Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: The role of stroma cells in tumor angiogenesis

Assaf A. Gilad, Tomer Israely, Hagit Dafni, Gila Meir, Batya Cohen, Michal Neeman

Research output: Contribution to journalArticlepeer-review

Abstract

Maintaining homogeneous perfusion in tissues undergoing remodeling and vascular expansion requires tight orchestration of the signals leading to endothelial sprouting and subsequent recruitment of perivascular contractile cells and vascular maturation. This regulation, however, is frequently disrupted in tumors. We previously demonstrated the role of tumor-associated myofibroblasts in vascularization and exit from dormancy of human ovarian carcinoma xenografts in nude mice. The aim of this work was to determine the contribution of stroma- and tumor cell-derived angiogenic growth factors to the heterogeneity of vascular permeability and maturation in MLS human ovarian carcinoma tumors. We show by RT-PCR and by in situ hybridization that VEGF was expressed by the tumor cells, while angiopoietin-1 and -2 were expressed only by the infiltrating host stroma cells. Vascular maturation was detected in vivo by vasoreactivity to hypercapnia, measured by BOLD contrast MRI and validated by immunostaining of histologic sections to α-smooth muscle actin. Vascular permeability was measured in vivo by dynamic contrast-enhanced MRI using albumin-based contrast material and validated in histologic sections by fluorescent staining of the biotinylated contrast material. MRI as well as histologic correlation maps between vascular maturation and vascular permeability revealed a wide range of vascular phenotypes, in which the distribution of vascular maturation and vasoreactivity did not overlap spatially with reduced permeability. The large heterogeneity in the degree of vascular maturation and permeability is consistent with the differential expression pattern of VEGF and angiopoietins during tumor angiogenesis.

Original languageEnglish (US)
Pages (from-to)202-211
Number of pages10
JournalInternational Journal of Cancer
Volume117
Issue number2
DOIs
StatePublished - Nov 1 2005

Keywords

  • Angiogenesis
  • Angiopoietins
  • Blood oxygen level-dependent contrast
  • Dynamic contrast enhancement MRI
  • Magnetic resonance imaging (MRI)
  • Vascular endothelial growth factor
  • Vascular maturation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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