Acquisition of anticancer drug resistance is partially associated with cancer stemness in human colon cancer cells.

Colorectal cancer (CRC) is one of the most aggressive cancers worldwide. Several anticancer agents are available to treat CRC, but eventually cancer relapse occurs. One major cause of chemotherapy failure is the emergence of drug-resistant tumor cells, suspected to originate from the stem cell compartment. The aim of this study was to ask whether drug resistance was associated with the acquisition of stem cell-like properties. We isolated drug-resistant derivatives of two human CRC cell lines, HT29 and HCT116, using two anticancer drugs with distinct modes of action, oxaliplatin and docetaxel. HT29 cells resistant to oxaliplatin and both HT29 and HCT116 cells resistant to docetaxel were characterized for their expression of genes potentially involved in drug resistance, cell growth and cell division, and by surveying stem cell-like phenotypic traits, including marker genes, the ability to repair cell-wound and to form colonospheres. Among the genes involved in platinum or taxane resistance (MDR1, ABCG2, MRP2 or ATP7B), MDR1 was uniquely overexpressed in all the resistant cells. An increase in the cyclin-dependent kinase inhibitor p21, in cyclin D1 and in CD26, CD166 cancer stem cell markers, was noted in the resistant cells, together with a higher ability to form larger and more abundant colonospheres. However, many phenotypic traits were selectively altered in either HT29- or in HCT116-resistant cells. Expression of EPHB2, ITGβ-1 or Myc was specifically increased in the HT29-resistant cells, whereas only HCT116-resistant cells efficiently repaired cell- wounds. Taken together, our results show that human CRC cells selected for their resistance to anticancer drugs displayed a few stem cell characteristics, a small fraction of which was shared between cell lines. The occurrence of marked phenotypic differences between HT29- and HCT116-drug resistant cells indicates that the acquired resistance depends mostly on the parental cell characteristics, rather than on the drug type used.