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Epithelial-Mesenchymal Transition
https://t.me/med1917
in Gastrointestinal Cancer: From a Basic
to a Clinical Approach
Simona Gurzu and Ioan Jung
Abstract
Since 1968, when Betty Hay first described the concept of epithelial-
mesenchymal transition (EMT), over 54,000 articles have been published on
this topic in the Medline and Web of Science databases. In the last 5 years,
over 5500 papers on EMT in physiological, tumor, and non-tumor lesions have
been issued annually. The first guideline for EMT research was edited in 2020 by
the EMT International Association (TEMTIA). Despite rapidly growing interest
in this subject, the EMT process is far from being understood. It is involved in
embryogenesis, organ development, and the regeneration or healing of damaged
tissues with fibrosis. However, its role in cancer is equally imp ortant. The present
chapter aims to provide a literature update regarding the EMT of gastrointestinal
cancers, which includes carcinomas, neuroendocrine neoplasms, stromal tumors
of the gastrointestinal tract from the esophagus to the anal canal, and hepatic and
pancreatic malignancies. Drawing on experimental studies, in vivo observations,
and microscop ic examinations of gastrointestinal cancers, the authors intend to
highlight the most important features of EMT, which might guide oncologists in
identifying the best approach for targeted anti-EMT therapy. The role of EMT in
inducing drug resistance was also explored for all types of cancer examined, in
the context of both basic and clinical approac hes.
Keywords
Cholangiocarcinoma · Colorectal · Gastric · Hepatocellular carcinoma ·
Melatonin · Mesenchymal to epithelial transition · Migrastatics ·
Neuroendocrine · Pancreas · Wnt
S. Gurzu (*) · I. Jung
Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and
Technology, Targu-Mures, Romania
e-mail: simonagurzu@yahoo.com; jungjanos@studium.ro
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2022_61
Published online: 6 October 2022
45
46 S. Gurzu and I. Jung
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Abbreviations
ACRG Asian Cancer Research Group
APC Adenomatous polyposis coli
CIN Chromosomal instability
CK Cytokeratin
CMS Consensus molecular subtypes
CRC Colorectal cancer
CSC Cancer stem cell
CTC Circulating tumor cell
EBV Epstein-Barr virus
E-cadherin Epithelial cadherin
ECM Extracellular matrix
EGFR Epidermal growth factor receptor
EMT Epithelial-mesenchymal transition
EMT-TF EMT-activating transcription factor
ENA/VASP Enabled/vasodilator stimulated phosphoprotein
EpCAM Epithelial cellular adhesion molecule
FAP Familial adenomatous polyposis
FAT1 FAT Atypical Cadherin 1
FDA Food and Drug Administration
FFPE Formalin-fixed paraffin-embedded tissue
FGFR Fibroblast growth factor receptor
FOLFIRINOX 5-fluorouracil/leucovorin/irinotecan/oxaliplatin
FU Fluorouracil
GATA GATA binding protein
GC Gastric cancer
GIST Gastrointestinal stromal tumor
GlcCer Glucosylceramide
GMS Glasgow Microenvironment Score
H. pylori Helicobacter pylori
HCC Hepatocellular carcinoma
HDAC Histone deacetylase
HE Hematoxylin and eosin
HER-2 Human epidermal growth factor receptor 2
HGFR Hepatocyte growth factor receptor
HIF Hypoxia-inducing factor
HMGN High mobility group nucleosome-binding protein
IBD Inflammatory bowel diseases
IHC Immunohistochemistry
IL Interleukin
ISH In situ hybridization
Epithelial-Mesenchymal Transition in Gastrointestinal Cancer: From a... 47
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ISLR Immunoglobulin superfamily containing leucine-rich repeat
Klf4 Kruppel-like factor 1
MANEC Mixed adeno-neuroend ocrine carcinoma
MET Mesenchymal epithelial transition
miRNA MicroRNAs
MMP Metalloproteinase
MSI Microsatellite instability
MSS Microsatellite stable status
