UICC study group on basic and clinical cancer research: Angiogenesis revisited

It is the purpose of these study group meetings, which are organized by the Tumor Biology Program of UICC, to establish a basis for possible clinical applications founded on molecular concepts. For this purpose, a few clinicians, pathologists and epidemiologists are invited together with a core group of cell and molecular biologists. The meetings are of a particularly informal nature, to foster the exchange of ideas rather than to discuss data. It is for this reason that no book is published as a follow-up but, rather, the present brief report. More detailed data can be requested from the participants directly. Their addresses are provided at the end of this report. Six years ago, at our last meeting on tumor angiogenesis (Burger and Folkman, 1994), presentations and, particularly, discussions centered primarily on the newly discovered endothelial growth factors and, to a lesser extent, on therapy and deeper insights into the process of tumor angiogenesis, to unravel more selective and tumor vessel growth–specific drug targets. This time, the emphasis was reversed. In view of the fact that 6 years later only the first human tumor angiogenesis–targeted drugs are in their latest clinical test stages and are not free from side effects, we thought it timely to revisit this topic and devote more time to the biology and the process of angiogenesis. Most study group meetings over the last 6 years have been one-sidedly devoted to molecular tumorigenesis issues (Burger and Harris, 1995; Burger and Harlow, 1995; Burger and Friend, 1996; Burger and Moses, 1997); this, then, was a second reason to revert to a topic like tumor angiogenesis, where pathobiological considerations are still in the foreground, to understand the neoplastic process and devise new therapeutic approaches. The highlight at this study group meeting dealt with a possible therapeutic breakthrough, consisting of continuous low-dose chemotherapy. Such an approach does not only reduce tumor-cell resistance but may prevent regrowth of vessels in the therapy-free interval and should be combined with specific angiogenesis inhibitors. The core discussions focused, nevertheless, on neovascularization. Is it different in tumor vs. embryonal or wounded tissue? How are newly formed vascular trees stabilized, and can the vascular maturation process be inhibited independently from the endothelial outgrowth from stem cells? How do concepts like heterogeneity of vessels, organ specificity and cross-talk between new vessels and peri-vascular tissue influence new therapeutic approaches? The fact that there was ample time for discussion compared to that for presentation guaranteed a lively exchange of opinion on such issues. Since chemotherapy may act not only on tumor cells but also on the growth of endothelial cells (ECs), Dr. J. Folkman discussed the finding of Dr. T. Browdar that the anti-tumor effect of cytotoxic chemotherapy (cyclophosphamide) can be significantly improved, and drug resistance circumvented, by optimizing dose and schedule for microvascular ECs instead of tumor cells. These results from “anti-angiogenic chemotherapy” may explain why certain patients whose cancer has failed to respond to all therapies become stable and relatively asymptomatic if chemotherapy is administered frequently and at a low dose for prolonged periods of time (e.g., years). Folkman speculated that anti-angiogenic chemotherapy could be more effective than conventional chemotherapy for brain tumors because the drug could be chosen to selectively inhibit proliferating ECs and would not need to cross the blood–brain barrier. In the same vein, Dr. R.S. Kerbel summarized his results of experiments designed to evaluate the effects of continuos low-dose (“metronomic”) chemotherapy used in combination with anti-vascular endothelial growth factor (VEGF) receptor-2 blocking antibodies as a non-toxic, “resistance-free” treatment strategy. The combination approach was reported to be effective against a variety of human tumor xenografts (neuroblastoma, breast carcinoma, prostate carcinoma) grown ectopically or orthotopically. The treatment was effective on cell lines previously selected for very high levels of acquired resistance to the cytotoxic drug used, e.g., vinblastine, paclitaxel (Taxol) or cisplatinum. In some cases, it took as long as 3 to 4 months of continuous therapy before differences emerged between the combination-treatment groups and the single-treatment arms (“delayed divergence”). Among the chemotherapeutic drugs tested, there was a suggestion that vinblastine may be the most effective for the metronomic dosing concept. The results of a phase II clinical study in cancer patients using a humanized anti-VEGF monoclonal antibody in combination with chemotherapy were presented by Dr. N. Ferrara. Evidence of clinical efficacy was found in colorectal and non-small-cell lung-carcinoma patients. Phase III studies to validate and extend such findings are in progress. Detailed criteria for an ideal anti-angiogenesis drug or for designing an anti-angiogenic cocktail were outlined by Dr. V.P. Sukhatme and would be too extensive to summarize here. He illustrated his concept with 2 examples: first, the partial purification of a protease derived from ovarian-cancer ascites fluid that is highly specific for ECs and, second, the potency of a cocktail of plasminogen activator, the ACE inhibitor captopril and vinblastine. A clinical trial to test this will soon be under way. While in earlier times the process of ontogenic angiogenesis was often considered to be similar to tumor angiogenesis and both types of vessel were thought to differ from