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Vascular endothelial growth factor (VEGF) is an important mediator of tumor-associated angiogenesis, and consequently it has been associated with metastasis. We report here that the overexpression of VEGF(165) in melanoma xenografts promotes an acceleration of tumor growth and an increase in angiogenesis as well as the spontaneous metastasis formation. In addition, VEGF receptors (VEGFR)1, VEGFR2 and neurophilin-1 are expressed in A375 melanoma cells. Forced overexpression of VEGF in these cells induces cell growth and triggers survival activity in serum-starved cultures, by a mechanism dependent on the mitogen-activating protein kinase signaling pathway. Furthermore, these effects are dependent MEK 1/2 activity. Kinase domain region-specific tyrosine kinase inhibitors dramatically reduced DNA synthesis to 20% with respect to the controls, although they did not completely suppress either the p44 or p42-phosphorylated forms of extracellular signal-regulated protein kinase. These inhibitors also provoked a decrease in Akt phosphorylation. We observed a dramatic reduction in survival after treatment with phosphatidylinositol 3'-kinase (PI3K)-specific inhibitor in the presence of specific tyrosinase inhibitors. We suggest that the overproduction of VEGF(165) concomitantly expressed with its receptors favors cell growth and survival of melanoma cells through MAPK and PI3K signaling pathways. These data support the involvement in melanoma growth and survival of a VEGF-dependent internal autocrine loop mechanism, at least in vitro.

Liver transplant recipients are at greater risk for de novo neoplasia, especially lymphoma and nonmelanoma skin cancer; however, risk factors for this complication have not been well studied. Clinical and pathological records of 137 consecutive liver transplant recipients who had survived for at least 1 year were reviewed to register de novo neoplasia. Ten variables were analyzed for their association with the development of de novo malignancies by means of a log-rank test and stepwise selection in a multivariate analysis using the Cox proportional hazard model. Thirty de novo neoplasias appeared in 22 of 137 transplant recipients between 12 and 104 months after orthotopic liver transplantation (OLT; median follow-up, 69 months): 14 patients had 21 skin cancers, 6 patients had solid-organ cancer, and 3 patients developed a lymphoproliferative disease. Probabilities of de novo neoplasia were 13% at 5 years post-OLT and 26% at 8 years post-OLT. The only associated risk factor for any neoplasia was age. Age and hepatocarcinoma were independent risk factors associated with skin cancer. That hepatocarcinoma in the explanted liver is an independent risk factor for skin cancer suggests there is individual susceptibility to both neoplasias. (Liver Transpl 2001;7:971-975.)