Page 441 - Read Online

Page 8 of 15 Safa. J Cancer Metastasis Treat 2020;6:36 I http://dx.doi.org/10.20517/2394-4722.2020.55

initiated before diagnosis of the primary tumor in cancer patients, and disseminated tumor cells can remain
dormant in secondary sites before forming metastatic tumors [125-128] . The majority of pancreatic cancer-
related mortality is due to metastatic disease.

EMT is critical for this rapid metastatic tumor progression, and it is a multi-stage trans-differentiation
cellular process that allows epithelial cells to undergo multiple biochemical changes to gain a mesenchymal
phenotype [128,129] . During this process, epithelial cells lose their epithelial markers (such as E-cadherin,
occludin, claudin, and laminin 1) and gain mesenchymal markers such as N-cadherin, vimentin, and
[130]
fibronectin . These changes are caused by the activation of specific EMT transcriptional programs. Some
transcriptional regulators such as TWIST, SNAI1, SNAI2, ZEB1, and ZEB2 repress E-cadherin expression,
while others play roles in promoting the expression markers of mesenchymal differentiation markers
including N- and/or R-cadherin and vimentin, as well as cellular matrix and focal adhesion proteins
involved in promoting motility [124,131,132] . Furthermore, EMT is associated with enhanced activity of matrix
metalloproteinases [124,131,132] .

After the invading cancer cells reach metastatic sites, they undergo the reverse EMT process, MET, and
adapt to proliferating in the invaded tissue microenvironment [133-136] . Since metastasis is the major cause
of cancer mortality, a detailed understanding of EMT could potentially lead to more effective therapeutic
strategies for PDAC.

METASTASIS AND CSC POPULATION
Emerging evidence indicates that as the tumor microenvironment opts for a CSC population, these cells
[137]
can also metastasize and initiate cells that participate in metastasis . Several cellular signaling pathways
regulate the self-renewal capacity of CSCs and control their inter-conversion between the dormantstate
and subsequent re-activation upon metastasis [137-140] . These re-activated cells are nurtured by extracellular
niches, which crosstalk and support positive cytoprotective signals such as Wnt and Notch [96,141-145] . As
[15]
Mu et al. described, tumor progression is driven by the cross-interaction between tumor cells, primarily
CSCs and surrounding stromal cells as well as distant organs, in which tumor-derived extracellular vesicles
[15]
(TEX) play a major and important role. Mu et al. report that the PCSC markers Tspan8, alpha6beta4,
CD44v6, CXCR4, LRP5/6, LRG5, claudin, EpCAM, and CD133 participate in the metastatic cascade at
different stages, often via PDAC TEX. In PDAC tumors, the PCSC population shows over-expression of
genes involved in EMT and the distinct ability to metastasize and colonize distant tissues.

CD44 is overexpressed in CSCs, frequently shows alternative spliced variants, and plays a role in cancer
development and progression. The CD44 major ligand, hyaluronan, binds to and activates CD44 resulting
in stimulation of several cell signaling pathways that trigger cell proliferation, survival, and increased
cellular motility [146] . Cancer cells that undergo an EMT acquire properties of CSC and show enhanced
[43]
CD44 expression . CD44 consists of two isoforms, standard (CD44s) and CD44 variants(CD44v), but the
different functional roles of these variants are not well known. CD44v may play a role in regulating EMT
and the plasticity of cancer cells [146-148] . Moreover, evidence shows that CD44 activates the MT1-MMP-
SNAI1 axis to promote metastasis in PDAC, and CD133 activates the IL1β-NF-κB pathway leading to
invasiveness and metastasis [108,149] . Interestingly, Zhang et al. [107] demonstrated that the CCR7–CCL21 axis in
PCSCs mediates EMT phenotype via activation of ERK/NF-κB signaling pathways. Additionally, it has been
shown that the Hh pathway is implicated in playing a role in EMT in PCSCs. Inhibition of Hh signaling in
[150]
CSCs reduced self-renewal, EMT tumorgenesis, invasiveness, drug resistance, and metastasis . Activation
of the PI3K/AKT/mTOR pathway [151] alone or in combination with the Hh pathway [152] in PCSCs also
increased metastasis in these cells.