Endothelial reprograming stimulated by oncostatin M promotes inflammation and tumorigenesis in VHL-deficient kidney tissue.

Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of RCC, and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. However, it is still not clear how mutations in VHL, encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor (HIF-α), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional Vhlh knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells. Interestingly, the endothelial cells (ECs), although not subject to genetic manipulation, nonetheless showed profound changes in gene expression that suggest a role in promoting inflammation and tumorigenesis. Oncostatin M (OSM) mediated the interaction between VHL-deficient renal tubule cells and the ECs, where the activated ECs in turn induce macrophage recruitment and polarization. The OSM-dependent microenvironment also promoted metastasis of exogenous tumors. Thus, OSM signaling initiates reconstitution of an inflammatory and tumorigenic microenvironment by VHL-deficient renal tubule cells, which plays a critical role in ccRCC initiation and progression.