Analysis of the tumor vasculature and metastatic behavior of xenografts of human melanoma cell lines transfected with vascular permeability factor.

Vascular permeability factor (VPF) is an important mediator of vascular development in tumors. Some human melanoma cell lines have a low VPF expression level in culture, but this level is upregulated when growing as a tumor in nude mice. Other melanoma lines have a constitutively high VPF expression. To compare the biological behavior of tumors with these two expression patterns, a human melanoma cell line with an inducible VPF expression was transfected with VPF expression constructs. In this way, several lines were obtained that constitutively produce either the soluble VPF121 or the matrix-associated VPF189 variant at levels of 4 to 30 times the VPF level in mature tumors derived from the parental line. The recombinant VPF RNA, which lacks most of the 5' noncoding sequences present in the endogenous VPF mRNA, was much more efficiently translated than the endogenous messenger. Upon injection in nude mice, all VPF-transfected lines developed tumors with aberrations in vascularization and in distribution of matrix components. In these tumors the blood vessels were hyperpermeable for an i.v. injected protein tracer. Transfection did not influence the in vitro growth rate of the cell lines, but the tumors from the VPF-transfected lines had higher growth rates in vivo than tumors from the parental line or the vector-transfected line. Although the incidence of lung metastasis was similar in all lines, the number of metastases per affected lung was significantly increased in mice carrying VPF-transfectant tumors. We conclude that the pattern and the level of VPF expression in a tumor are important determinants of the architecture and functionality of the vascular bed, but that overexpression of VPF does not necessarily lead to an increase of microvascular density or metastatic spread. The role of VPF in melanoma progression is obviously complex and may be difficult to derive in its generality from a single experimental model.