).
• Transcriptional EMT – EMT of GC cells is mostly driven via the Wnt pathway. It
has been primarily analyz ed for intestinal-type carcinomas (adenocarcinomas).
During EMT, E-cadherin/ZO-1 suppression with further N-cadherin/vimentin
upregulation can also be modulated by miR-4742e5p (Bae et al. 2022). Like
other carcinomas, EMT is influenced by inflammation and the immune status of
tumor cells. The human immunoglobulin superfamily containing leucine-rich
repeat (ISLR) is one of the newest factors proven to stimulate invasion and
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metastasis of GC cells via EMT. Physiologically, ISLR is involved in the
differentiation of myofibroblasts, muscle regeneration, and muscle atrophy. In
GC, ISLR expression is inversely correlated with E-cadherin and positively
correlated with MMP2 and EMT-mesenchymal markers N-cadherin, vimentin,
SNAIL, and Twist (Sun et al. 2022). ISLR association with the density of immune
stromal components CD8+ T cells, macrophages, and dendritic cells has also
been demonstrated (Li et al. 2020).
• EMT and Helicobacter pylori (H. pylori) – Infection with H. pylori proved to
enhance the stemness of gastric mucosa cells. In chronic gastritis, the stem
properties are determined by positivity of atrophic gastric mucosa for cell-cell
surface mark ers such as CD44. CD133 and TFs Oct4, Nanog, Sox2/Sox9, and
c-myc can then be expressed in areas with intestinal metaplasia, co-localized with
H. pylori. Unusual CD117 (c-KIT) positivity of gastric mucosa might also be an
indicator of stemness properties. When the microenvironment of the mucosa is
altered, carcinogenesis may be the next step. H. pylori-related tumorigenesis can
be driven via Wnt/β-catenin (CagA/E-cadherin interaction), TGF-β (SNAIL
inducer), or HIPPO (YAP1 activation) signaling pathways. The CD44+ CSCs
are chemoresistant against 5-fluorouracil (5-FU) and cisplatin (He et al. 2022;
Okabe et al. 2015).
• EMT in adenocarcinomas of the gastroesophageal junction – Adenocarcinomas
of the esophagus and those located at the junction between the esophagus and
stomach share similar signaling pathways. EMT was reported to occur via the
TGF-β superfamily, which includes TGF-ß1, the mothers against decapentaplegic
homolog 4 (SMAD4), and bone morphogenetic protein 7. They interact with the
stem cell marker CD44 and other TFs (such ZEB1 and ZEB2) and downregulate
expression of EpCAM (Okabe et al. 2015).
6 Cancer of the Small Intestine
Fewer than 40 Medline-indexed papers focused on the EMT of the small intestine and
its premalignant disorders. The most common premalignant lesions of the small
intestine are inflammatory bowel diseases (IBD), mainly Crohn disease. A challenging
therapeutic target is the synthesis of anti-fibrosis drugs. It was experimentally proven
that this synthesis should be focused on inhibition of TGF-ß and AMP-activated
protein kinase pathways, which are EMT inductors (Huang et al. 2022).
In inflammatory processes, EMT of enterocytes occurs via the Wnt/ß-catenin
signaling pathway. Like other segments of the GI tract, it includes E-cadherin/Ncadherin switch, loss of tight junction proteins ZO-1 and ZO-2 and some claudins,
and upregulation of vimentin and nuclear SNAIL. In experimental studies in pigs,
EMT of enterocytes was more obvious in the jejunum, along with a high expression
of TGF-ß1, and not in the ileum. As the number of Peyer’ s patch M cells decreased
in the ileum in synchrony with EMT of enterocytes, it was supposed that immune
surveillance can be significantly affected in patients with IBD-induced EMT (Chen
et al. 2021 ).
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6.1 Adenocarcinoma and Carcinoma of Ampulla of Vater
Although transcriptional EMT occurring via the Wnt/ß-catenin pathway can be seen
in both intestinal- and pancreatobiliary-type carcinomas of the ampulla of Vater,
some notable features should be highlighted. In intestinal-type carcinomas,
membrane-to-nuclear translocation of ß-catenin is an indicator of EMT. The
non-intestinal carcinoma is characterized by membranous loss of both E-cadherin
and ß-catenin, a more desmoplastic stroma, and high tumor budding degree, as in
colorectal carcinomas (CRC). EMT is more intense in the invasive edges than in the
tumor center (Sung et al. 2014 ).