adult mature vessels, it became increasingly evident that slight histologic differences do exist between embryonal and tumor vasculature and even between tumor and wound neovasculature. Such differences may exist also on the molecular level and may become therapeutic targets. Dr. P.A. D'Amore reminded the participants that anti-angiogenic therapy for tumors or ocular neovascularization is based on the fact that growing and/or nascent vessels are phenotypically very different from stable, mature vessels. For this reason, it is important to understand the mechanisms by which new vessels become stabilized and, conversely, how mature vessels are stabilized. Pointing out that intercellular dynamics and signaling will become a cornerstone in understanding such a maturation process, she concluded specifically that heterotypic cell–cell interactions between ECs and pericytes, ECs and tumor cells or ECs and tissue parenchymal cells will contribute decisively to the state of vessel stabilization via paracrine communication. Dr. L.E. Benjamin has shown that regulation of vessel survival is one of the roles of VEGF in both development and cancer. Her group found that normal vascular remodeling includes vessel regression in blood vessels without peri-vascular smooth muscle when VEGF levels are reduced. Similar results were demonstrated in xenograft tumors and human prostate carcinoma in situ, suggesting that anti-VEGF therapies may function not only by blocking EC proliferation but also by inducing EC apoptosis and vessel regression. Dr. J.M. Isner pointed out that the heterogeneity of post-natal neovascularization, occurring naturally or in response to therapeutics, constitutes an important enigma. One factor contributing to such heterogeneity is variable enhancement of ligand expression in response to ischemia. A second factor is variable ability to mobilize, home and integrate precursor ECs. An adenoviral vector was used by Dr. H.F. Dvorak to express murine vascular permeability factor (VPF)/VEGF in a variety of tissues of normal adult immunodeficient (nude) mice. The initial response (1 to 3 days) was the same in all tissues studied: increased vascular permeability, extravasation of plasma proteins, extravascular clotting of fibrinogen to deposit an extravascular and pro-angiogenic fibrin gel. “Mother” vessels (greatly enlarged, pericyte-poor vessels) developed within 18 hr from pre-existing microvessels as a result of basement-membrane degradation and pericyte detachment. Thereafter, the angiogenic response was tissue-specific in that different types of vessel evolved from mother vessels in different tissues. These included normal capillaries, large arteries and glomeruloid bodies. In sum, the angiogenic response to VPF/VEGF mimics tumor vessels but is heterogeneous and tissue-specific. Dr. R.K. Jain discussed the structural and functional heterogeneity of tumor vessels. He showed that this may stem from, in part, the incorporation of cancer cells into the lining of tumor vessels, leading to the so-called mosaic vessels. This heterogeneity in tumor vessels may also result from the tumor–host interaction. The tumor–host interaction may govern not only the beneficial response of tumors to various therapies but also the adverse (toxic) effects in normal tissues. Since the conceptual questions in neovascularization do not primarily lie in the receptor-signaling field anymore, this was not a main topic. The 2 contributions in this field, therefore, dealt specifically with migration signaling and whether vascular growth factors may also have a role in non-solid tumor growth, i.e., leukemias. Dr. M. Klagsbrun pointed out that neuropilin (NRP1) is a receptor for both semaphorins, inhibitors of neuronal axon migration, and VEGF. NRP1 is expressed by ECs and tumor cells, and these cells bind VEGF165 to NRP1. In ECs, NRP1 appears to be a co-receptor for VEGFR-2, which enhances VEGF165 binding to VEGFR-2 and VEGFR-2–mediated chemotaxis. However, semaphorins acting via NRP1 are inhibitors of EC migration and in vitro angiogenesis. Semaphorins and VEGF compete for binding to NRP1. It was suggested that NRP1 is either a positive or a negative regulator of angiogenesis, depending on whether it binds VEGF165 or semaphorin, respectively. Dr. S. Rafii discussed emerging data which suggest that growth and proliferation of leukemias and lymphomas are also angiogenesis-dependent. Autocrine and paracrine pathways generated by VEGF and its receptors, specifically VEGFR-2 (KDR, Flk-1), are essential for the growth of leukemias and lymphomas. Incorporation of precursor ECs into the vascular bed of leukemias and lymphomas is critical for growth. Inhibition of the VEGF/VEGFR-2 signaling pathway blocks the growth of leukemias and lymphomas, in part by blocking recruitment of precursor ECs. These studies set the stage for evaluations of anti-angiogenesis therapy of liquid tumors, including leukemias and lymphomas. Pro-angiogenesis is an area of interest primarily for the cardiologist who looks forward to agents promoting reperfusion. Oncologists, however, must be aware that anti-angiogenic treatment will eventually lead to risks in elderly patients, where pro-angiogenic processes become relevant. Cardiologists, such as Dr. P. Libby, are aware that atherosclerosis has features which resemble a neoplastic disease, benign from the cancer biologist's viewpoint but quite malignant clinically. Like some cancers, atherosclerosis has important immune and inflammatory aspects. Like tumors, atheromas do not kill only by a mass effect. Rather, arterial occlusion most often results from thrombosis. Lesion evolution and complication may relate in part to the rich microvasculature engendered by