Intratumoral heterogeneity, including in
clear cell renal cell carcinoma, is a potential cause of drug resistance and metastatic
cancer progression. We specified the heterogeneous population marked by
endoglin (also known as CD105) in a preclinical model of
clear cell renal cell carcinoma progression. Highly malignant derivatives of human
clear cell renal cell carcinoma OS-RC-2 cells were established as OS5Ks by serial orthotopic inoculation in our previous study. Expression of both ENG (encoding
endoglin)
mRNA and
protein were heterogeneously upregulated in OS5Ks, and the
endoglin-positive (ENG+ ) population exhibited growth dependency on
endoglin in anchorage-independent cultures. Despite the function of
endoglin as a type III receptor,
transforming growth factor β and bone morphogenetic protein-9 signaling were unlikely to contribute to the proliferative phenotype. Although
endoglin has been proposed as a marker for
renal cancer-initiating cells, the OS5K-3 ENG+ population did not enrich other reported
cancer-initiating cell markers or differentiate into the ENG- population. Mouse
tumor inoculation models revealed that the
tumor-forming capabilities of OS5K-3 ENG+ and ENG- cells in vivo were highly dependent on the microenvironment, with the renal microenvironment most preferable to ENG+ cells. In conclusion, the renal microenvironment, rather than the hypothesized ENG+ cell-centered hierarchy, maintains cellular heterogeneity in
clear cell renal cell carcinoma. Therefore, the effect of the microenvironment should be considered when evaluating the proliferative capability of
renal cancer cells in the experimental settings.