title: CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis.
abstract: Anti-angiogenic and anti-lymphangiogenic drugs slow tumor progression and dissemination. However, an important difficulty is that a tumor reacts and compensates to obtain the blood supply needed for tumor growth and lymphatic vessels to escape to distant loci. Therefore, there is a growing consensus on the requirement of multiple anti-(lymph)angiogenic molecules to stop cell invasion efficiently. Here we studied the cooperation between endogenous anti-angiogenic molecules, endostatin and fibstatin, and a chemokine, the Platelet Factor-4 variant 1, CXCL4L1. Anti-angiogenic factors were co-expressed by IRES-based bicistronic vectors and their cooperation was analyzed either by local delivery following transduction of pancreatic adenocarcinoma cells with lentivectors, or by distant delivery resulting from intramuscular administration in vivo of adeno-associated virus derived vectors followed by tumor subcutaneous injection. In this study, fibstatin and CXCL4L1 cooperate to inhibit endothelial cell proliferation, migration and tubulogenesis in vitro. No synergistic effect was found for fibstatin-endostatin combination. Importantly, we demonstrated for the first time that fibstatin and CXCL4L1 not only inhibit in vivo angiogenesis, but also lymphangiogenesis and tumor spread to the lymph nodes, whereas no beneficial effect was found on tumor growth inhibition using molecule combinations compared to molecules alone. These data reveal the synergy of CXCL4L1 and fibstatin in inhibition of tumor angiogenesis, lymphangiogenesis and metastasis and highlight the potential of IRES-based vectors to develop anti-metastasis combined gene therapies.
authors.affiliation: Université de Toulouse, UPS, TRADGENE, EA4554, F-31432 Toulouse, France.
authors.forename: A C
authors.initials: AC
authors.lastname: Prats
authors.forename: L
authors.initials: L
authors.lastname: Van den Berghe
authors.forename: A
authors.initials: A
authors.lastname: Rayssac
authors.forename: N
authors.initials: N
authors.lastname: Ainaoui
authors.forename: F
authors.initials: F
authors.lastname: Morfoisse
authors.forename: F
authors.initials: F
authors.lastname: Pujol
authors.forename: S
authors.initials: S
authors.lastname: Legonidec
authors.forename: A
authors.initials: A
authors.lastname: Bikfalvi
authors.forename: H
authors.initials: H
authors.lastname: Prats
authors.forename: S
authors.initials: S
authors.lastname: Pyronnet
authors.forename: B
authors.initials: B
authors.lastname: Garmy-Susini
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D004338:Drug Combinations; D043169:Endostatins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007797:Laminin / Q000737:chemistry; D042583:Lymphangiogenesis / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic; D010978:Platelet Factor 4 / Q000378:metabolism*; D011509:Proteoglycans / Q000737:chemistry; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D004338:Drug Combinations; D043169:Endostatins; D007797:Laminin; D008565:Membrane Proteins; C064936:PF4V1 protein, human; D011509:Proteoglycans; D011994:Recombinant Proteins; C493535:fibstatin protein, human; C059485:matrigel; D010978:Platelet Factor 4; D003094:Collagen