title: Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab.
abstract: Bevacizumab-resistant tumor vessels were characterized by an increased vessel diameter and normalization of vascular structures by the recruitment of mature pericytes and smooth muscle cells. Here, we analyzed human liver metastases which were taken at clinical relapse in patients with colorectal adenocarcinoma treated with anti-angiogenic therapy using the humanized monoclonal anti-VEGF bevacizumab. Tumor vessels which are resistant to anti-VEGF therapy are increased in size and characterized by a normalization of the vascular bed. These results were confirmed using NOD SCID mice as animal model and xenograft transplantation of human PC-3 prostate carcinoma cells in combination with bevacizumab treatment. Our results confirmed that anti-angiogenic therapy results in enhanced vascular remodeling by vascular stabilization. This process is apparently accompanied by enhanced necrosis of tumor tissue. These processes interfere with the efficacy of anti-angiogenic therapy because of reduced susceptibility of stabilized vessels by this therapy. These results demonstrate the importance for the development of second generation anti-angiogenic combination therapy concepts to rule out the balance between vascular stabilization followed by a possible de-stabilization making the remained vessels susceptible to a second wave of anti-angiogenic therapy.
authors.affiliation: Institute of Anatomy, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany. philip.weisshardt@gmx.de
authors.forename: Philip
authors.initials: P
authors.lastname: Weisshardt
authors.forename: Tanja
authors.initials: T
authors.lastname: Trarbach
authors.forename: Jan
authors.initials: J
authors.lastname: Dürig
authors.forename: Andreas
authors.initials: A
authors.lastname: Paul
authors.forename: Henning
authors.initials: H
authors.lastname: Reis
authors.forename: Derya
authors.initials: D
authors.lastname: Tilki
authors.forename: Inna
authors.initials: I
authors.lastname: Miroschnik
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
authors.forename: Diana
authors.initials: D
authors.lastname: Klein
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab