Treatment of Renal-Cell Cancer by Transplantation of Allogeneic Stem Cells

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Abstract
Childs et al. (Sept. 14 issue)1 report the spectacular success of nonmyeloablative allogeneic stem-cell transplantation in a subgroup of patients with metastatic renal-cell carcinoma. Only the patients with clear-cell carcinomas had responses. Previous work indicates that most renal-cell carcinomas with clear-cell histology are caused by mutation of the von Hippel–Lindau tumor-suppressor gene, located on chromosome band 3p26.2,3 The von Hippel–Lindau gene produces two proteins that can suppress tumor formation in clear-cell renal-cell carcinoma in a nude-mouse model.4 My colleagues and I have demonstrated that the von Hippel–Lindau gene, in addition to its tumor-suppressor function, protects cells from apoptosis mediated by ultraviolet radiation.5 I would like to suggest that the mechanism by which stem-cell transplantation induces regression of disease relates to the differential susceptibility of cells, according to whether they do or do not have a mutation in the von Hippel–Lindau gene, to signaling pathways induced in the renal-cell carcinoma cells by the donor T cells or locally released cytokines. I predict that the renal-cell carcinoma cells are negative for a von Hippel–Lindau mutation in the patients with a response and that apoptosis can be detected on biopsy of the regressing lesions. Moreover, I suggest that identification of the specific ligands responsible for the induction of regression might be sufficient to effect a response similar to that of the transplantation. These are testable hypotheses that could lead to mechanism-based therapies — the ultimate in translational research.