title: Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours.
abstract: Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2-neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. Small hairpin RNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network-forming ability of endothelial cells, suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultrasonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents were previously found to improve the delivery of chemotherapeutic agents into tumours and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours.
authors.affiliation: Cancer and Vascular Biology Research Center, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Zaffryar-Eilot
authors.forename: Derek
authors.initials: D
authors.lastname: Marshall
authors.forename: Tali
authors.initials: T
authors.lastname: Voloshin
authors.forename: Avinoam
authors.initials: A
authors.lastname: Bar-Zion
authors.forename: Rhyannon
authors.initials: R
authors.lastname: Spangler
authors.forename: Ofra
authors.initials: O
authors.lastname: Kessler
authors.forename: Haben
authors.initials: H
authors.lastname: Ghermazien
authors.forename: Vera
authors.initials: V
authors.lastname: Brekhman
authors.forename: Edith
authors.initials: E
authors.lastname: Suss-Toby
authors.forename: Dan
authors.initials: D
authors.lastname: Adam
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D016222:Fibroblast Growth Factor 2; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human