AACR Special Conference in Cancer Research

A great amount of progress has been made in the last few years in elucidating the mechanisms of how blood vessels are formed in both normal and pathological processes. Vasculogenesis and angiogenesis are critical pathways in embryonic development. Aberrant angiogenesis is a major contributor to tumor growth and ocular disease. The discovery of positive and negative regulators of angiogenesis has led to a heightened understanding of how angiogenesis works and to the development of exciting new strategies to inhibit pathological angiogenesis, particularly in cancer. The AACR meeting was organized by Drs. Judah Folkman and Michael Klagsbrun (Children’s Hospital, Harvard Medical School, Boston, MA) for the purpose of updating new developments in angiogenesis research. About 450 people from over 25 countries representing academics, industry, and government attended the meeting, attesting to the heightened interest in the field of angiogenesis. Besides the 25 speakers, over 140 posters were presented. An important aspect of the conference was the refinement of older concepts of angiogenesis and the presentation of new concepts. Briefly, the topics and new concepts discussed included the following issues. (a) Normal blood vessel development was discussed. Hemangioblasts are the precursors of endothelial cells. Vasculogenesis, which was previously thought to be restricted to the embryo, occurs in the adult as well by virtue of the recruitment of EPCs from the peripheral circulation. Larger blood vessels are formed by the recruitment of smooth muscle cells, a process regulated by growth factors such as platelet-derived growth factor, transforming growth factor b, and angiopoietins. (b) Angiogenesis factors and their receptors were discussed. Extensive analysis has implicated VEGF and its two tyrosine kinase receptors, Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), as major regulators of normal and pathological angiogenesis. In tumors, VEGF synthesis is regulated by a number of factors including the environment (e.g., hypoxia, glucose levels, and nature of the host tissue), growth factors, oncogenes such as ras, and mutated tumor suppressor genes such as inactivated VHL. Angiopoietins and their receptors, Tie-1 and Tie-2, are also important regulators of angiogenesis. Vascular malformation appears to be a familial syndrome correlated with mutations in and overactivation of the Tie-2 receptor. The intensity of angiogenesis in tumor biopsies has been shown to be diagnostic as a tumor predictor for breast cancers and other tumors. Angiogenesis factors such as FGF and VEGF have therapeutic uses in vascularizing ischemic tissues. (c) Angiogenesis inhibitors and clinical applications were discussed. Novel strategies for inhibiting angiogenesis and subsequent tumor growth are being developed in many laboratories with potentially exciting therapeutic consequences. One approach has been to antagonize angiogenesis factors such as VEGF and angiopoietin 1 using humanized antibodies and soluble receptors that act as competitive inhibitors. Another approach has been to develop reagents that presumably act directly on endothelial cells to block their migration and/or proliferation or induce endothelial cell apoptosis. These novel inhibitors include angiostatin, endostatin, TSP, antibodies directed against the endothelial cell-associated integrin avb3,, ME inhibitors, and IFNs. Mouse models have been established to screen the various antiangiogenesis drugs. The keynote speaker was N. Le Douarin (Institute of Molecular and Cellular Embryology, Nogent/Marne, France). Dr. Le Douarin discussed the development of blood vessels in the avian embryo, in particular, the concept that there is a hemangioblast that is a common precursor to hematopoietic and endothelial cells. Hemangioblasts express VEGFR-2 (KDR/Flk-1), an endothelial cell marker. Fluorescence-activated cell-sorting analysis was used to isolate VEGFR-2positive cells from the lateral plate of somites. It was shown that the addition of VEGF caused these cells to become endothelial cells, whereas in the absence of VEGF, the colonies became hematopoietic. The first session addressed the mechanisms of blood vessel development. P. D’Amore (Children’s Hospital, Harvard Medical School) discussed the regulation of blood vessel assembly in which mural cells (pericytes and smooth muscle cells) are attracted by endothelial cells. In a coculture system. endothelial cells were shown to recruit undifferentiated 10T1/2 mesenchymal cells via the paracrine activity of platelet-derived growth factor BB. Contact between endothelial cells and 10T1/2 cells induced the 10T1/2 cells to express differentiated smooth muscle cell markers including smooth muscle a-actin, smooth muscle myosin, calponin, and SM22. Activated transforming growth factor b was demonstrated to be the inducing agent. Proliferation of both cells types was suppressed in the cocultures, but the identity of the inhibitory activity is unknown. Dr. D’Amore described a differential gene expression study in which quiescent bovine aortic endothelium in vivo expressed a soluble form of FrzA, whereas the expression of soluble FrzA was reduced rapidly when the endothelial cells were cultured. FrzA is a receptor for members of the Wnt family, and soluble FrzA might act as a functional antagonist of Wnt. The role of FrzA and Wnt in vascular growth and differentiation is under investigation. D. Ingber (Children’s Hospital, Harvard Medical School) discussed the role of mechanical forces and cell geometry in regulating endothelial cell proliferation, differentiation, and apoptosis based on the use of micropatterned substrates. This novel technology uses extracellular matrix-coated adhesive islands to vary the degrees of endothelial cell spreading and adhesion and makes it possible to dissociate these two variables and to individually determine their effects on Received 9/8/98; accepted 12/1/98. 1 This meeting, sponsored by The American Association for Cancer Research, Inc., took place January 24–28, 1998, in Orlando, FL. 2 To whom requests for reprints should be addressed, at Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. Phone: (617) 355-7503; Fax: (617) 355-7291; E-mail: [email protected]. 3 The abbreviations used are: EPC, endothelial progenitor cell; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; VHL, von Hippel Landau; FGF, fibroblast growth factor; bFGF, basic FGF; FrzA, frizzled receptor; sFlt, soluble Flt; VPF, vascular permeability factor; VVO, vesiculo-vacuolar organelle; TSP, thrombospondin; ME, metalloproteinase; MMP, matrix metalloproteinase; ADAM, a disintegrin and metalloproteinaise; CAM, chorioallantoic membrane; IFN, interferon; CNS, central nervous system.