title: Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors.
abstract: Tubulin-binding vascular-disrupting agents (VDA) are currently in clinical trials for cancer therapy but the factors that influence tumor susceptibility to these agents are poorly understood. We evaluated the consequences of modifying tumor vascular morphology and function on vascular and therapeutic response to combretastatin-A4 3-O-phosphate (CA-4-P), which was chosen as a model VDA. Mouse fibrosarcoma cell lines that are capable of expressing all vascular endothelial growth factor (VEGF) isoforms (control) or only single isoforms of VEGF (VEGF120, VEGF164, or VEGF188) were developed under endogenous VEGF promoter control. Once tumors were established, VEGF isoform expression did not affect growth or blood flow rate. However, VEGF188 was uniquely associated with tumor vascular maturity, resistance to hemorrhage, and resistance to CA-4-P. Pericyte staining was much greater in VEGF188 and control tumors than in VEGF120 and VEGF164 tumors. Vascular volume was highest in VEGF120 and control tumors (CD31 staining) but total vascular length was highest in VEGF188 tumors, reflecting very narrow vessels forming complex vascular networks. I.v. administered 40 kDa FITC-dextran leaked slowly from the vasculature of VEGF188 tumors compared with VEGF120 tumors. Intravital microscopy measurements of vascular length and RBC velocity showed that CA-4-P produced significantly more vascular damage in VEGF120 and VEGF164 tumors than in VEGF188 and control tumors. Importantly, this translated into a similar differential in therapeutic response, as determined by tumor growth delay. Results imply differences in signaling pathways between VEGF isoforms and suggest that VEGF isoforms might be useful in vascular-disrupting cancer therapy to predict tumor susceptibility to VDAs.
authors.affiliation: Cancer Research UK Tumour Microcirculation Group, Academic Unit of Surgical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom. g.tozer@sheffield.ac.uk
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tozer
authors.forename: Simon
authors.initials: S
authors.lastname: Akerman
authors.forename: Neil A
authors.initials: NA
authors.lastname: Cross
authors.forename: Paul R
authors.initials: PR
authors.lastname: Barber
authors.forename: Meit A
authors.initials: MA
authors.lastname: Björndahl
authors.forename: Olga
authors.initials: O
authors.lastname: Greco
authors.forename: Sheila
authors.initials: S
authors.lastname: Harris
authors.forename: Sally A
authors.initials: SA
authors.lastname: Hill
authors.forename: Davina J
authors.initials: DJ
authors.lastname: Honess
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Ireson
authors.forename: Katie L
authors.initials: KL
authors.lastname: Pettyjohn
authors.forename: Vivien E
authors.initials: VE
authors.lastname: Prise
authors.forename: Constantino C
authors.initials: CC
authors.lastname: Reyes-Aldasoro
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
authors.forename: David T
authors.initials: DT
authors.lastname: Shima
authors.forename: Chryso
authors.initials: C
authors.lastname: Kanthou
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C058728:fosbretabulin