mTOR Mammalian target of rapamycin kinase
N-cadherin Neural cadherin
NCCN National Comprehensive Cancer Network
NEC Neuroendocrine carcinoma
NET Neuroendocrine tumor
OS Overall survival rate
PanIN Pancreatic intraepithelial neoplasia
PD-1 Programmed cell death protein-1
PDAC Pancreatic ductal adenocarcinoma
PDGFR Platelet-derived growth factor receptor
PD-L1 Programmed death ligand 1
PRRX Paired related homeobox 1
ROCK Rho kinase
SCC Squamous cell carcinoma
SIN3A SIN3 transcription regulator family member A
SLUG Snail-related transcription factor or Snai2
SMA Smooth muscle actin
SMAD Mothers against decapentaplegic homolog
SNAIL Zinc finger protein SNAIL or Snai1
SOX Sex-determining region Y-Box
TCGA Cancer Genome Atlas Consortium
TEMTIA EMT International Association
TF Transcription factor
TGF Transforming growth factor
TNF Tumor necrosis factor
Twist Twist Basic Helix-Loop-Helix Transcription factor 1
UBE2T Ubiquitin conjugating enzyme E2T
VEGF Vascular endothelial growth factor
WHO World Health Organization
Wnt Wingless and INT-1
YAP1 Yes-associated protein 1
ZEB Zinc finger E-box binding homeobox
ZO-1 Zonula occludens-1
48 S. Gurzu and I. Jung
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1 Introduction
Epithelial-mesenchymal transition (EMT) is defined as a cellular reprogramming
process in which the cytoskeleton remodeling of epithelial structures induces
phenotypic and genotypic conversion from an epithelial to a mesenchymal-like
state. The epithelial cells are transformed from polygonal to elongated cells with
spindle-shaped morphology. The loss of epithelial cadherin (E-cadherin) polarity,
acquirement of fibroblastic properties, and high motility have also been observed to
accompany the EMT process (Aiello et al. 2019; Dong et al. 2022; Ikenaga et al.
2012; Luu 2021; Qiu et al. 2022; Xue et al. 2022).
Three subtypes of EMT are known. Type 1 drives early embryogenesis and organ
development and is involved in several processes such as neural crest formation, the
genesis of heart valves, and Müllerian duct regression. Type 2 is responsible for the
physiologic response to tissue injury, wound healing, tissue self-renewal, fibrosis,
and epithelial tissue explants in vitro. Type 3 is known to be involved in carcinogenesis, cancer progression, invasion, immune escape, and metastasis (Aiello et al.
2019; Clevers 2006; Gurzu et al. 2015; Ieda et al. 2019; Yang et al. 2020). EMT
plays roles in the migration of tumor cells through actin remodeling and the loss of
cell-cell adhesion. It also strongly influences the incorporation of tumor cells in
metastatic organs (Gandalovicova et al. 2017; Vasarri et al. 2022).
This chapter aims to characterize the EMT phenomenon of gastrointestinal
cancers, which include not only malignant tumors developed in the gastrointestinal
(GI) tract from the esophagus to the anal canal but also pancreatic and hepatobiliary
cancers. A better understanding of EMT from both a basic and a clinical perspective
might yield the necessary insight for oncologists to develop new therapeutic
approaches (NCCN 2022).
2 Epithelial Plasticity and EMT Subtyping in Cancer
Epithelial plasticity is a dynamic and partially reversible process characterized by
the interconversion of tumor c ells between EMT and mesenchymal-to-epithelial
transition (MET) phenotype (Liu et al. 2021; Yang et al. 2020). Most of the studies
focusing on EMT examined this phenomenon based on immunohistochemical (IHC)
antibodies or in situ hybridization (ISH) methods and formalin-fixed paraffinembedded tissues (FFPE). Al though EMT is a process characteristic of epithelial
tumors, EMT-like changes were also descri bed in non-epithelial neoplasms such as
leukemia, sarcoma, gastrointestinal stromal tumors (GIST), and melanoma (Kovecsi
et al. 2017 ; Yang et al. 2020).
