Pancreatic Cancer and Therapy: Role and Regulation of Cancer Stem Cells

Abstract

Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-β, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.

Keywords: MASTL; chemoresistance; pancreatic cancer.

Figure 1

A schematic representation of distinct cancer stem cell populations in pancreatic cancer (PC). ATP-binding cassette (ABC); Epithelial cell adhesion molecule (EpCAM); Aldehyde dehydrogenase 1 (ALDH1); C-X-C Motif Chemokine Receptor 4 (CXCR4); Doublecortin-like kinase 1 (Dclk1).

Figure 2

A schematic representation of major signaling cascades in normal stem cells vs. pancreatic cancer stem cells and their therapeutic strategies. Jagged1,2 (JAG1,2); Notch intracellular domain (NICD); Low-density lipoprotein receptor-related protein 5/6 (LRP5/6); Dishevelled (Dvl); Adenomatous polyposis coli (APC); T-cell factor/lymphoid enhancer factor (TCF/LEF); Hedgehog (Hh).