Type III transforming growth factor-β (TGF-β) receptor mediates apoptosis in renal cell carcinoma independent of the canonical TGF-β signaling pathway

Alterations in transforming growth factor- β (TGF-β) signaling occur early during malignant transformation of renal epithelial cells and are associated with loss of type III TGF-β receptor (Tβ-RIII) expression. We evaluated the rote of Tβ-RIII in mediation of apoptosis using in vitro cell culture and in vivo animal models of clear cell renal cell carcinoma. Experimental Design: TβR3 expression was manipulated with adenoviral gene vector delivery system in vitro and in vivo. Induction of apoptosis and signaling through the Smad and mitogenactivated protein kinase (MAPK) pathways were examined at various time points after infection. To study viral oncolysis in vivo, human renal cell carcinoma cells were implanted s.c. in the flanks of nude mice and treated with intratumoral injections of adenovirus. Results: Restoring Tβ-RIII expression in clear cell renal cell carcinoma resulted in a marked induction of apoptosis using in vitro cell culture and in vivo animal models. The expression of the cytoplasmic domain, but not the extracellular domain, of TβRIIl mimicked the induction of apoptosis by full-length TβRIII in cell culture and the growth inhibition of tumors in athymic nude mice. TβRlllassociated apoptosis was not dependent on signaling through the canonical TGF-β/Smad pathway but was mediated through p38 MAPK. Conclusion: These findings indicate a novel mechanistic antitumor function forTβRIII and further support its role as an important tumor suppressor in clear cell renal cell carcinoma.