Vascular endothelial growth factor isoform expression as a determinant of blood vessel patterning in human melanoma xenografts.

Sunnybrook and Women's College Health Sciences Centre, Molecular and Cellular Biology Research, Toronto, Ontario M4N 3M5, Canada.
Cancer Research (Impact Factor: 9.33). 04/2002; 62(6):1838-46.
Source: PubMed


Vascular endothelial growth factor (VEGF) occurs in at least five different isoforms because of alternative splicing of the gene. To investigate the roles of different VEGF isoforms in tumor blood vessel formation and tumorigenicity, the three major isoforms (VEGF(121), VEGF(165), and VEGF(189)) were overexpressed in an early-stage human melanoma cell line (WM1341B), which is VEGF-negative and nontumorigenic in immunodeficient mice. Although overexpression of VEGF(121) and VEGF(165) resulted in aggressive tumor growth, WM1341B cells transfected with VEGF(189) remained nontumorigenic and dormant on injection. Although tumor growth rate depended on the level and not the isoform of VEGF expressed, striking isoform-specific differences in vascular patterning were associated with VEGF(121)- versus VEGF(165)-dependent tumorigenic conversion of human melanoma. Thus, tumors overexpressing VEGF(165) generated dense, highly heterogeneous vessel networks that were distinctly different from those of tumors expressing VEGF(121) (poorly vascularized and necrotic). Paradoxically, although VEGF(165) expression appears to result in the most effective tumor perfusion, it is the expression of VEGF(121) that is observed during human malignant melanoma progression. Indeed, unbiased selection of spontaneously tumorigenic variants of WM1341B (by coinjection with Matrigel) led to predominant expression of the VEGF(121) isoform. The vascular patterning in these tumors (1341-P3N1, 1341-P3N2) resembled that of the VEGF(121)-transfected WM1341B tumors. These results suggest that, for reasons that remain to be elucidated, a "minimal" program of tumor vascularization may be favored during melanoma progression.

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    • "Tozer et al (2008) showed that fibrosarcomas derived from transgenic mice expressing only VEGF188 under constitutive promoter control developed highly vascularised well-defined tumours. Melanoma cells transfected with VEGF189 remain non-tumourigenic and dormant (Yu et al, 2002). One study, in which VEGF isoform profile was classified into three groups, VEGF121 only (type 1), VEGF121 þ 165 (type 2) and VEGF121 þ VEGF165 þ VEGF189 (type 3) (Tokunaga et al, 1998), showed the higher incidence of liver metastasis in colon cancer patients for the type 3. Higher levels of cell-associated VEGF189 expression were also observed in lung cancers (Yuan et al, 2001). "
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    • "Transfection and overexpression of VEGF isoforms in cell lines normally producing baseline VEGF levels have been an invaluable tool for identifying differences in tumorigenicity between isoforms. VEGF121 and VEGF165 promote aggressive tumour growth in mouse xenografts, contrasting VEGF189 (high heparin affinity/lower bioavailability) where overexpression demonstrates poor tumour growth [25]. "
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    • "It inhibits several coagulation factors such as thrombin, FXa, FIXa, FXIa, FXIIa [50] and inhibits cell proliferation, particularly of those cells that over express PAR-1 [115]. Heparin also it interacts with VEGF-165 and VEGF-189 expressed on malignant cells [116] and could inhibit angiogenesis via blocking of P-and L-selectin [117]. We have recently shown that low molecular weight heparin (LMWH) can decrease the angiogenic and chemoattractant activity of PC patients' sera [118]. "
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