Adenocarcinomas are rare and mainly occur in the jejunum and ileum. Independent of location, mesenchymal phenotype/high-EMT is characterized by negative
E-cadherin and diffuse positivity for vimentin and fibronectin. It is also associated
with poorly differentiated histology, especi ally in the invasive edges, and proved an
independent negative prognostic factor. SMA is not a marker of EMT of small
intestine adenocarcinoma cells (Kim et al. 2013).
6.2 Gastrointestinal Stromal Tumor (GIST)
Although unusual, EMT-TFs proved to influence the behavior of such mesenchymal
tumors including GISTs. E-cadherin can be seen in 30% of GISTs, as a positive
prognostic parameter. Half of the cases express nuc lear SLUG, which induces CSC
properties in the tumor cells, along with CD44 (Kovecsi et al. 2017).
7 Colorectal Cancer
CRC has the third highest incidence rate and is the fourth most common cause of
cancer-related death worldwide (Lu et al. 2022; Sadoughi et al. 2022). It is one of the
carcinomas for which targeted molecular therapy has been implemented, with good
results, for more than 10 years. There are still cases, however, which do not respond
to this therapy. About 20% of patients with metastatic CRCs remain alive 5 years
after diagnosis (Yang et al. 2022). As in other carci nomas, EMT seems to contribute
to rapid evolution and chemoresistance.
• EMT and hereditary polyposis cancer syndromes – The first connection between
EMT and cancer was suggested when nuclear β-catenin, an important component
of the Wnt signaling pathway, proved to be linked on the cytoplasmic adenoma-
tous polyposis gene (APC). Its mutations can be responsible by occurrence of
familial adenomatous polyposis (FAP) (Jung et al. 2015). In the absence of APC
mutation, Axin2 mutation can also induce β-catenin membrane-to-nuclear trans-
location, with further predisposition for hereditary CRC (Clevers 2006).
• EMT-based molecular subtyping of CRC – The four consensus molecular
subtypes (CMS) include the following groups: (1) CMS1, hypermutated
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carcinomas with MSI, BRAF mutations, or significant immune reaction;
(2) CMS2, carcinomas displaying CIN with/without activation of the
EMT-related pathways Wnt and myc (low EMT or epithelial phenotype);
(3) CMS3, metabolic-activated KRAS-mutated carcinomas; and (4) CMS4,
carcinomas with highly developed angiogenesis and TGF-β-induced mesenchy-
mal phenotype. CMS4 carcinomas also show stromal activation, immunosup-
pression, and large amounts of CD68-positive cytokine-secreting macrophages.
They are also associated with an increased risk of lymph node and peritoneal
carcinomatosis and unfavorable prognoses (Banias et al. 2020; Ieda et al. 2019).
The CMS4 tumors are also known as stem-like carcinomas. In these cases, the
EMT-TFs can acquire a stem-like phenotype characterized by double positivity of
tumor cells for EMT-TFs and markers of CSCs, such as CD44, CD133, or CD24
(Wang et al. 2017; Zheng et al. 2015).
• EMT and microsatellite status – Although the relation between EMT and
microsatellites is far too complex to be characterized, it has been experimentally
determined that MSI-CRCs, which are associated with mutations of TGF-β recep-
tor type II, do not appear during TGF-induced EMT. MSI or MSS carcinomas with
intact TGF-β type II receptors are more prone to EMT. The loss or reduction of
junctional E-cadherin along with the acquirement of N-cadherin and vimentin is
more frequently seen in MSS than in MSI carcinomas (Banias et al. 2020;Ieda
et al. 2019;Pinoetal.2010). Although E-cadherin downregulation is considered
“thehallmarkofEMT” (Roseweir et al. 2019), it usually has a patchy expression in
tumor glands, and its complete loss is extremely rare. β-catenin loss or membrane-
to-cytoplasm/membrane-to-nuclear translocation defines the EMT (Clevers 2006).
EMT features are correlated with the morphological particularities of MSI vs. MSS
carcinomas; as MSI tumors present high levels of inflammation compared with
MSS, inflammation-induced EMT may be predominantly expressed in MSI
carcinomas (Pino et al. 2010;Tothetal.2011).
