Gastroenterology

Gastroenterology

Volume 144, Issue 6, May 2013, Pages 1241-1248
Gastroenterology

Biology of the Pancreas
Review
Biology and Clinical Applications of Pancreatic Cancer Stem Cells

https://doi.org/10.1053/j.gastro.2013.01.072Get rights and content

Pancreatic ductal adenocarcinomas comprise a hierarchy of tumor cells that develop around a population of cancer stem cells. The cancer stem cells promote tumor growth and progression through a number of mechanisms, including differentiation into bulk tumor cells, metastasis, alteration of adjacent stromal cells, and evasion of conventional therapies. As with other cancer stem cells, pancreatic cancer stem cells (PCSCs) can be distinguished from bulk tumor cells based on their expression of unique surface markers, abilities to form spheres under nonadherent conditions and tumors in mice, and self-renewal and differentiation capacities. We review the markers used to identify PCSCs, the signaling pathways that regulate PCSC functions, the complex interactions between PCSCs and stromal cells, and approaches to therapeutically target PCSCs and improve treatment of patients with pancreatic cancer.

Section snippets

What are CSCs?

Although cancer cells have unrestrained proliferative capabilities and are resistant to apoptotic cues,1 only a limited number of cancer cells are actually capable of establishing tumors in immunodeficient mice. Built off of these observations, a cellular hierarchy was identified in hematopoietic malignancies, such as acute myelogenous leukemia and chronic myelogenous leukemia.2, 3 In these malignancies, a minority of cells identified based on specific cell-surface molecules (the CSCs), can

CD44, CD24, and ESA

The first population of PCSCs was described in 2007 by Li et al.7 Using tumor xenografts grown from patients' cancer cells, the authors studied the cell-surface markers CD44, CD24, and ESA, based on the CSC properties reported for CD44+/ESA+/CD24low cells from breast tumors.5 Sorting cells by single-, double-, or triple-positive or -negative status, Li et al found that CD44+/CD24+/ESA+ cells (which comprised 0.2%–0.8% of the cells in 10 tumors studied) were far more tumorigenic than other

Other Markers

Although the markers described are extracellular proteins that can be used in cell sorting, some internal markers and properties of PCSCs have been reported. A high level of aldehyde dehydrogenase 1 (ALDH1) activity has been associated with CSC function. A marker of normal and malignant breast stem cells33 and lung CSC,34 ALDH1 was associated with highly tumorigenic PDAC cells, regardless of CD133 status.35 Like c-Met and CD44, ALDH1 could be a functional marker of PCSCs. Studies suggest that

Signaling Pathways

Several markers have been used to define PCSCs, but the signaling pathways that regulate these markers have not been fully defined. Almost all PDACs contain activating mutations in K-Ras and have lost p16INK4A, and about half contain mutations in the tumor suppressors SMAD4 and p53.41 Stable genetic alterations might determine the properties (including surface marker profiles) of PCSCs, as observed in murine models for lung cancer,42 and could account for some of the differences observed in

Tumor Microenvironment

The tumor microenvironment comprises not only cancer cells that interact with each other, but also surrounding pancreatic cells, such as stellate cells, pan-endothelial cells, and infiltrating immune cells. These interactions promote tumor growth and progression, maintain the population of CSCs, and alter the stromal compartment to reduce the effects of chemotherapy. Although there are many cellular interactions involved in development of pancreatic cancer, we focus on interactions between

Targeting PCSCs

Most therapies for pancreatic cancer are aimed at debulking tumors, which comprise mostly differentiated tumor cells. These therapies, however, do not affect PCSCs, which can then re-establish tumors after treatment. Additionally, it is unclear whether some bulk tumor cells can de-differentiate into CSCs, similar to breast cancer cells during the EMT.52 New approaches are therefore needed to debulk existing tumors and eliminate PCSCs, to prevent relapse. Although no reagents have been tested to

Conclusions

The discovery of CSCs has introduced a number of interesting and important concepts to cancer biology, namely that only a select subset of cancer cells is tumorigenic, and that these cells are more resilient than bulk tumor cells, so they can re-establish tumors after treatment. As such, CSCs are one of the best targets for cancer treatment. However, we need to improve our understanding of PCSCs and pancreatic cancer biology to develop optimal treatment regimens. It is not clear how PCSCs

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    Conflicts of interest The authors disclose no conflicts.

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