Abstract
Identification of a specific biomarker for cancer stem cells (CSCs) is of potential applications in the development of effective therapeutic strategies for renal cell carcinoma (RCC). In this study, both the RCC cell line 786-O and surgically removed clear cell RCC (ccRCC) tissues were implemented to grew as spheroids in serum-free medium supplemented with mitogens. This subpopulation possessed key characteristics defining CSCs. We also identified that surgically removed ccRCC tissues were heterogenic and there was a subpopulation of cells that was highly stained with rhodamine-123. Based on membrane-proteomic analyses, CD73 was identified as a candidate biomarker. We further found that CD73high cells were highly tumorigenic. As few as 100 CD73high cells were capable of forming xenograft tumors in non obese diabetic/severe combined immunodeficiency disease mice, whereas 1 × 105 CD73low cells did not initiate tumor formation. During successive culture, the CD73high population regenerated both CD73high and CD73low cells, whereas the CD73low population remained low expression level of CD73. Furthermore, the CD73high cells were more resistant to radiation and DNA-damaging agents than the CD73low cells, and expressed a panel of ‘stemness’ genes at a higher level than the CD73low cells. These findings suggest that a high level of CD73 expression is a bona fide biomarker of ccRCC stem-like cells. Future research will aim at the elucidation of the underlying mechanisms of CD73 in RCC development and the distinct aspects of ccRCC stem-like cells from other tumor types.
Highlights
Renal cell carcinoma (RCC) is a form of urologic tumor with a high metastatic index and a high rate of relapse [1]
We identified CD73 as a specific cell surface biomarker of clear cell RCC (ccRCC) cancer stem cells (CSCs) basing on our previous studies [26, 27] and discovered the association of CD73 intensive expression levels with ccRCC tumor formation by using siRNA technology
Katsuta et al [36] identified CSCs basing on ALDH activity in pancreatic neuroendocrine tumor clinical specimens and cell lines, and found that CD73 was overexpressed in ALDHhigh cells, and inhibition of CD73 significantly attenuated in vitro sphere formation and cell motility, as well as in vivo tumor growth for ALDHhigh cells
Summary
Renal cell carcinoma (RCC) is a form of urologic tumor with a high metastatic index and a high rate of relapse [1]. To date identification of CSC still holds mystery owing to a lack of specific stem cell biomarker for RCC. Bossolati et al [21] proposed that the CD105+ stem cell population in RCC may be derived from transformed CD105+ bone marrow-derived MSCs or mesenchymal/stromal cells [22], rather than from the kidney itself. This marker was found not suitable for use in all RCC cells to identify CSC [23,24,25]. It is of major interest to develop new approaches in order to identify new putative renal CSCs biomarker
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