title: VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans.
abstract: Tumor angiogenesis depends on the vascular endothelial growth factor (VEGF), which exists in multiple splicing isoforms, including the most abundant VEGF165 and VEGF121. We have previously shown that the differential capacity of these two VEGF isoforms to bind Neuropilin-1 accounts for their diverse ability to recruit Nrp1-expressing monocytes (NEMs), resulting in a different arteriogenic potential. Here we measure the expression of VEGF165 and VEGF121 in human cancer and their influence on tumor growth and vascularization. We measured the expression levels of VEGF165 and VEGF121 in human colorectal cancer and found that VEGF121 was more expressed than VEGF165, particularly in patients with extensive lymph node infiltration. Overexpressing either VEGF165 or VEGF121 in a cancer mouse model, we observed that the former decreased, whereas the latter increased tumor growth. In both clinical and experimental tumors, VEGF165 expression resulted in the recruitment of NEMs, paralleled by maturation of the tumor vascular network. Finally, hypoxia induced a shift toward the VEGF165 isoform in the central core of human cancers, as well as in various types of cultured cells. These results demonstrate that the two VEGF splicing isoforms are differentially expressed in colorectal cancers, exerting opposite effects on tumor growth and vessel maturation.
authors.affiliation: Molecular Medicine, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Kazemi
authors.affiliation: Molecular Medicine, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Carrer
authors.affiliation: Molecular Medicine, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.|Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Moimas
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Zandonà
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bussani
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Casagranda
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Palmisano
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Prelazzi
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Molecular Medicine, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Zentilin
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: N
authors.initials: N
authors.lastname: De Manzini
authors.affiliation: Molecular Medicine, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.|Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Trieste, Italy.|Cardiovascular Biology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zacchigna
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A