the immune/inflammatory response. Intra-plaque hemorrhage and thrombosis in situ may promote lesion growth and rapid plaque expansion. Dr. P. Libby's group has uncovered important links between the immune and inflammatory response in atheromas and stimuli for angiogenesis. The potential adverse effects of stimulating plaque angiogenesis should be kept in mind when designing pro-angiogenic therapies for ischemic heart disease. Dr. B.R. Zetter described his work with thymosin (15, a protein that is up-regulated in metastatic prostate cancer. He showed how the appearance of thymosin (15 in a primary prostate cancer can predict whether that particular tumor gives rise to distant metastases. In addition, he pointed out that thymosin (15 is pro-angiogenic and that release of thymosin (15 by prostate cancer cells may potentiate tumor angiogenesis. Although these processes have been in the limelight of the metastasis and tumor angiogenesis field for a long time and numerous molecular culprits have been implicated as influencing them, therapeutically important breakthroughs are still missing; therefore, outlooks, as in the 3 following presentations, were extremely helpful contributions to the meeting. Dr. R. Hynes reminded the participants that antagonists of αv integrins can inhibit angiogenesis in a number of situations. In contrast, genetic ablation of αv integrins has surprisingly little impact on angiogenesis, again in a number of situations. These 2 sets of data need to be reconciled. Several possible explanations can be considered and need to be investigated experimentally. Metastasis must involve alterations in cell adhesion. The pending availability of a complete list of genes encoding adhesion molecules makes possible a systematic investigation of this hypothesis. Screening of around 10,000 genes has revealed 32 genes that are consistently up-regulated in highly metastatic melanomas. Many of these involve regulation of extracellular matrix and/or the cytoskeleton. One of these genes, rhoC, is an essential player in metastasis. Further investigation along these lines should reveal other important metastasis genes. Dr. D. Hanahan described murine models of multistage tumorigenesis, wherein angiogenesis is activated in pre-malignant stages and persists in tumors. A matrix metalloproteinase (MMP), gelatinase B/MMP-9, is activated during carcinogenesis of the pancreatic islets and the epidermis. Among its functions is the regulation of the bioavailability of VEGF since gene knockout mice, MMP inhibitors and a VEGF-receptor inhibitor produce similar impairment of angiogenic switching and tumor growth in the islet carcinoma model. Other results suggest that the key suppliers of gelatinase B in both models are cells of the immune system, raising the notion that inflammatory cells are conscripted to serve the developing neoplasias. Dr. S.C. Silverstein described neutrophil transmigration across the endothelium as an instructional process in which chemoattractant-stimulated neutrophils signal a rise in calcium in ECs, activation of myosin light-chain kinase phosphorylation of threonine-18 and serine-19 of myosin regulatory light chains (MRLCs), EC retraction and opening of junctions between ECs. Agents that block this rise in EC calcium or activation of EC myosin light-chain kinase block phosphorylation of MRLCs and inhibit neutrophil transmigration, indicating that myosin-mediated EC retraction is required for neutrophil extravasation. Both secreted products and binding of activated leukocyte integrins to their counter-receptors on ECs have been suggested as signaling mechanisms. This meeting was sponsored by Novartis, Inc. (Basel, Switzerland). The Tumor Biology Program of UICC (Dr. K. Höffken) and the participants express their gratitude for the unselfish support and low-key presence of the sponsor. BENJAMIN, L.E., Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA BURGER, M.M., Friedrich Miescher Institut, Basel, Switzerland D'AMORE, P.A., Center For Research on the Aging Eye, Schepens Eye Research Institute, Boston, MA, USA DVORAK, H.F., Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA FERRARA, N., Genentech, Inc., South San Francisco, CA, USA FOLKMAN, J.M., Surgery Research Laboratory, Children's Hospital, Harvard Medical School, Boston, MA, USA HANAHAN, D., Department of Biochemistry and Biophysics, Hormone Research Institute, University of California, San Francisco, CA, USA HEIM, J., Novartis Inc., Basel, Switzerland HYNES, R., Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA ISNER, J.M., Division of Vascular Medicine, St. Elizabeth's Medical Center, Boston, MA, USA JAIN, R.K., Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA KERBEL, R.S., Division of Cancer Biology Research, Sunnybrook and Women's College Health Science Center, Toronto, Ontario, Canada KLAGSBRUN, M., Children's Hospital, Medical Center, Harvard Medical School, Boston, MA, USA LIAU, G., Genetic Therapy, Inc., Gaithersburg, MD, USA LIBBY, P., Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA PARDEE, A.B., Department of Pharmacology, Dana Farber Cancer Institute, Boston, MA, USA RAFII, S., Weill Medical College, Cornell University, New York, NY, USA SILVERSTEIN, S.C., Department of Physiology and Cell Biophysics, Columbia University, New York, NY, USA SUKHATME, V.P., Renal Division, Beth Israel Deaconess Medical Center, Boston, MA, USA WATNICK, R., Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA WOOD, A., Novartis Pharmaceutical Corp., Summit, NJ, USA WOOD, J., Novartis Inc., Basel, Switzerland ZETTER, B.R., Surgery Research Laboratory, Children's Hospital, Harvard Medical School, Boston, MA, USA

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.