• EMT and tumor buds – If simultaneous E-cadherin/β-catenin junctional activity is
diffusely seen in the center of the tumor and invasive edge, along with cytoplas-
mic maspin, the case is considered as having an epithelial phenotype. This
immunoprofile characterizes one third of CRCs (Banias et al. 2020; Gurzu and
Jung 2021). If the EMT is observed in both the tumor co re and invasive area
(buds), it is classified as having a mesenchymal phenotype (CMS4). If only the
buds exhibit EMT, the carcinomas are considered hybrid/quasi-mesenchymal.
For these reasons, quantification of EMT and the EMT-TFs in both the tumor
center and tumor buds is recommended. The budding degree is recognized by the
WHO as an important prognos tic parameter (Banias et al. 2020; Gurzu et al.
2018; Studer et al. 2021; Wang et al. 2017). The mesenchymal phenotype/high
EMT/CMS4 is encountered in fewer than 15% of CRCs and is reflected by
nuclear β-catenin or simultaneously loss of β
membrane positivity for ZEB1 and fascin, cytoplasmic SNAIL reactivity,
increased tumor budding, and a worse prognosis (Alexander et al. 2022; Banias
et al. 2020; Roseweir et al. 2019). Low EMT/hybrid phenotype/transitory status is
observed in one third of CRCs and is characterize d by low membrane E-cadherin,
-catenin and maspin, along with
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cytoplasm-to-nuclear translocation of maspin in tumor buds, and positivity for at
least one of the EMT-TFs (ZEB1, fascin, or SNAIL) (Banias et al. 2017, 2020;
Gurzu and Jung 2021; Roseweir et al. 2019).
• EMT and tumor stroma – For CRC, the Glasgow Microenvironment Score
(GMS) is calculated based on the inflammatory score and tumor stroma percent-
age at the invasive edge (Alexander et al. 2021). The Klintrup-Mäkinen inflam-
matory grade is estimated using hematoxylin and eosin (HE) stains and is based
on the density of inflammatory cells in the invasive areas. Under this system,
CRCs are categorized as score 0, no stromal inflammation; score 1, few inflam-
matory cells without glandular destruction; score 2, moderate amount of inflam-
matory cells with patchy arrangement and focal destruction of glands; and score
3, high-grade inflammatory cell reaction (mainly macrophages) forming a band in
the invasive edge, with significant destruction of glands (Klintrup et al. 2005).
Intra-tumor-stroma ratio is counted at low-power field (100× magnification) using
pictures of the invasive area, which show tumor cells in all borders of the image
and do not include inflammation, necroses, or mucus. Cases are classified as
stroma-low (≤50%) and stroma-high, which is fibrotic/dense and comprises
>50% of image (Huijbers et al. 2013). GMS includes three prognostic groups:
good, score 0 (high inflammation in the invasive areas [scores 2/3], independent
of stromal ratio); intermediate, score 1 (low inflammation, low stroma); and poor
prognosis (low inflammation, high stroma), score 2 (Alexander et al. 2021;
Jakubowska et al. 2017). GMS 2 reflects a mesenchymal subtype with a high
risk of local relapse and distant metastases (Alexander et al. 2021). Based on
desmoplastic reaction, CRCs can also be classified as mature (collagen fibers,
without hyalin), inte rmediate (keloid-like collagen and hyalinization), and imma-
ture (myxoid stroma with an amorphous mucinous material). Immature types are
CRCs with mesenchymal or quasi-mesenchymal phenotype which express the
EMT-TFs called ZEB1 and Twist1 (Hashimoto et al. 2022).
• EMT in colitis-induced CRC – In patients with inflammation, TGF-β1, SMA,
TNF-
α (tumor necrosis factor), NF-kB signaling pathway, ECM, ISLR, and
interleukins (IL) (mainly IL-1, IL-6, and IL-8) are triggers of EMT and fibrosis
(Clevers 2006; Ieda et al. 2019; Lu et al. 2022; Sun et al. 2022). In the acute
phase, neutrophils and CD-68 macrophages expressing IL-1β favor stromal
storage of TNF-α, TGF-β, and IL-1β. If the inflammatory cytokines TNF-α and
IL-1β are removed, the EMT process is reversible in its early phases. In the
chronic phase of colitis, fibrosis is mainly induced by growth factors such as basic
fibroblast growth factor (FGF), epidermal growth factor (EGF), hepatocyte
growth factor (HGF), and their receptors (Ieda et al. 2019). In these cases, EMT
can be characterized by Wnt-mediated loss of E-cadherin and the upregulation of
EMT-TFs but can also result from the activation of the vitamin D receptor
pathway. Vitamin D receptor interacts with the TGFβ 1/SMAD3 signaling pathway (Lu et al. 2022), but the Wnt/Ca
2+
pathway can also be an EMT signaling
mechanism (Clevers 2006).