From an IHC perspective, EMT is defined as the partial loss of positivity for
cytokeratin (CK) and other membrane markers of cell-cell adhesion such as
E-cadherin, β-catenin, EpCAM (epithelial cellular adhesion molecule), claudins
(especially claudin 7), and occludins (e.g., zonula occludens-1 [ZO-1]). EMT is
also characterized by the increased activity of mesenchymal antibodies such as
vimentin, neural cadherin (N-cadherin), fibronectin, metalloproteinases (MMP),
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smooth muscle actin (SMA), or vitronectin which are regulated by EMT-activating
transcription factors (EMT-TF) (Aiello et al. 2019; Dardare et al. 2021; Gurzu et al.
2015; Xue et al. 2022; Zheng et al. 2015). Most of the TFs – like SNAIL (zinc finger
protein SNAIL or Snai1), SLUG (snail-related transcription factor or Snai2), and
ZEB1 and ZEB2 (zinc finger E-box binding homeobox 1 and 2) – are zinc finger
proteins (Liu et al. 2021).
Based on the EMT phenomenon, carcinomas are classified as having an “epithelial,”“mesenchymal,” or “quasi-mesenchymal” phenotype:
• Epithelial phenotype/absent EMT – Carcinomas are usually defined by positivity
for CKs, which are epithelial markers, and for cell-cell adhesion markers such
E-cadherin (CDH1 gene) or β-catenin (CTNNB1 gene), which show membrane
positivity. Diffuse expression of pan-CK (clone AE1/AE3) and membrane
E-cadherin ± β-catenin, without positivity for mesenchymal markers or
EMT-TFs, is an indicator of the epithelial phenotype. Carcinomas showing epithe-
lial phenotype are less aggressive than other molecular groups (Banias et al. 2020;
Gurzu et al. 2015; Liu et al. 2021;Roseweiretal.2019).
• Mesenchymal phenotype/high EMT – This phenotype is specific to carcinomas
that are negative or show patchy positivity for E-cadherin and present loss or
membrane-to-nuclei translocation for β-catenin, along with positivity for mesen-
chymal markers. Positive reaction for at least three EMT-TFs is also considered
an indicator of high or “complete EMT.” The commonest examined TFs are
SNAIL, SLUG, Twist, ZEB1, and ZEB2. Other EMT-TFs are HDAC1/HDAC2
(histone deacetylase), SIN3A (SIN3 transcription regulator family member A),
and Ovol 1/2, among others. The mesenchymal phenotype is found more fre-
quently in poorly or undifferentiated carcinomas and is known as a factor of
aggressivity, high mobility in tumor cells, resistance to apoptosis or senescence,
enhanced capacity for metastasis, the promotion of genomic instability, immune
suppression, stemness, and drug resistance (Luu 2021; Okuda et al. 2022;
Roseweir et al. 2019; Sadoughi et al. 2022).
• Hybrid phenotype/low EMT – This phenotype is characterized by simultaneous
retained epithelial and gained mesenchymal features. It is also known as “partial
EMT,”“
type,” or “intermediated hybrid epithelial and mesenchymal phenotype.” These
carcinomas can be positive for CKs and E-cadherin but also show immuno-
expression for antibodies such as vimentin, fibronectin, N-cadherin (CDH2), or
EMT-TFs (Banias et al. 2020; Collisson et al. 2011; Gurzu et al. 2015; Okuda
et al. 2022; Raja gopal et al. 2021; Roseweir et al. 2019).
transitory status,”“transition phenotype,”“quasi-mesenchymal sub-
3 Molecular Pathways of EMT: General Data
Triggers of EMT are mechanical stress, inflammation, low pH, hypoxia,
neo-angiogenesis, immune response, alterations of the extracellular matrix (ECM),
and oncologic therapy, along with Wingless and INT-1 (Wnt), Notch, or transforming
50 S. Gurzu and I. Jung
https://t.me/med1917
growth factor β (TGF-β) signaling pathways (Dardare et al. 2021;Iedaetal.2019;Luu
2021; Vasarri et al. 2022).
