ANALYSIS OF THE TUMOR VASCULATURE AND METASTATIC BEHAVIOR OF XENOGRAFTS OF HUMAN-MELANOMA CELL-LINES TRANSFECTED WITH VASCULAR-PERMEABILITYFACTOR

Vascular permeability factor (VPF) is an important mediator of vascula r development in tumors, Some human melanoma cea lines have a low VPF expression level in culture, but this level is upregulated when growth as a tumor in nude mice, Other melanoma lines have a constitutively h igh VPF expression. To compare the biological behavior of tumors with these two expression patterns, a human melanoma cell line with an indu cible VPF expression was transfected with VPF-expression constructs, I n this way, several lines were obtained that constitutively Produce ei ther the soluble VPF121 or the matrix-associated VPF189 variant at lev els of 4 to 30 times the VPF level in mature tumors derived from the p arental line, The recombinant VPF RNA, which lacks most of the 5' nonc oding sequences present in the endogenous VPF mRNA, was much more effi ciently translated than the endogenous messenger Upon injection in nud e mice, all VPF-transfected lines developed tumors with aberrations in vascularization and in distribution of matrix components lit these tu mors the blood vessels were hyperpermeable for an i.v. injected protei n tracer, Transfection did not influence the in vitro growth rate of t he cell lines, but the tumors from the VPF-transfected lines had highe r growth rates in vivo than tumors front the parental line or the vect or-transfected line, Although the incidence of lung metastasis was sim ilar in all lines, the number of metastases per affected lung was sign ificantly increased in mice carrying VPF-transfectant tumors, We concl ude that the pattern and the level of VPF expression ia a tumor are im portant determinants of the architecture and functionality of the vasc ular bed but that over expression of VPF does not necessarily lead to an increase of microvascular density or metastatic spread, The rob of VPF in melanoma progression is obviously complex and may be difficult to derive in its generality from a single experimental model.