Isoforms of vascular endothelial growth factor act in a coordinate fashion To recruit and expand tumor vasculature.
Vascular endothelial growth factor (VEGF) is an essential regulator of vascularization. It is expressed as several splice variants; the major forms contain 120 amino acids, 164 amino acids, and 188 amino acids. We utilized transformed cells nullizygous for VEGF to specifically express each of these isoforms in isolation, in order to determine the role of each in tumorigenic neo-vascularization. We found that only the intermediate isoform, VEGF164, could fully rescue tumor growth; VEGF120 partially rescued tumor growth, and VEGF188 failed completely to rescue tumor expansion. Surprisingly, the vascular density of VEGF188 isoform-expressing tumors is significantly greater than that of wild-type VEGF cells and the other isoform-specific tumors. The failure of the hypervascular VEGF188-expressing tumors to grow may be due to inadequate perfusion of the massive number of microvessels in these tumors; three-dimensional imaging of the tumorigenic vasculature indicated little or no recruitment of the peripheral vasculature. This demonstrates that the VEGF isoforms perform unique functions which together enable tumorigenic vascularization.
Grunstein
J
J
Department of Biology, University of California, San Diego, La Jolla, California 92093-0366, USA.
Masbad
J J
JJ
Hickey
R
R
Giordano
F
F
Johnson
R S
RS
D017398:Alternative Splicing; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D016228:Endothelial Growth Factors / Q000737:chemistry / Q000502:physiology*; D005354:Fibrosarcoma / Q000098:blood supply*; D018390:Gene Targeting; D011905:Genes, ras; D008222:Lymphokines / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009994:Osmolar Concentration; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors