Overproduction of VEGF165 Concomitantly Expressed with its Receptors Promotes Growth and Survival of Melanoma Cells through MAPK and PI3K Signaling

Abstract

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.

Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones

“…3, both isoforms stimulated the proliferation of breast tumor cells. However, VEGF 165 appeared to be more potent as previously reported for endothelial cells (Graells et al 2004). Quantitatively, both cell lines responded similarly to increasing concentrations of VEGF 165 and VEGF 121, though with 200 ng/ml, VEGF 165 BT-474 cells responded significantly better than T47-D cells (as also observed in Fig.…”

“…2D, VEGF-dependent proliferation of breast cancer cells was dependent on VEGFR2. Other investigators have shown that the interaction of VEGF with VEGFR2 can activate the PI3-kinase/Akt-dependent signaling pathway and the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signal transduction pathway (Graells et al 2004, Svensson et al 2005. We used specific inhibitors of four different signaling modules to identify the pathway involved in mediating VEGFinduced tumor cell proliferation in BT-474 and T47-D breast cancer cells.…”

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

“…Similarly, a great majority of human cancers overexpress or contain constitutively activated receptor and non-receptor tyrosine kinases and/or growth factor autocrine loops that also result in hyperactivation of the Raf-1/Mek-1/Erk1/2. (Di Marco et al, 1989;Fleming et al, 1992;Watanabe et al, 1996;Graells et al, 2004). More importantly, hyperactivation of this pathway is critical to the growth and survival of human tumors (Sebolt-Leopold et al, 1999).…”

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

“…In many cancers, both the overexpression of the growth factor and the receptor, besides mutations at the cytoplasmic tyrosine kinase domain, contribute to constitutive signaling; thus, these receptors make attractive targets for targeted therapies [80]. For example, in the transition from radial to vertical growth phase, melanoma as well as angiogenesis is heralded by both the expression and release of vascular endothelial growth factor (VEGF), which facilitates both growth of new blood and the tumor [29,81,82] …”