Possible role of mural cell-covered mature blood vessels in inducing drug resistance in cancer-initiating cells.

ABSTRACT

Cancer recurrence has been suggested to be induced by residual cancer-initiating cells (CICs) or cancer stem cells (CSCs) after chemotherapy. Moreover, it is possible that CICs/CSCs acquire more aggressive behavior after therapy as shown by invasion and metastasis. In the cancer microenvironment, CICs/CSCs may localize in a specific area, the so-called stem cell niche, and isolation of this niche is important to elucidate the molecular mechanism of how CICs/CSCs acquire malignancy. We analyzed whether CICs acquire drug resistance after cancer drug treatment in a tumor cell allograft model in which we could identify and isolate living CICs by detecting a higher level of transcriptional activity of the PSF1 gene promoter. In our models using Lewis lung carcinoma (LLC) mouse lung cancer and colon26 mouse colon cancer cell lines, we found that CICs in both tumors acquired drug resistance after cancer drug treatment. Interestingly, response to the anticancer drug was quite different between LLC and colon26 original tumors (ie, the proportion of CICs in LLC tumors increased but in colon26 tumors the proportion decreased). We found that CICs frequently localized near mature blood vessels in which endothelial cells were covered with mural cells and that the incidence of mature blood vessels in LLC tumors was four times higher than in colon26 tumors. These results suggest a relationship between mature blood vessels and CIC drug resistance.