Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels.

Abstract

Vascular permeability factor (VPF) is a highly conserved 34-42-kD protein secreted by many tumor cells. Among the most potent vascular permeability-enhancing factors known, VPF is also a selective vascular endothelial cell mitogen, and therefore has been called vascular endothelial cell growth factor (VEGF). Our goal was to define the cellular sites of VPF (VEGF) synthesis and accumulation in tumors in vivo. Immunohistochemical studies were performed on solid and ascites guinea pig line 1 and line 10 bile duct carcinomas using antibodies directed against peptides synthesized to represent the NH2-terminal and internal sequences of VPF. These antibodies stained tumor cells and, uniformly and most intensely, the endothelium of immediately adjacent blood vessels, both preexisting and those newly induced by tumor angiogenesis. A similar pattern of VPF staining was observed in autochthonous human lymphoma. In situ hybridization demonstrated VPF mRNA in nearly all line 10 tumor cells but not in tumor blood vessels, indicating that immunohistochemical labeling of tumor vessels with antibodies to VPF peptides reflects uptake of VPF, not endogenous synthesis. VPF protein staining was evident in adjacent preexisting venules and small veins as early as 5 h after tumor transplant and plateaued at maximally intense levels in newly induced tumor vessels by approximately 5 d. VPF-stained vessels were also hyperpermeable to macromolecules as judged by their capacity to accumulate circulating colloidal carbon. In contrast, vessels more than approximately 0.5 mm distant from tumors were not hyperpermeable and did not exhibit immunohistochemical staining for VPF. Vessel staining disappeared within 24-48 h of tumor rejection. These studies indicate that VPF is synthesized by tumor cells in vivo and accumulates in nearby blood vessels, its target of action. Because leaky tumor vessels initiate a cascade of events, which include plasma extravasation and which lead ultimately to angiogenesis and tumor stroma formation, VPF may have a pivotal role in promoting tumor growth. Also, VPF immunostaining provides a new marker for tumor blood vessels that may be exploitable for tumor imaging or therapy.

Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors.

“…Studies from our laboratory (Nagy et al, 1988;Dvorak et al, 1991) support the hypothesis that VPF plays an important role in aiding growth of some tumors by promoting both tumor angiogenesis and stroma generation. In accord with earlier findings (Senger et al, 1986) .k-A w expression was correlated with tumorigenicity in matched pairs of cultured cell lines.…”

Intraperitoneal VEGF Inhibition Using Bevacizumab: A Potential Approach for the Symptomatic Treatment of Malignant Ascites?

“…In addition, peritoneal mesothelial cells [35], monocytes/macrophages infiltrating malignant effusions [36], and even tumor-infiltrating T cells [37] are capable of producing VEGF. By interacting with two high-affinity tyrosine kinase receptors (Flt-1 and KDR/Flk-1), which are selectively expressed in the vascular endothelium [38], VEGF acts on the endothelium both normal and newly induced by tumor angiogenesis [39].…”

“…In vitro and in vivo, VEGF stimulates the full cascade of events required for angiogenesis [44] and is thought to play a decisive role in the vascularization of neoplastic tissue [45]. In addition to its ability to promote angiogenesis, VEGF is also capable of mark-edly augmenting the permeability of pre-existing microvasculature [29,39,46]. VEGF is overexpressed in a variety of tumors causing malignant ascites [47][48][49].…”

Stabilization of breast cancer xenograft tumour neovasculature by angiopoietin-1

“…Ang1 gene expression in utero is closely associated with vascular endothelial cell growth factor (VEGF, initially known as vascular permeability factor, VPF (Dvorak et al, 1991)) and in physiological angiogenic processes in adults such as ovulation (Maisonpierre et al, 1997). Null mutation of the Ang1 gene in transgenic animals led to failure of endothelial cells to form stable associations with supporting mesenchymal cells and failure of primitive capillaries to develop into a mature branched network (Suri et al, 1996).…”