• EMT and circulating tumor cells (CTC) – Exosomes are tiny CRC cells and
cancer-associated fibroblast-derived vesicles of 30–150 nm in diameter that
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contain DNA, ncRNAs, epigenetic modulation, and metabolites. They can be
detected in circulating blood and other bodily fluids, such as urine or saliva (Yang
et al. 2022). As circulating tumor cells (CTCs) can express both epithelial and
mesenchymal markers, it has been suggested that EMT plays a crucial role in the
systemic spread of carcinoma cells (Wang et al. 2017).
• EMT and neuroendocrine components – Although rare, neuroendocrine tumors
(NET), NECs, mixed neuroendocrine-non-neuroen docrine tumors, and mixed
adenocarcinomas with neuroendocrine components (MANEC) are difficult to
treat and are frequently chemoresistant. Their incidence increased 6.4 times
from 1973 to 2012. The EMT phenomenon is poorly understood in these tumors.
The TGF-β1/SMAD signaling pathway was hypothesized as an EMT promoter of
NECs, with further E-cadherin/N-cadherin switch and upregulation of SLUG (but
not SNAIL). TGF-β1 is respon sible for partial EMT and collective migration of
NEC cells, which usually maintain E-cadherin junctional activity. During cell
migration, TGF-β1 stimulates MMP2, which promotes the adhesion of cancer
cells to the extracellular matrix and stimulates metastasis (Sasaki et al. 2022).
8 Pancreatic Cancer
8.1 Pancreatic Ductal Adenocarcinoma (PDAC)
PDAC is the eighth most common cause of cancer-related death worldwide, with a
5-year overall surviv al rate (OS) of less than 10% and a median survival time of less
than 8–10 months (Luu 2021; Safa 2020; Wang et al. 2017). It is the fourth leading
cause of cancer-related death and is proje cted to become the second most lethal
cancer by 20 30 (Dardare et al. 2021; Rajagopal et al. 2021). Two of the factors which
induce aggressivity in PDACs are excessive desmoplastic stroma with rich ECM and
EMT plasticity, which is more intense in undifferentiated/mesenchymal-type
carcinomas (Ikena ga et al. 2012). Several mechanisms of EMT have been proposed
for PDAC, as follows:
• Stromal-related EMT – Dense acellular stromal ECM forms bands of fibrous
stroma surrounding cancer cells, creating a physical barrier around them. It can
induce hypoxia and physically blocks the penetration of chemotherapics (such as
gemcitabine) or immunotherapics in tumor cells. On the other hand, it is rich in
collagen, laminin, fibronectin, hyaluronic acid, cytokines, chemokines, growth
factors, and other components that actively participate in EMT. Collagen internalization is the first step of stromal-related EMT. Pancreatic stellate cells then
play the role of CSCs and induce intracellular and stromal internalization of
collagen with further ECM remodeling through simultaneous activity with
MMPs, urokinase plasminogen activator, and other remodeling factors (Dardare
et al. 2021; Ikenaga et al. 2012; Rajagopal et al. 2021; Safa 2020).
• Transcriptional EMT in classic/epithelial phenotype/pancreatic progenitor –
Although TFs such as SNAIL and ZEB act as epithelial repressors in most of
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carcinomas, their preventive role against metastasis in PDAC is controversial (Liu
et al. 2021;Wangetal.2017). In a spontaneously metastatic genetically engineered
mouse model of PDAC, it was observed that deletion of SNAIL or Twist, which is
regulated by the miR-200 family, does not delay carcinogenesis or metastasis and
did not improve the OS. The histology of the tumor remained unaffected. However,
tumor architecture, desmoplasia, number of myofibroblasts, microvascular density,
intensity of CD3-positive tumor-infiltrating T cells, cancer cell apoptosis, and IHC
expression of SNAIL and Twist remained restricted to the areas displaying
intraepithelial neoplasia (PanIN). These carcinomas co-express MUC5AC and
MUC1, but not MUC2 or MUC6 (Aiello et al. 2019;Baileyetal.2016;Zheng
et al. 2015). On the other hand, FOXA1/2 is inhibited by GATA binding protein
6 (GATA6), which is essential for a proper pancreas development during embryogenesis (Collisson et al. 2011). Classic PDAC is mostly a GATA6
high
tumor.
