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Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma.

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Al-Lamki, Rafia S 
Yang, Jun 
Maxwell, Patrick H 


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.



CD133, TNFR2, cyclophosphamide, renal clear cell carcinoma, AC133 Antigen, Antineoplastic Agents, Alkylating, Apoptosis, Biomarkers, Tumor, Carcinoma, Renal Cell, Cell Proliferation, Cyclophosphamide, Humans, Kidney Neoplasms, Receptors, Tumor Necrosis Factor, Type II, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha

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MRC (MR/N501876/1)
MRC (unknown)
Wellcome Trust (096956/Z/11/Z)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0514-10122)
Medical Research Council (MC_UU_12022/7)
MRC (MR/N501876/1)
The National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (RSA, JRB, AYW, PHM), Kidney Research UK (RSA, JW, SP, JRB), NIH grant R01-HL36003 (JSP), Cancer research UK grant RG75464 (TE), The Welcome Trust (NB, PHM), NSFC (national natural science foundation of China) grant 81400278 (JY), Medical Research Council Cancer Unit (SV), Belgian grants (Interuniversity Attraction Poles), Flemish grants (Methusalem grant (BOF09/01M00709) and grants from the Research Foundation Flanders and Foundation against Cancer, Ghent University grants and grants from Flanders Institute for Biotechnology (VIB) (PV).