Figure 5.

Model of TGF-α as the factor that might confer a growth advantage on RCC cells on the loss of VHL function. (A) VHL^−/− RCC cells abnormally overproduce factors, such as TGF-α and VEGF, that would otherwise accumulate only in hypoxic conditions. This overproduction may be because of HIFα stabilization. Because RPTECs are sensitive to TGF-α but not to VEGF for growth, we suggest that these cells might engage in a TGF-α-mediated autocrine/paracrine circuit loop that can stimulate their growth. This loop might be an important oncogenic event on the loss of VHL function, explaining why VHL^−/− RCC cells are able to grow in low serum. (B) Reintroduction of VHL into VHL^−/− RCC causes levels of TGF-α to be down-regulated, possibly explaining why these cells do not grow in low serum and do not form tumors in nude mice.