GATA6 silencing induces not only dedifferentiation, basality phenotype, and
EMT but also resistance to adjuvant 5-FU, specifically 5-FU/leucovorin regimen
(Martinelli et al. 2017).
• EMT of KRAS-mutated carcinomas – TGF-β plays role in EMT genesis and KRAS
activation with further synthesis of ILs, mainly IL-6, which maintains an active
stroma (Dardare et al. 2021; Sadoughi et al. 2022). KRAS-mutated carcinomas are
even classic PDACs or exocrine-like/aberrantly differentiated endocrine exocrine
carcinomas (Bailey et al. 2016; Collisson et al. 2011). Although KRAS-wild type
carcinomas are usually treated with anti-EGFR drugs, erlotinib resistance does not
depend on the KRAS status in PDACs (Collisson et al. 2011). Alterations of TGF-β
can also be induced by other genes involved in pancreatogenesis, such as SMAD4
(Bailey et al. 2016; Rajagopal et al. 2021).
• EMT of basal-like/quasi-mesenchymal carcinomas – PDACs with squamous
component, marked by CKs 5/6/14, and positivity for vimentin are called basallike carcinomas. Their high aggressivity compared with classic PDACs seems to
occur as a result of EMT activation via silencing of the GATA6 pro-epithelial/
anti-mesenchymal gene. These carcinomas are GATA6
low
tumors. Despite chemotherapy, the progression rate after implementation of the FOLFIRINOX
(5-FU/leucovorin/irinotecan/oxaliplatin) protocol is about 60%, compared with
15% in classic PDAC (Bailey et al. 2016; Collisson et al. 2011; Dardare et al.
2021; Martinelli et al. 2017).
• EMT of mesenchymal/stem-like carcinomas – The EMT-TFs can acquire stemlike features, which are defined by double positivity for CD44 or CD133 and
CD24, and are associated with proliferation of pancreatic stellate cells and
resistance to chemotherapy. Gemcitabine sensitivity is decreased in PDACs
with the mesenchymal phenotype, which are usually poorly differentiated
carcinomas rich in CSCs. Mesenchymal stem cells from desmoplastic stroma
(which result from secretion of cytokine granulocyte-macrophage colonystimulating of PDAC cells and intracellular collagen internalization by cancer
cells) exert pro-stemness effect upon tumor cell s (Aiello et al. 2019; Ikenaga et al.
2012; Luu 2021; Rajagopal et al. 2021; Safa 2020; Zheng et al. 2015).
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• Transcriptional EMT in metastatic tissues – In metastatic organs, such as liver
metastases from a PDAC, activation of metastasis-associated macrophages
can indu ce the transformation of hepatic stellate cells in to SMA-positive
myofibroblasts. This results in fibrotic stromal expansion and resistance to chemo-
therapy. In pulmonary metastases from a PDAC, myofibroblast activation is more
intense in areas with CD68-pos itive ma crophages (Nielsen et al. 2016). This data
demonstrates that in PDACs, EMT mediated by TFs is not primarily re sponsible for
tumor invasion but rather for fibrogenesis and subsequent chemoresistance to both
gemcitabine and FOLFIRINOX prot ocols (Bailey et al. 2016;Martinellietal.2017).
• EMT and HIPPO pathway – Downregulation of HIPPO pathway signaling
increases risk of metastasis through the formation of a complex called ZIP4miR-373-LATS2-ZEB1/YAP1-ITGA3 (Liu et al. 2021).
• EMT-driven metabolomics – The TGF-β-induced metabolic alterations increase
the intracellular levels of retinoic acid with further activation of fibronectin and
collagen, as well as ECM proliferation. This results in high-intensity stromal
desmoplasia (Rajagopal et al. 2021).
8.2 Neuroendocrine Tumors (NETs)
Gastroenteropancreatic NETs can be driven by TGF-ß, which mediates the EMT
phenomenon (Xue et al. 2021). In grade 1 and 2 pancreatic NETs, E-cadherin can be
lost in 50% of cases. Twenty percent of them are also marked by vimentin, which is
an indicator of EMT and of increased risk of lymph node and systemi c metastases.
