Angiogenesis Program Meeting
The most recent meeting of the Angiogenesis Group, marking the 10th Anniversary of the Program was hosted by Dr. Ralf Pettersson (Stockholm Branch Director) on March 30th and 31st, and was designed to allow the Program Members to present novel findings and exchange ideas for future collaborative studies. Because much of the data has not been published, only brief summaries are given herein.
The Angiogenesis Program has focused particularly on the localization, function and activation of angiogenic ligands, members of the Program having discovered three of the five vascular endothelial growth factors (VEGFs) and two of the four platelet-derived growth factors (PDGFs) involved in angiogenesis and lymphangiogenesis. However, with the progression of this research, the Program members are now extending their investigations inter alia into the structure and function of tumor stroma, angiogenic and lymphangiogenic vasculature, mechanisms of metastases, and ligand processing and action. The collaborative work has also progressed to the point where therapeutic targets and approaches can now be examined rationally in light of current knowledge.
Angiogenesis Program Meeting attendees on a frosty Stockholm morning.
Genetics
Dr. Arne Ostman (Karolinska Hospital) outlined gene expression studies of the stroma isolated from basal cell carcinomas compared to stroma from other cancers and from wounds. Fascinatingly, a series of genes were identified that were not upregulated in the stroma from other forms of cancer (e.g. breast) but were upregulated in stroma from wounds and basal cell carcinomas (which seldom metastasize). The functional role of the identified genes is being investigated.
Dr. Kari Alitalo (Helsinki Affiliate Center) presented some results on his analysis into the distinct genetic makeup of lympho-endothelial cells (the cells that line lymphatic channels) compared to vascular endothelial cells as part of his studies on the functional anatomy of the lymphatic system.
Biochemistry
Dr. Marc Achen (Melbourne Branch) has been investigating ligand processing, and described methods for producing the active form of VEGF-D from its higher molecular weight precursor. This is effected by a series of enzymes known as preprotein convertases all of which could be targets for therapy. The down regulation of convertases may have importance in relation to tumor biology in general and forms a particularly interesting area of Dr. Achen’s future research.
Dr. Ulf Eriksson (Stockholm Branch) has continued his extensive study of PDGFs and has shown that PDGF-C is degraded specifically to yield an active form. PDGF-D, produced by a variety of tumors, appears to be responsible at least for the formation for their stroma, and Dr. Eriksson’s findings suggest that PDGF-D also needs to be metabolized to produce an active form. The analysis and comparison of PDGF ligand-processing are ongoing.
Dr. Xin Lu (London Branch) discussed her findings on the contribution of the ASPP family of proteins to neoplasia and the vascular system of tumors following her observation of the presence of such molecules in endothelial cells. Additionally, surprising overlaps between the findings of Drs. Lu and Eriksson with regard to the intracellular effects of ASPPs and VEGFs have now initiated a new collaboration.
Dr. Seppo Ylä-Herttuala (Kuopio Affiliate Center) presented results from a series of experiments with adenovirus constructs of VEGF ligands in animal models. The VEGF ligands have surprisingly different activities in vivo, and most of the findings can be directly extrapolated to ligand expression and pathologies in human tumors. Relief of myocardial and peripheral vascular insufficiency are further areas amenable to this technology.
Cell Biology
Dr. Alitalo described in some detail his recent studies of the function of lympho-endothelial cells and the anatomy of the lymphatic system, including its role in metastases.
Dr. Anne Ridley (London Branch) discussed her research into endothelial cells in culture and the mechanisms by which cells transverse either between endothelial cells or through them directly. The model developed by Dr. Ridley is currently being modified to allow the additional analysis of pericytes, a cell type about which Dr. Christer Betsholtz (Gothenburg Affiliate Center) has published extensively. Recent data on novel extra- and intracellular pericyte markers were presented by Dr. Eriksson on behalf of Dr. Betsholtz who could not attend the meeting in person.
Dr. Peter ten Dijke (Amsterdam Affiliate Center) discussed TGF-β and its role in endothelial cell biology and mechanisms whereby the signal is transduced through the ALK1 and ALK5 receptors. Areas where inhibitory antibodies and small molecules could be important for future clinical studies were highlighted.
Therapy Targets
Dr. Steve Stacker (Melbourne Branch) discussed the functional properties of antibodies against VEGF receptor-3 (VEGFR-3) obtained through an industrial collaborative venture with LICR and their role in inhibiting the development of experimental metastases. Dr. Stacker compared these results with those obtained by Drs. Achen and Stacker using their own neutralizing antibody to VEGF-D. The alternative, as presented by Dr. Alitalo, is the VEGFR-3 trap, which may be a more effective reagent than either antibody, albeit being more difficult to produce and use.
Dr. Kristian Pietras (University of California, San Francisco) described the rip-tag model of islet cell carcinoma (transgenic mice expressing the oncogenic SV40 large T antigen under the transcriptional control of the insulin promoter) and the therapeutic role of PDGF-R inhibitors and metronomic therapy, which he has been studying as a postdoctoral fellow with Dr. Douglas Hanahan. He additionally described interesting models of cervical cancer and its evolution through various stages following experimental induction with HPV16 limited to a keratin promoter.
The meeting was viewed by all as most successful. It was notable in several respects, not least for extending its perspectives including the introduction of further biological systems to explore the functions of the various ligands and the commencement of new anti-cancer clinical objectives particularly related to the PDGF-C/D’s and cancer stroma.