A variety of tumor cells of both rodent and human origin secrete in vitro and in vivo, a novel vascular permeability factor with an approximate molecular weight of 38,000. This permeability factor (VPF) causes a rapid and completely reversible increase in microvascular permeability without causing endothelial cell damage or exciting an inflammatory cell infiltrate. Furthermore, VPF is active in the species from which it is derived (e.g., guinea pig tumor-secreted VPF is active on guinea pig vessels), and it does not appear to mediate its effects through histamine release, kinin generation, or prostaglandin synthesis. VPF is abundantly present in animal tumor ascites fluids but is not detectable in normal serum or plasma, and furthermore, while it is secreted by a variety of tumor cell lines (carcinomas and sarcomas), it is apparently not secreted by normal epithelial cells or fibroblasts. Direct comparisons between non-tumorigenic human cell lines and their tumorigenic derivatives suggest that expression of VPF is closely linked to neoplastic transformation, and taken together, out data suggest that tumor-secreted VPF is responsible, at least in part and perhaps to a large extent, for the fluid accumulation and increased vessel permeability commonly associated with tumor growth. A major goal is to purify this permeability factor to homogeneity and to obtain a panel of monoclonal antibodies specific for this protein. In addition, the purified protein will be subjected to amino acid sequence analysis; partial amino acid sequence and highly-specific antibodies will greatly facilitate efforts at cloning cDNA encoding VPF (not within the scope of the present proposal). A second major goal is to continue our study of the biology of VPF. Specific antibodies to VPF will be employed in immunoassays to investigate further the apparent correlation between expression of VPF and neoplastic transformation. In addition, blocking antibodies will be employed in animal models to ascertain the potential significance of VPF for tumor growth and fluid accumulation. Finally, experiments will be undertaken to identify non-malignant situations in which VPF might be expressed; and in particular the possibility that inflammatory cells secrete this protein will be examined.
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