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Safa. J Cancer Metastasis Treat 2020;6:36 I http://dx.doi.org/10.20517/2394-4722.2020.55 Page 7 of 15

hedgehog, and the Desert hedgehog homolog [90,91] . It has been shown that one of these three ligands binds
to the receptor Patched1 and releases the protein smoothened (Smo) [63,89,90] . Smo triggers the activation
[92]
of downstream target genes such as the GLI family of transcription factors and PTCH. Yamasaki et al.
have reported that a nine-fold increase in Shh mRNA levels has been found in CD44+CD24+ESA+ PCSCs
when compared to the bulk of unsorted pancreatic cancer cells. Inhibition of Hedgehog signaling by Smo
suppression has been shown to reverse EMT and suppress the invasion of pancreatic cancer cells [93-95] .

Substantial evidence has shown that Wnt/β-catenin signaling is involved in cell proliferation, migration,
apoptosis, differentiation, and self-renewal of CSCs in several types of cancers [96-98] . Dysregulation of the
Wnt/β-catenin signaling pathway is associated with chemotherapy resistance in PDAC, and significant
evidence suggests that nuclear β-catenin plays an essential role in EMT [97,99] . The Wnt signaling pathway
also plays a significant role in regulating PCSCs [99,100] . Additionally, Wnt signals significantly regulate CSCs
in solid tumors including PDAC in the niche environments [98,101,102] . Because of dysregulation in the Wnt
signaling pathway, PCSCs are significantly susceptible to Wnt signal inhibitors [98,99,103,104] . Hence, Wnt in the
PDAC niche of PCSCs offers a critical therapeutic target in PDAC.

A significantly activated signaling pathway in CSCs is the NF-κB pathway; its inhibition triggers the loss of
CSC properties [105,106] . Interestingly, the CCL21/CCR7 axis known to facilitate metastasis to distant organs
promoted the metastasis and survival of CD133+ PCSCs and regulated their metastasis by modulating
EMT and the Erk/NF-κB pathway [107] . Moreover, NF-κB-mediated invasiveness in CD133+ PCSCs is
[108]
regulated by autocrine and paracrine activation of IL1 signaling . Furthermore, the crucial role of PCSCs
in developing resistance to gemcitabine treatment through the Nox/ROS/NF-κB/STAT3 signaling pathway
[109]
was demonstrated by Zhang et al. . Significantly, therapeutic targeting of the FGFR1/Src/NF-κB signaling
axis has been shown to inhibit PCSCs and oncogenicity [110] . These findings will provide new directions
for identifying potential targets that regulate NF-κB-mediated invasiveness of PCSCs and can be used to
sensitize pancreatic cells to chemotherapy. In addition to the above major signaling pathways, the mTOR
pathway has been shown to be essential for the self-renewal of PCSCs [111,112] .

Like other cancers, miRNA expression is dysregulated in PDAC [113,114] . Two classes of miRNAs play crucial
[117]
roles in cancer cells, oncogenic miRNAs and tumor suppressor miRNAs [23,115,116] . Jung et al. demonstrated
that PCSCs exhibit differential expression of miR-99a, miR-100, miR-125b, miR-192, and miR-429
compared with controls. Another study reported the loss of miR-34 in CD44+CD133+ PCSCs, while miR-34
restoration led to the inhibition of spheroidal growth of CSCs and tumor formation [118] . Wellner et al. [119]
showed that miR-200c, miR-203, and miR-183 down regulate stem cell factors and described a regulatory
feedback loop between miRNAs and CSC in pancreatic cancer. Moreover, they demonstrated that ZEB1
represses expression of stemness-inhibiting miR-203 and that ZEB1 links EMT activation and stemness
maintenance by suppressing stemness-inhibiting miRNA expression, and therefore promotes mobile
migrating CSCs. These authors concluded that targeting the ZEB1-miR-200 feedback loop may potentially
be a valid and promising therapeutic approach for PDAC.

While this review discusses abnormalities in the intracellular signaling pathways known to be involved
in carcinogenesis, growth, metastasis, EMT, and chemoresistance in PDAC, the significance of these
regulatory pathways to the major risk factors for pancreatic cancer including diabetes, smoking, alcoholism,
and psychological stress remains to be discovered.

EPITHELIAL-MESENCHYMAL (EMT) TRANSITION
A small number of cancer cells in the primary tumor are capable of undergoing EMT, which critically
promotes tumor invasion and metastatic dissemination [120,121] in human cancer patients including
PDAC [40,41,122] , as well as in PCSCs and circulating tumor cells [122-124] . Metastatic seeding is frequently