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Oncotarget. 2016 Apr 26;7(17):24111-24. doi: 10.18632/oncotarget.8125.

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

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Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK.
School of Clinical Medicine, Cambridge Institute of Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, UK.
Department of Pathology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 0XZ, UK.
VIB Inflammation Research Center, Ghent University, UGhent-VIB Research Building FSVM, 9052 Ghent, Belgium.
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8089, USA.


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

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