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

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, 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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    ABSTRACT: Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that has important roles in angiogenesis. Our knowledge of the significance of VEGF isoforms in human cancer remains incomplete. Bioluminescence imaging and transcriptomic analysis were used to study the colonisation capacity of the human breast cancer cells MDA-MB-231 controlling or overexpressing the VEGF165 or VEGF189 isoform (named cV-B, V165-B and V189-B, respectively) in nude mice. When injected into the bloodstream, V189-B cells induced less metastasis in the lungs and bone than V165-B and cV-B control cells, consistent with longer survival of these mice and delay in tumour uptake in the mice injected with a V189-B clone. Histological analysis confirmed that there were less αSMA-positive cells in the lungs of the mice injected with V189-B. In vitro V189-B cells decreased both cell invasion and survival. Using transcriptomic analysis, we identified a subset of 18 genes expressed differentially between V189 and V165 cell lines and in 120 human breast tumours. V165 was associated with poor prognosis, whereas V189 was not, suggesting a complex regulation by VEGF isoforms. Our results showed a negative correlation between the expression pattern of VEGF189 and the levels of expression of seven genes that influence metastasis. Our findings provide the first evidence that VEGF isoforms have different effects on breast cancer cell line colonisation in vivo.British Journal of Cancer advance online publication, 21 July 2015; doi:10.1038/bjc.2015.267
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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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    ABSTRACT: Blood vessels arose during evolution carrying oxygen and nutrients to distant organs via complex networks of blood vessels penetrating organs and tissues. Mammalian cells require oxygen and nutrients for survival, of which oxygen has a diffusion limit of 100 to 200 μm between cell and blood vessel. For growth beyond this margin, cells must recruit new blood vessels, first by vasculogenesis, where embryonic vessels form from endothelial precursors, then angiogenesis which is the sprouting of interstitial tissue columns into the lumen of preexisting blood vessels. Angiogenesis occurs in many inflammatory diseases and in many malignant disease states, including over 90% of solid tumours. Malignant melanoma (MM) is the most lethal skin cancer, highly angiogenic, highly metastatic, and refractory to all treatments. Raised serum levels of vascular endothelial growth factor (VEGF) strongly correlate MM disease progression and poor prognosis. Melanoma cells secrete several proangiogenic cytokines including VEGF-A, fibroblast growth factor (FGF-2), platelet growth factor (PGF-1), interleukin-8 (IL-8), and transforming growth factor (TGF-1) that modulate the angiogenic switch, changing expression levels during tumour transition from radial to invasive vertical and then metastatic growth. We highlight modern and historical lines of research and development that are driving this exciting area of research currently.
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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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