VHL induces renal cell differentiation and growth arrest through integration of cell-cell and cell-extracellular matrix signaling

Mutations in the von Hippel-Lindau (VHL) gene are involved in the family ca ncer syndrome for which it is named and the development of sporadic renal c ell cancer (RCC), Reintroduction of VHL into RCC cells lacking functional V HL [VHL(-)] can suppress their growth in nude mice, but not under standard tissue culture conditions, To examine the hypothesis that the tumor suppres sor function of VHL requires signaling through contact with extracellular m atrix (ECM), 786-O VHL(-) RCC cells and isogenic sublines stably expressing VHL gene products [VHL(+)] were grown on ECMs, Cell-cell and cell-ECM sign alings were required to elicit VHL-dependent differences in growth and diff erentiation. VHL(+) cells differentiated into organized epithelial sheets, whereas VHL(-) cells were branched and disorganized. VHL(+) cells growth to high density on collagen I underwent growth arrest, whereas VHL(-) cells c ontinued to proliferate. Integrin levels were up-regulated in VHL(-) cells, and cell adhesion was down-regulated in VHL(+) cells during growth at high cell density. Hepatocyte nuclear factor Icu, a transcription factor and gl obal activator of proximal tubule-specific genes in the nephron, was marked ly up-regulated in VHL(+) cells grown at high cell density. These data indi cate that VHL can induce renal cell differentiation and mediate growth arre st through integration of cell-cell and cell-ECM signals.