Angiogenic Profile of Uveal Melanoma

Abstract

Uveal melanoma develops in one of the most capillary-rich tissues of the body and is disseminated hematogenously. Knowledge of the nature and the spatiotemporal expression of angiogenic factors in uveal melanoma is essential to the development of new treatment strategies, especially with regard to improving survival. In this study, we measured the angiogenic potential of several angiogenic factors in different uveal melanoma cell lines, in an in vivo model, and in primary tumor material from patients with melanoma. Most uveal melanoma cell lines expressed vascular endothelial growth factor (VEGF)-A (isoforms 121, 165, 189), VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF) to various extents. The expression of VEGF-A 121 was always higher than that of the other VEGF-A isoforms, suggesting that VEGF-A 121 is the most abundant VEGF-A isoform. All experimentally induced tumors expressed VEGF-A, VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF). Similarly, significant amounts of mRNA for VEGF-B, VEGF-C, VEGF-D, and b-FGF were detected in uveal melanoma material from patients. In contrast, VEGF-A mRNA (121, 165, 189) was low (9/28) or not detectable in the tumor samples. The synthesis of VEGF-A 165 and b-FGF protein by various cell lines was measured by enzyme-linked immunosorbent assay (ELISA). Most uveal melanoma cell lines, but not normal melanocytes, strongly synthesized and secreted VEGF-A 165 and b-FGF during cell culture. Our data suggest that the expression of (lymph) angiogenic factors may play a causal role in the angiogenesis and progression of uveal melanoma and distant metastasis.

Intraocular Activation of Angiogenic and Inflammatory Pathways in Uveal Melanoma

“…[25][26][27][28] As reported in the literature, uveal melanoma cell lines are known to express VEGF and basic FGF to various extents. [10][11][12]14,15 Ijland et al 12 found human uveal melanoma cell lines to express also PDGF. Vascular endothelial growth factor itself was increased in the aqueous humor of eyes with uveal melanoma.…”

“…[5][6][7][8][9] So far VEGF, FGF, and a number of inflammatory cytokines have been described in aqueous samples of uveal melanoma. [10][11][12][13][14][15] However, to this date, this is the only work describing cytokine levels in the vitreous fluid of eyes with uveal melanoma in detail.…”

A Mutated EGFR Is Sufficient to Induce Malignant Melanoma with Genetic Background-Dependent Histopathologies

“…Uveal melanomas are also observed in human patients. The mostly used murine uveal melanoma model relies on injection of uveal melanoma cells of murine or human origin into the eye, thus allowing to monitor maintenance and progression, but not initial development of the tumor (Notting et al, 2006;Yang et al, 2008). In addition, there is a transgenic murine model for pigmented ocular neoplasm, in which large T antigen, driven by the Tyrp promoter, is causative for the disease (De la Houssaye et al, 2008).…”

Differential effects of imatinib mesylate against uveal melanoma in vitro and in vivo

“…Uveal melanoma cells have been shown to produce a variety of factors, which modify angiogenesis and the tumor stroma [27,30,31]. The ability of imatinib mesylate to reduce the production of proangiogenic factors such as VEGF has been implicated in its antitumor activity in other malignancies, such as neuroblastoma and lung Groups of six mice were treated with PBS, with 150 mg/kg temozolomide (TMZ) on days 9 and 10, with 1 mg/mouse/day imatinib mesylate (IM) days 6-9, or with IM days 6-9 and TMZ on days 9 and 10 (IM + TMZ).…”