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

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 a-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. ' 2005 Wiley-Liss, Inc.

Labeling fibroblasts with biotin‐BSA‐GdDTPA‐FAM for tracking of tumor‐associated stroma by fluorescence and MR imaging

“…It is well known, however, that both endothelial cells and fibroblasts are located in close association in many epithelial tumors, i.e., in those expressing a desmoplastic response. We recently reported the critical role of myofibroblasts in the initiation of growth of dormant MLS ovarian epithelial tumor xenografts (14), and in the stabilization and maturation of the tumor vasculature (22). These tumor xenografts are not only massively infiltrated by ␣SMA-positive stromal cells (myofibroblasts/pericytes), they are also characterized by a moderate and nonleaky vasculature.…”

“…This model is of particular interest since in a previous study we reported that the exit of implanted human MLS ovarian carcinoma spheroids from dormancy correlated with the infiltration of ␣-SMA-positive (myo)fibroblasts into the tumor mass, suggesting a critical role for these cells in the initiation of tumor progression (14). Moreover, we recently showed that these stroma myofibroblasts contributed to vascular stabilization and maturation in ovarian tumors by the expression of angiopoietin-1 (22).…”

Detecting gas‐induced vasomotor changes via blood oxygenation level‐dependent contrast in healthy breast parenchyma and breast carcinoma

“…This is an unsurprising result, based on previous histological studies in tumors that reveal inadequate smooth muscle cells lining the vasculature,3 which would result in an inability to constrict and dilate in response to vasoactive stimuli. The mucinous carcinoma exhibited a notably large response to the gas stimulus relative to surrounding fibroglandular tissue.…”

“…However, heterogeneity of vascular maturation has been demonstrated both between and within tumor subtypes 2. Histological staining of endothelial cells to alpha smooth muscle actin (α‐SMA) can assess vascular maturation,3 but this requires a biopsy, which is invasive, unsuitable for longitudinal measurements, and prone to sampling error. Noninvasive methods that probe vascular function would have potential for characterizing individual tumors, predicting susceptibility to targeted therapies, and monitoring response.…”

“…Administering either pure oxygen or carbogen (conventionally 95% O 2 , 5% CO 2 ) increases blood oxygen levels, but with opposite effects on vascular tone, since carbon dioxide is a potent vasodilator. Several groups have therefore proposed exploiting the differential vasomotor effects of hyperoxia and hypercapnia to employ BOLD contrast as a functional biomarker of vascular maturity 3, 12, 13. Immature tumor vessels lacking appropriate smooth muscle vasculature should be unable to either dilate or constrict in response to vasoactive challenges, whereas surrounding healthy mature vessels should show a response.…”