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. 1998 Oct;153(4):1239-48.
doi: 10.1016/S0002-9440(10)65668-4.

Host microvasculature influence on tumor vascular morphology and endothelial gene expression

W G Roberts  1 , J Delaat, M Nagane, S Huang, W K Cavenee, G E Palade
Affiliations

Host microvasculature influence on tumor vascular morphology and endothelial gene expression

W G Roberts et al. Am J Pathol. 1998 Oct.

Abstract

We have previously demonstrated that vascular endothelial growth factor-165 (VEGF), a tumor-secreted angiogenic factor, can acutely and chronically induce fenestrations in microvascular endothelium (Cancer Res 1997, 57:765-772). Because the morphology and function of microvascular endothelium differs from tissue to tissue, we undertook studies to examine whether the neovasculature in tumors also differed depending upon tumor location. Four tumor types implanted in the brain or subcutis in nude mice were studied: a murine rhabdomyosarcoma (M1S), a murine mammary carcinoma (EMT), and two human glioblastomas (U87 and U251). In addition, we studied Chinese hamster ovary cells stably transfected with human VEGF165. As previously reported, tumors grown in the subcutaneous space had a microvasculature that was fenestrated and had open endothelial gaps. The identical tumors when grown in the brain also had fenestrated endothelium and vessels with open endothelial gaps, but they were drastically reduced in occurrence. Open endothelial gaps were not seen in all tumors implanted in the brain (EMT and M1S), although fenestrated endothelium was always seen. VEGF and VEGF receptors were measured in tumors from both locations by immunoblotting and competitive polymerase chain reaction, respectively. VEGF amount was not significantly different between the tumor locations. Interestingly, total tumor vascular mRNA expression of both Flk-1 and Flt-1 was greater in tumor vessels derived from the brain compared with tumor vessels derived from subcutaneous tissues. These results demonstrate that the host microvascular environment determines the morphology and function of the tumor vasculature and that endothelia from different tissues vary in their ability to express the VEGF receptors given identical stimuli.

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Figures

Figure 1.
Figure 1.
Electron micrographs of vessels in the normal brain (A), VEGF:CHO (B), and M1S (C) tumors growing in the brain. An extensive electron-dense endothelial junction is common to normal brain vessels (A, j). This junction is drastically compromised in tumor vessels, in which the intercellular gaps can be as large as 260 nm (B and C, asterisks). VEGF:CHO tumors had numerous gaps (B, asterisks), which may be remnants of fenestrations (arrowheads). B: Boxed areas are shown as insets. Bars (A, B, insets, and C), 500 nm.
Figure 2.
Figure 2.
Tumor vascular morphometry of tumors grown in the brain (i.c.) or in the subcutis (s.c.). Bars represent the percentage of vessels with fenestrated endothelium (solid and narrow cross-hatch) and open endothelial gaps (hatch and cross-hatch). ND, not determined. All s.c. data are taken from Ref. 19 . *P < 0.001, #P < 0.005, and ∧P < 0.05 compared with host tissue vessels; see Materials and Methods for details on statistics.
Figure 3.
Figure 3.
Immunoblot of tumor lysates for VEGF. Tumors were grown either s.c. or in the brain. Twenty μg of protein were resolved on a nonreducing 10% polyacrylamide gel, transferred to nitrocellulose, and blotted as described in Materials and Methods. The VEGF:CHO tumors (VEGF) always had the most VEGF, whereas the glioblastomas (U87 and U251) generated the least amount of immunodetectible VEGF. Location minimally affected the amount of VEGF in these tumors. The ∼30-kd band in the U251 i.c. lane may be a VEGF monomer, given that RT-PCR determined that VEGF 121 and 189 were not substantially produced by any tumor. This band was variably present in other samples of tumor lysates.
Figure 4.
Figure 4.
Competitive PCR analysis of VEGF receptors. Data were acquired from phosphor imager analysis and plotted to obtain fg of receptor per reaction (A). Data were then normalized to μg of total RNA and plotted (B). Flk-1 (▪) and Flt-1 (░⃞), from tumors grown in the brain (i.c.) or in the subcutis (s.c.). Flk-1 mRNA always had equal or increased expression compared with Flt-1 regardless of tumor location. Tumors grown i.c. generally had increased expression of both receptors compared with tumors grown s.c. Data are represented as average ±SD of triplicate experiments on two to five tumors.
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