Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells

At least some cancer stem cells (CSCs) display intrinsic drug resistance that may thwart eradication of a malignancy by chemotherapy. We explored the genesis of such resistance by studying mouse models of liver cancer driven by either MYC or the combination of oncogenic forms of activation of v‐akt...

Full description

Saved in:
Bibliographic Details
Published in:Hepatology (Baltimore, Md.) Md.), 2012-10, Vol.56 (4), p.1331-1341
Main Authors: Chow, Edward Kai-Hua, Fan, Ling-ling, Chen, Xin, Bishop, J. Michael
Format: Article
Language:English
Subjects:
Animals
ATP-Binding Cassette Transporters - genetics
ATP-Binding Cassette Transporters - metabolism
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Biological and medical sciences
Blotting, Western
Cell Differentiation - drug effects
Cell Differentiation - genetics
Cell Line, Tumor
Cell Survival
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - pathology
Drug resistance
Drug Resistance, Neoplasm
Flow Cytometry
Gastroenterology. Liver. Pancreas. Abdomen
Hepatology
Humans
Hydrocortisone - analogs & derivatives
Hydrocortisone - pharmacology
Immunohistochemistry
Liver cancer
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mice
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - metabolism
Real-Time Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Sensitivity and Specificity
Stem cells
Transplantation, Homologous
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:At least some cancer stem cells (CSCs) display intrinsic drug resistance that may thwart eradication of a malignancy by chemotherapy. We explored the genesis of such resistance by studying mouse models of liver cancer driven by either MYC or the combination of oncogenic forms of activation of v‐akt murine thymoma viral oncogene homolog (AKT) and NRAS. A common manifestation of chemoresistance in CSCs is efflux of the DNA‐binding dye Hoechst 33342. We found that only the MYC‐driven tumors contained a subset of cells that efflux Hoechst 33342. This “side population” (SP) was enriched for CSCs when compared to non‐SP tumor cells and exhibited markers of hepatic progenitor cells. The SP cells could differentiate into non‐SP tumor cells, with coordinate loss of chemoresistance, progenitor markers, and the enrichment for CSCs. In contrast, non‐SP cells did not give rise to SP cells. Exclusion of Hoechst 33342 is mediated by ATP binding cassette drug transporter proteins that also contribute to chemoresistance in cancer. We found that the multidrug resistance gene 1 (MDR1) transporter was responsible for the efflux of Hoechst from SP cells in our MYC‐driven model. Accordingly, SP cells and their tumor‐initiating subset were more resistant than non‐SP cells to chemotherapeutics that are effluxed by MDR1. Conclusion: The oncogenotype of a tumor can promote a specific mechanism of chemoresistance that can contribute to the survival of hepatic CSCs. Under circumstances that promote differentiation of CSCs into more mature tumor cells, the chemoresistance can be quickly lost. Elucidation of the mechanisms that govern chemoresistance in these mouse models may illuminate the genesis of chemoresistance in human liver cancer. (HEPATOLOGY 2012)
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.25776