• Wnt signaling pathway – The canonical Wnt is the most explored signaling
pathway of EMT. Activation of the Wnt signaling is defined by a trimeric
complex which includes 19 Wnt genes, the Wnt receptor Frizzled, and
low-density lipoprotein receptor-related protein 5/6 (LRP5/6). This complex is
synthesized in the cell membrane and plays a role in preventing the phosphoryla-
tion and degradation of β-catenin. The consequence of Wnt signaling activation is
membrane-to-cytoplasm and then to nucleus translocation of β-catenin with
further activation of other EMT-mediated genes, such as cyclin D1 and c-myc
(Clevers 2006; Gurzu et al. 2015, 2016; Qiu et al. 2022).
• Transcriptional EMT – β-catenin links E-cadherin to the cytos keleton (Roseweir
et al. 2019). Some TFs, such as SNAIL and ZEB, act as epithelial repressors
rather than mesenchymal promoters. Other TFs, such as Twist and PRRX (paired
Related Homeobox 1), are mesenchymal inducers. SNAIL and ZEB1/2 repress
transcription of E-cadherin, miR-200 family members, and other EMT-related
epithelial molecules such as Mucin-1, desmoplakin, claudins, and occludins.
SNAIL stimulates the activity of the mesenchymal genes fibronectin and
MMP9, while ZEB is known as a “metastasis promoter” that induces the expres-
sion of vimentin and N-cadherin. Twist induces transcription of SLUG, with
further activation of vimentin and N-cadherin (Dardare et al. 2021; Liu et al.
2021; Sadoughi et al. 2022). Independent of the organ or the type of malignancy,
EMT-TFs act as key upstream regulators of EMT (Yang et al. 2020).
• EMT and microRNAs (miRNAs) – The most common EMT-mediating miRNAs
are miR-200 and miR-34 (Gurzu et al. 2015, 2016; Dardare et al. 2021). The
mi-R200 family plays a role in the inhibition of the tumorigenesis and local
invasion or stimulates cell mobility and capacity for metastasis. It directly targets
the E-cadherin and exerts an inhibitory effect against EMT-TFs such as Twist,
ZEB1/2, SNAIL, and SLUG and influences DNA methylation. Members such as
miR-200, miR-203, sex-determining region Y-Box 2 (SOX2), and Kruppel-like
factor 1 (Klf4) play a double role, acting as both EMT and stemness modulators
(Ieda et al. 2019; Liao et al. 2021; Wang et al. 2017). Mi-R34a/b/c gene
expression is induced by activation of the TP53 gene and SNAIL downregulation.
The miR-34SNAIL axis influences the miR-200/ZEB axis, which plays a role in
maintaining the full epithelial phenotype (miR-200
(miR-200
medium
/ZEB
medium
), or mesenchymal phenotype (miR-200
high
/ZEB
low
), partial EMT
low
/ZEB
high
(Liao et al. 2021; Lu et al. 2013). The miR-151a controls contact between tumor
and endothelial cells, along with endothelial cell movement and angiogenesis,
through the upregulation of SLUG. It also regulates the expression of E-cadherin,
SLUG, and fibronectin (Liao et al. 2021). Other miRNAs involved in the EMT
phenomenon are mi-R7, mi-R9, miR-103/107, and miR-181, among others (Luu
2021; Okabe et al. 2015).
• EMT and HIPPO pathway – This pathway signaling is involved in controlling
cell shape and motility during physiologic and pathologic EMT through the
)
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