Studies of VEGF-B and novel PDGFs in tumorigenesis and angiogenesis

Sammanfattning: The family of VEGF/PDGF growth factors and their receptors are important regulators of tumorigenesis and angiogenesis. VEGFs have been shown to play important roles in development of both blood and lymphatic vessels by effect on endothelia cells. PDGFs, on the other hand, are essential for normal function of perivascular cells, also for induction of tumor stroma reactions. This thesis work has focused on elucidating the expression pattern of two isoforms of VEGF-B and functional regulation of two novel PDGF family members, PDGF-C and PDGF-D in tumor growth and tumor angiogenesis. Characterization of the expression pattern of two isoforms of VEGF-B, VEGF-B167 and VEGF-B186 in tissues and cell lines indicate that VEGF-B167 is the predominant isoform in most mouse tissues, accounting for about 80% of the total VEGF-B transcripts. VEGF-B186 is almost non-detectable within the same tissues. However, VEGF-B186 is up-regulated in mouse and human tumor cell lines, and primary tumors compared with their corresponding normal tissues. These data suggest a fine genetic control of the expression of two isoforms of VEGF-B, implying that VEGF-B186 might be involved in tumor development. The novel PDGFs, PDGF-C and PDGF-D have a unique domain structure compared with the classical PDGFs, PDGF-A and PDGF-B. They contain a CUB domain besides the VEGF/PDGF homology domain. Importantly, the CUB domain has to be proteolytically removed before these factors could bind and activate their cognate receptors. We have focused on two issues, 1) to characterize the role of the novel PDGFs during tumor development, and 2) to identify the protease involved in activation of the novel PDGFs. The tumorigenecity of the novel PDGFs were determined by their transformation efficacy in NIH/3T3 cells and in tumor cell lines. We identified that the novel PDGFs are potent transforming growth factors. The transformed cells displayed increased proliferation rate, anchorage-independent growth in soft agar, upregulation of VEGF, ability to induce tumors in nude mice. This data suggested that the novel PDGFs play an important role in cellular transformation and in tumor stromal reaction. We identified the clot-busting protease, tissue-plasminogen activator (tPA), as a specific PDGF-C, but not PDGF-D, activating protease. The identification of tPA as an activator of PDGF signaling establishes a novel role for the protease, distinct from its well-known role in plasminogen activation and fibrinolysis. Most importantly, it shed light on regulation control of PDGF-C in vivo.