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Page 2 of 15 Safa. J Cancer Metastasis Treat 2020;6:36 I http://dx.doi.org/10.20517/2394-4722.2020.55

are summarised. This information may provide potential therapeutic strategies to prevent EMT and trigger CSC
growth inhibition and cell death.

Keywords: Pancreatic cancer, cancer stem cells, epithelial-mesenchymal transition, metastasis, drug resistance

INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the world
[1]
with a low probability of early diagnosis . KRAS, CDKN2A, TP53, and SMAD4 are frequently mutated
genes that define the genetic landscape of PDAC. PDAC is one of the most lethal cancers due to its high
[2,3]
metastatic potential and delayed detection . The median survival time following diagnosis remains at
[1-3]
less than 6 months, with an overall survival rate of less than 4% . Gemcitabine (GEM) treatment has
[4-6]
only increased the median survival of PDAC patients from 3-4 months to 6-7 months . Recent evidence
shows that using FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) in PDAC patients was
more effective than GEM as it demonstrated longer survival in pancreatic cancer patients (11.1 months vs.
[6,7]
6.8 months) . Resistance to apoptosis is a common feature of PDAC and a major reason why this
[8]
devastating disease is resistant to various treatment strategies including GEM and FOLFIRINOX . Another
major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer
stem cells (PCSCs) or cancer-initiating cells in pancreatic tumors; PCSCs may represent sub-populations
of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth [9-13] . The
PCSCs express a wide array of markers such as CD44, CD24, epithelial specific antigen (ESA), CD133,
c-mesenchymal to epithelial transition (c-MET), CXCR4, PD2/Paf1, and ALDH1 [14-17] . These cells are
capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted
into mice [13-17] . Therefore, the presence of PCSCs has prognostic relevance and influences the therapeutic
response of tumors.

Metastasis is the major cause of high PDAC mortality. As Mu et al. recently described, tumor
[15]
progression is driven by the cross-interaction between tumor cells, primarily cancer stem cells (CSCs) (or
cancer-initiating cells) and surrounding stromal cells as well as distant organs, in which tumor-derived
[15]
extracellular vesicles (TEX) play a major and important role. Mu et al. report that the PCSC markers
Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, participate in a
metastatic cascade at various steps, often via PDAC CSC-TEX.

In this review, the models of CSCs in PDAC and their cell-intrinsic and - extrinsic regulatory pathways
are described. Insights into the heterogeneity of cell sub-populations of PDAC, plasticity, cancer stemness,
and the involvement of epithelial-mesenchymal transition (EMT), which participates in metastasis are
highlighted. These properties may account for the unsuccessful clinical trials that test therapeutics designed
to directly target CSCs.

PCSCS
[18]
CSCs from epithelial tissues were first identified in breast cancer in 2003 by Al-Hajj et al. , who found
that a distinct sub-population of cancer cells expressing CD44+CD24-/low ESA+ develop into tumors
[19]
in immunodeficient mice. In PDAC, the presence of CSCs was reported in 2007 by Shah et al. who
demonstrated that CD44+CD24+ESA+ cells exhibit high tumorigenic potential.

Two models are proposed to describe the origin of CSCs [Figure 1] and their role in tumorigenesis [20-22] .
The first one is the hierarchical model in which the CSCs represent a small distinct sub-population within
the tumor with capacity for self-renewals and also the ability to differentiate into progeny cells; the progeny