No 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.

To study angiogenesis in early steps of melanoma progression, 113 cutaneous melanomas 1 mm or less in thickness were stained with Ulex europaeus lectin. Vascular density was determined in the areas of greatest vascularization. To avoid the effect of anatomic location, the quotient between vascular density at the tumor base and in normal skin (vascular ratio) was obtained in each case. Of these melanomas, 46 were immunohistochemically stained for the presence of vascular endothelial growth factor (VEGF). Positivity was scored from 1-4 by comparing staining of melanoma cells with keratinocytes. Vascular ratio values in vertical growth phase melanomas were higher than those in radial growth phase when counting per 200 or 400 magnification (2.29 +/- 1.3 and 2.48 +/- 1.5 for vertical growth phase and 1.34 +/- 0.62 and 1.41 +/- 0.83 for radial growth phase melanomas, respectively). This difference was statistically significant (p < 0.0001 and p < 0.001 at x200 and x400, respectively). Also, VEGF staining was stronger in vertical growth phase melanomas when compared with radial growth phase melanomas (Chi square, p < 0.025). In conclusion, our findings suggest that angiogenesis and VEGF expression are associated with the development of vertical growth phase.

No abstract

The prognostic significance of 20 clinical and histologic parameters was evaluated in a series of 416 laryngeal carcinomas treated between 1969 and 1981 at the Hospital de Santa Cruz y San Pablo, Barcelona, Spain. Clinical follow-up ranged from 2 to 13 years. The variables considered were: age, smoking habits, previous laryngeal disease, duration of clinical symptoms, motility of vocal cords, interval between diagnosis and treatment, postoperative infection, topographic location of the tumor, previous tracheostomy, ulceration, tumor size, resection margins, histologic grading, patterns of growth, types of invasion, mitotic index, depth of invasion, positive lymph nodes, T categories and N categories. Fourteen parameters were found to be significantly related to survival. After a multifactorial study using Cox's life table regression model, 5 of those 14 parameters were found to influence survival independently. The five variables ordered according to prognostic significance were: (1) positive lymph nodes, (2) T categories, (3) histologic grading, (4) ulceration, and (5) location.