Abstract
Compared to normal kidney, renal clear cell carcinomas (ccRCC) contain increased numbers of interstitial, non-hematopoietic CD133+cells that express stem cell markers and exhibit low rates of proliferation. These cells fail to form tumors upon transplantation but support tumor formation by differentiated malignant cells. We hypothesized that killing of ccRCC CD133+ (RCCCD133+) cells by cytotoxic agents might be enhanced by inducing them to divide. Since tumor necrosis factor-alpha (TNF), signalling through TNFR2, induces proliferation of malignant renal tubular epithelial cells, we investigated whether TNFR2 might similarly affect RCCCD133+cells. We compared treating organ cultures of ccRCC vs adjacent nontumour kidney (NK) and RCCCD133+ vs NK CD133+ (NKCD133+) cell cultures with wild-type TNF (wtTNF) or TNF muteins selective for TNFR1 (R1TNF) or TNFR2 (R2TNF). In organ cultures, R2TNF increased expression of TNFR2 and promoted cell cycle entry of both RCCCD133+ and NKCD133+ but effects were greater in RCCCD133+. In contrast, R1TNF increased TNFR1 expression and promoted cell death. Importantly, cyclophosphamide triggered much more cell death in RCCCD133+ and NKCD133+cells pre-treated with R2TNF as compared to untreated controls. We conclude that selective engagement of TNFR2 by TNF can drives RCCCD133+ proliferation and thereby increase sensitivity to cell cycle-dependent cytotoxicity.
Highlights
Renal cell carcinoma (RCC) accounts for 85% of renal cancers, of which clear cell RCC is the most prevalent form [1,2,3,4,5]
Since tumor necrosis factor-alpha (TNF), signalling through TNFR2, induces proliferation of malignant renal tubular epithelial cells, we investigated whether TNFR2 might affect RCCCD133+cells
Since the low rate of proliferation of RCCCD133+cells may be protecting them from chemotherapy, we have investigated the effects of TNFR2 on RCCCD133+cells and asked whether such pre-treatment would induce proliferation and thereby render them more susceptible to cell cycle-dependent chemotherapeutic drugs [38]
Summary
Renal cell carcinoma (RCC) accounts for 85% of renal cancers, of which clear cell RCC (ccRCC) is the most prevalent form [1,2,3,4,5]. Higher numbers of CD133+cells in RCC tissue has been correlated with increasing tumor grade [22] and was associated with a favourable prognosis in some studies [27, 30] but not others [31] While it is unclear whether RCCCD133+cells are true tumor stem cells and their prognostic significance is uncertain, their ability to promote tumor formation by CD133- RCC cells may contribute to the resistance of these tumors to conventional chemotherapy so that elimination of this population may improve outcomes
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