Abstract
Cancer stem cells (CSCs) typically have the capacity to evade chemotherapy and may be the principal source of metastases. CSCs for human pancreatic ductal carcinoma (PDAC) have been identified, but neither the metastatic potential nor the chemoresistance of these cells has been adequately evaluated. We have addressed these issues by examining side-population (SP) cells isolated from the Panc-1 and BxPC3 lines of human PDAC cells, the oncogenotypes of which differ. SP cells could be isolated from monolayers of Panc-1, but only from spheroids of BxPC3. Using orthotopic xenografts into the severely immunocompromised NSG mouse, we found that SP cells isolated from both cell lines produced tumors that were highly metastatic, in contrast to previous experience with PDAC cell lines. SP cells derived from both cell lines expressed the ABCG2 transporter, which was demonstrably responsible for the SP phenotype. SP cells gave rise to non-SP (NSP) cells in vitro and in vivo, a transition that was apparently due to posttranslational inhibition of the ABCG2 transporter. Twenty-two other lines of PDAC cells also expressed ABCG2. The sensitivity of PDAC SP cells to the vinca alkaloid vincristine could be greatly increased by verapamil, a general inhibitor of transporters. In contrast, verapamil had no effect on the killing of PDAC cells by gemcitabine, the current first-line therapeutic for PDAC. We conclude that the isolation of SP cells can be a convenient and effective tool for the study of PDAC CSCs; that CSCs may be the principal progenitors of metastasis by human PDAC; that the ABCG2 transporter is responsible for the SP phenotype in human PDAC cells, and may be a ubiquitous source of drug-resistance in PDAC, but does not confer resistance to gemcitabine; and that inhibition of ABCG2 might offer a useful adjunct in a therapeutic attack on the CSCs of PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal of human malignancies
Our results suggest that the Cancer stem cells (CSCs) included in PDAC SP fractions may be the progenitors of metastasis, and demonstrate that the transporter ABCG2 is a widespread, if not ubiquitous source of potential drug resistance in PDAC, but is not responsible for resistance to the first-line therapeutic gemcitabine
The SP phenotype in monolayers and spheroid cultures of human PDAC cell lines We first compared the SP content of two human PDAC cell lines, the oncogenotypes of which differ: Panc-1 cells, which contain an oncogenic KRAS mutation and a loss of function TP53 mutation; and BxPC3 cells, which contain a loss of function mutation in SMAD4 and CDKN2A genes [12]
Summary
Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal of human malignancies. Despite aggressive surgery and use of contemporary neoadjuvant and adjuvant chemotherapy, the overall 5-year survival is approximately 10–26% depending on the severity of dissemination (cancer.org and cancer.net). Chemotherapeutic agents such as gemcitabine reduce primary tumor burden, but fail to eliminate metastatic liver disease, the major cause of mortality in PDAC. Our results suggest that the CSCs included in PDAC SP fractions may be the progenitors of metastasis, and demonstrate that the transporter ABCG2 is a widespread, if not ubiquitous source of potential drug resistance in PDAC, but is not responsible for resistance to the first-line therapeutic gemcitabine. SP cells derived from human PDAC cell lines offer a convenient means by which to explore the mechanisms of tumorigenesis, metastasis and drug resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
