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Safa. J Cancer Metastasis Treat 2020;6:36 I http://dx.doi.org/10.20517/2394-4722.2020.55 Page 9 of 15

RELEVANCE OF PCSCS IN PDAC DEVELOPMENT
The foregoing discussion provided ample evidence related to the role of PCSCs in carcinogenesis, growth,
metastasis, EMT, and chemoresistance in PDAC. The above aberrant signaling pathways govern cancer
cell plasticity, which give rise to tumor cellular heterogeneity, EMT, therapeutic resistance, and recurrence
through clonal replacement and activation of dormant CSCs in PDAC as well as other cancers [80,88,153,154] .
PDAC is characterized by molecular alterations regulating PCSCs, including mutations of K-RAS, TP53,
transforming growth factor-β, Hedgehog, WNT and NOTCH signaling pathways. Many genetic alterations
[155]
[156]
were defined in PDAC such as earlier events including K-ras point mutation , INK4a/Arf deficiency ,
the epidermal growth factor receptor (EGFR) over-expression, gene amplification and HER2/neu over-
expression and TP53, transforming growth factor-β, Hedgehog, WNT and NOTCH signaling pathways
maintain PCSCs. Furthermore, the roles of EGFR, Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTORC1/
GSK-3 pathways in PCSCs and their relationship to PDAC tumor initiation, EMT, malignant development
has been investigated [157] . As discussed above, recent advances in the role of EMT and PCSCs in tumor
progression, metastasis, chemo-resistance, and the mechanisms integrated with aberrant biochemical
signals and the underlying pathways have been surveyed in this review. Furthermore, WNT signaling
cascades cross-interaction with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate
expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49) [40,153-158] .
Aberrant canonical and non-canonical WNT signaling in human malignancies, including PDAC are
[158]
involved in CSC survival, bulk-tumor expansion and invasion/metastasis . Despite these advances, the
significance of these regulatory pathways to the major risk factors for pancreatic cancer including diabetes,
smoking, alcoholism, and psychological stress remain to be studied in detail in the future.

CONCLUSION
Substantial evidence has demonstrated that CSCs including PCSCs trigger the characteristic hallmarks of
various tumors including self-renewal, invasiveness, tumor recurrence, resistance, metastasis, and resistance
to chemotherapeutic agents and radiotherapy. Moreover, the bulk of cancer cell population displays
plasticity in most tumors including PDAC, which enables them to dynamically inter-convert between non-
CSC and CSC states. Another critically important and intriguing characteristic of CSCs including PCSCs
is their capacity to disseminate, migrate, and form metastatic lesions expressing resistance to therapies.
In some tumors including PDAC, this plasticity has been associated with the EMT process. Furthermore,
cytokines and growth factors, provided by the CSC niche containing CAFs, MSCs, endothelial cells and
specific immune cells, and hypoxia, trigger transcriptional and epigenetic regulations leading to the
induction of plasticity, stemness, EMT, and metastasis. Taken together, the foregoing discussion in this
review provides a better understanding of the molecular mechanisms underlying these behaviours in CSCs,
including PCSCs, and may lead to the identification of specific therapeutics and novel strategies to prevent
EMT and metastasis, trigger CSC growth inhibition and cell death, and increase the sensitivity of tumors
including PDAC to cancer therapeutics.

DECLARATIONS
Acknowledgments
I would like to thank Dr. Mary D. Kraeszig for her excellent editorial assistance.

Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.