Tumor initiating cells in pancreatic cancer: A critical view

Emerging evidence points to the existence of pancreatic cancer stem cells (CSC) as the culprit in the initiation, maintenance, metastasis, and treatment resistance of pancreatic cancer. The existence of such a cell population would have an important impact on the design of novel therapies against this devastating disease. However, no in vivo validation or rebuttal of the pancreatic CSC hypothesis exists. Major backlashes in the discussion on CSC are firstly, the confusion between the terms CSC and cell of origin of pancreatic ductal adenocarcinoma (PDAC), secondly the ambiguity of the cell of origin itself and thirdly, the fact that the CSC hypothesis is based on cell sorting and xenografting experiments; the latter of which often precludes solid conclusions because of the lack of a natural microenvironment and differences in drug delivery. Nonetheless, recent studies in other cancers partially support the CSC hypothesis by demonstrating a link between epithelial-to-mesenchymal transdifferentiation/transition (EMT) and CSC properties. Such a link is again open to dispute as EMT is a reversible process which is highly dependent on major oncogenic pathways in PDAC [e.g. K-Ras, transforming growth factor-β (TGF-β)] rather than on presumed cancer stem cell pathways. Hence, the available evidence does not robustly support the CSC concept in PDAC and a thorough validation of this hypothesis in well-defined genetically engineered mouse models of pancreatic cancer is required.