SNAIL and Twist can be upregulated (Zhou et al. 2021).
9 Hepatobiliary Cancers
9.1 Hepatocellular Carcinoma (HCC)
The incidence of HCC has significantly increased in last decades (Turdean et al.
2012). It is ranked as the sixth most frequent cancer worldwide and the fourth
leading cause of cancer-related death (Negri et al. 2022). Although similarities
with other carcinomas exist, some particularities of the EMT phenomenon seem to
characterize HCC.
• EMT signaling pathways – As in other carcinomas, transcriptional EMT is the most
common pathway that occurs via Wnt/β-catenin signaling and activation of
EMT-TFs (such SNAIL), which is seen in half of HCCs (Cakil et al. 2022).
β-catenin membrane-to-nuclear translocation could also be the consequence of
Axin2 mutation (Clev ers 2006). Ubiquitin-conjugating enzyme E2T (UBE2T) is a
linker of Wnt/β-catenin with MAPK/ERK and AKT/mammalian target of rapamycin
(mTOR) signaling pathways. UBE2T can activate the Wnt/β-catenin signal independently of β-catenin mutational status in HCC cells (Lioulia et al. 2022). Another
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mechanism of activation of transcriptional EMT is TGF-β signaling, which induces a
mesenchymal phenotype in HCC cells (Cakil et al. 2022; Chung et al. 2018).
Activation of GBA1, which catalyzes the conversion of glucosylceramide (GlcCer)
to ceramide, can also activate EMT (Qiu et al. 2022). As in PDACs, metastasisassociated macrophages can suppress EMT-TFs and promote myofibroblast activation and metastasis (Nielsen et al. 2016;Wangetal.2017).
• EMT and resistance to systemic inhibitors – HCC is known to have a high
resistance to most available target therapies. The multi-kinase inhibitor sorafenib
was approved by the Food and Drug Administration (FDA) as the first-line
treatment for patients with HCCs showing mutations of the platelet-derived
growth factor receptor (PDGFR) gene (NCCN 2022; Negri et al. 2022; Qiu
et al. 2022). Second-line treatment is done with multi-kinase inhibitor
regorafenib, with everolimus, which is a mTOR inhibitor, or using immune
checkpoint inhibitors (Cakil et al. 2022; Negri et al. 2022). The platinum compound cisplatin can be used in sorafenib-resistant cases (Cakil et al. 2022). On the
one hand, sorafenib is believed to be involved in inhibition on TGF-β1-induced
EMT by degradation of type II TGF-β receptors. It has produced positive results
in patients with epithelial-phenotype HCC (Chung et al. 2018). On the other
hand, EMT, activation of hepatic stellate cells, and the mesenchymal phenotype
were shown to play an incriminating role in the development of resistance to these
drugs (Chung et al. 2018). CD44, a stemness inductor, can be responsible for
translocation of the TGF-β receptor to lipid raft membrane domains and further
blocking of sorafenib-induced TGF-β1 inhibition (Chung et al. 2018). GBA1, an
EMT activator, can also induce sorafenib resistance, but the exact mechanism is
unknown (Qiu et al. 2022). HCC cell- and fibroblast-derived exosomes are
involved in acquired resistance to everolimus (Negri et al. 2022; Yang et al.
2022). Vi tamin D has been suggested as a drug resistance reversing agent that
may re-sensitize HCC cells to everolimus (Negri et al. 2022). Although cisplatin
can be included in therapeutic regimens of HCC, it has been shown that low doses
can induce the expression of CSCs, which are marked by CD44, CD133, and
CD90. EMT-like features, such as the transformation of hepatocytes into
fibroblast-like cells and increased drug resistance, were also observed in HepG2
cells in a dose- and time-depen dent manner (C akil et al. 2022).
9.2 Cholangiocarcinoma
Although the incidence of cholangiocarcinoma is not high (3% of all GI
malignancies and 10–30% of all hepatobiliary cancers), the prognosis is extremely
unfavorable, and few therapeutic options are available (Lefler et al. 2022; Lin et al.
2022; Turdean et al. 2012).
Inflammation is the key target in the development of cholangiocarcinomas (Lin
et al. 2022). Transcriptional EMT, mainly based on E-cadherin/ZO-1 suppression
and enrichment of SLUG , is modulated by several factors, including high mobility of
the group nucleosome-binding protein 3 (HMGN3) (Sorin et al. 2022).
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