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Page 4 of 15 Safa. J Cancer Metastasis Treat 2020;6:36 I http://dx.doi.org/10.20517/2394-4722.2020.55

cells then proliferate to initiate and sustain tumor development and progression. Therefore, this model
indicates that in the clinical setting, eradication of CSCs may prevent tumor recurrence.

The second model is stochastic model in which every cell within a tumor is capable of promoting tumor
[21]
initiation and progression . Furthermore, the heterogeneity within the tumor cell population is due to
[21]
accumulated genetic mutations . These CSCs models may express plasticity in the presence of tumor
microenvironmental stimuli including oxidative and nutritional stress, low oxygen tension, and cytotoxic
drugs to which the tumor can be subjected to [16,21-25] . These factors influence the inter-conversion of a non-
CSC population to a CSCs [21,22] [Figure 1]. Previous studies have demonstrated that extracellular matrix
components like collagen can influence clonogenic tumor growth, tumor initiation, and invasion of PDAC
due to activation of the FAK signaling pathway [26,27] . Additionally, a hypoxic tumor microenvironment is
[8]
known to promote the conversion of non-CSC to CSC populations in PDAC . These data corroborate with
observations that the CSCs within the tumor are the cells’ survival advantage, capable of living under stress
conditions and to express resistance to cancer therapies.

Accumulated evidence obtained through large-scale genomic studies and single cell RNA sequencing
analysis has indicated the existence of CSCs in hematological malignancies and solid tumors including
PDAC, breast cancer, malignant glioma, prostate cancer, non-small cell lung cancer, colorectal cancer, and
hepatocellular carcinoma [28-37] . Substantial in vitro and in vivo studies have provided convincing evidence
supporting CSCs as the critical cause of cancer initiation, growth, metastasis, and treatment resistance in
cancers [20-24] . CSCs were also found to exhibit characteristics of an EMT, a process known to enable cancer
cell dissemination and metastasis to other organs [35-41] . Additionally, significant and convincing evidence
shows that inducing EMT in cancer cells confers cancer stem cell-like characteristics, which promote their
metastatic and tumor-initiating abilities [37,38] . While PCSCs self-renewal is essential in the progression,
migration, and metastasis of PDAC, clonal evolution and plasticity of PCSCs within PDAC tumors are
[47]
not well understood [38-46] . In this regard, Ball et al. showed that long-term progression of PDAC in
serial xenotransplantation happens by a succession of transiently active PCSCs producing tumor cells in
a temporally restricted manner with little overlap between subsequent xenograft generations. Therefore,
the clonal PCSC activity in PDAC differs from the continuous activity of limited numbers of self-renewing
PCSCs with a defined and rigid cellular hierarchy. Indeed, PCSCs heterogeneity and plasticity make
[24]
therapeutic targeting of PCSCs very difficult and challenging . Furthermore, several investigations have
suggested that CSCs exist in dynamic equilibrium with more differentiated cancer cells via bi-directional
regeneration or interconversion of differentiated cancer cells to CSCs, caused by various factors [23,24,48,49,50] .

A distinct characteristic of PDAC is its desmoplasia, consisting of a significant amount of cancer-associated
fibroblasts (CAFs) and a very dense fibrotic stroma [Figure 2]. The CAFs are pro-inflammatory due to
[51]
activation of several signaling factors including nuclear factor kappa B (NF-κB), signal transducer and
activator of transcription (STAT)-1 and STAT-3, and transforming growth factor (TGF)-β/SMAD [51-54] .
These signaling factors cooperate in active cross-talk with cancer cells through paracrine signaling factors
including chemokines, insulin-like growth factor, and proteases [52-56] . Furthermore, several pro-stemness
paracrine factors are secreted by distinct CAFs [56-62] and support the self-renewal and the stemness
properties of initial PCSCs in tumors or promote the conversion of cancer cells into PCSCs . Additionally,
[63]
chemotherapy (e.g., GEM), can affect CAFs in PDAC, which then acquire a senescence-like secretory
phenotype and increase the production of pro-stemness chemokines which enhance tumorstemness and
[13]
aggressiveness of PDAC after therapy . It is known that CAFs consist of a heterogeneous population, with
[64]
specific functions within tumors and in the process of metastasis .
Interestingly, besides CAFs, the PDAC stroma also contains bone marrow-derived mesenchymal stem
[65]
cells (MSCs) . The MSCs significantly contribute to tumor progression and promote cancer stemness