The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer

Abstract

The mechanical properties of epithelial to mesenchymal transition (EMT) and a pancreatic cancer subpopulation with stem cell properties have been increasingly recognized as potent modulators of the effective of therapy. In particular, pancreatic cancer stem cells (PCSCs) are functionally important during tumor relapse and therapy resistance. In this review we have surveyed recent advances in the role of EMT and PCSCs in tumor progression, metastasis and treatment resistance, and the mechanisms of integrated with biochemical signals and the underlying pathways involved in treatment resistance of pancreatic cancer. These findings highlight the importance of confirming stem-cells markers and complex molecular signaling pathways controlling EMT and cancer stem cells in pancreatic cancer during tumor formation, progression, and response to therapy.

Keywords: Cancer stem cell; Epithelial-to-mesenchymal transition; Pancreatic cancer; Resistance.

Fig. 1

The Core Regulatory Machinery of EMT. Tumorigenesis activate EMT-promoting transcription factors of the TWIST, SNAIL and ZEB families through pathways known to play critical roles in both embryogenesis and tumour development, including the WNT, NOTCH, TGF-β, RAS and NF-κB cascades. MicroRNAs suppress production of these transcription factors as well as multiple markers defining the epithelial or mesenchymal characteristics. These microRNAs can therefore promote EMT (blue) or repress EMT and enhance MET programs (orange)

Fig. 2

Contribution of EMT and related signaling to PCSCs. a PCSCs with tumor-initiating capability can be identified by the expression of a distinct set of marker proteins, such as CD44, CD24, CD133 or c-Met. These CSCs can self-renew and differentiate into a number of cell types to generate the heterogeneity of the originating tumor. Inducers of EMT such as TGF-β, HH or Notch cause cells to acquire a CD44+ CD24 + ESA+ phenotype, reminiscent of PCSCs. b The PCSC cell surface markers CD24, and CD44 likely promote cell–cell interactions, the c-Met respond to secreted ligands to active developmental pathways, such as β-catenin, Notch and Stat3 in PCSCs. These pathways stimulate the expression of genes that regulate stem-cell properties, such as self-renewal