title: Influence of soluble or matrix-bound isoforms of vascular endothelial growth factor-A on tumor response to vascular-targeted strategies.
abstract: Antiangiogenic therapy based on blocking the actions of vascular endothelial growth factor-A (VEGF) can lead to "normalization" of blood vessels in both animal and human tumors. Differential expression of VEGF isoforms affects tumor vascular maturity, which could influence the normalization process and response to subsequent treatment. Fibrosarcoma cells expressing only VEGF120 or VEGF188 isoforms were implanted either subcutaneously (s.c.) or in dorsal skin-fold "window" chambers in SCID mice. VEGF120 was associated with vascular fragility and hemorrhage. Tumor-bearing mice were treated with repeat doses of SU5416, an indolinone receptor tyrosine kinase inhibitor with activity against VEGFR-2 and proven preclinical ability to induce tumor vascular normalization. SU5416 reduced vascularization in s.c. implants of both VEGF120 and VEGF188 tumors. However, in the window chamber, SU5416 treatment increased red cell velocity in VEGF120 (representing vascular normalization) but not VEGF188 tumors. SU5416 treatment had no effect on growth or necrosis levels in either tumor type but tended to counteract the increase in interstitial fluid pressure seen with growth of VEGF120 tumors. SU5416 pretreatment resulted in the normally fragile blood vessels in VEGF120-expressing tumors becoming resistant to the vascular damaging effects of the tubulin-binding vascular disrupting agent (VDA), combretastatin A4 3-O-phosphate (CA4P). Thus, vascular normalization induced by antiangiogenic treatment can reduce the efficacy of subsequent VDA treatment. Expression of VEGF120 made tumors particularly susceptible to vascular normalization by SU5416, which in turn made them resistant to CA4P. Therefore, VEGF isoform expression may be useful for predicting response to both antiangiogenic and vascular-disrupting therapy.
authors.affiliation: Tumor Microcirculation Group, CR-UK/YCR Sheffield Cancer Research Centre, University of Sheffield, Department of Oncology, Sheffield, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Akerman
authors.forename: Matthew
authors.initials: M
authors.lastname: Fisher
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Daniel
authors.forename: Diane
authors.initials: D
authors.lastname: Lefley
authors.forename: Constantino C
authors.initials: CC
authors.lastname: Reyes-Aldasoro
authors.forename: Sarah Jane
authors.initials: SJ
authors.lastname: Lunt
authors.forename: Sheila
authors.initials: S
authors.lastname: Harris
authors.forename: Meit
authors.initials: M
authors.lastname: Bjorndahl
authors.forename: Leigh J
authors.initials: LJ
authors.lastname: Williams
authors.forename: Helen
authors.initials: H
authors.lastname: Evans
authors.forename: Paul R
authors.initials: PR
authors.lastname: Barber
authors.forename: Vivien E
authors.initials: VE
authors.lastname: Prise
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojnovic
authors.forename: Chryso
authors.initials: C
authors.lastname: Kanthou
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tozer
mesh_terms: D000818:Animals; D005354:Fibrosarcoma / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; D020033:Protein Isoforms; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: VEGF isoforms; receptor tyrosine kinase inhibitors; red cell velocity; vascular disrupting agents; vascular normalization