Recent Advances in Angiogenesis and ... - Bentham Science

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FOREWORD It has been known for a very long time that blood vessels are essential to deliver oxygen, nutrients and key regulatory signals to the tissues. Early pioneers like Glenn Algire and Isaac Michaelson observed several decades ago that tumor growth and certain eye disorders resulting in impaired vision, including proliferative diabetic retinopathy, are accompanied by increased vascular proliferation and proposed that the new vessels play a pathogenic role in these disorders. In 1971 Judah Folkman was the first to appreciate the therapeutic potential of the field, proposing that anti-angiogenesis might represent a therapy for solid tumors. This vision has been, at least in part, fulfilled by the recent approval of several anti-angiogenic drugs for the treatment of advanced tumors and age-related macular degeneration. Also, as of February 2009, almost 40,000 Medline citations are found under the keyword “angiogenesis”, reflecting the interest among basic scientists and clinicians in this field. The progress in basic biology and in the clinical applications notwithstanding, much more needs to be done. Indeed, the clinical results with anti-angiogenic agents posed a series of questions that will need to be addresses before the field can advance in a meaningful way. To mention a few, it will be of great importance to identify the molecular pathways mediating tumor resistance to angiogenesis inhibitors, establish the most effective combinatorial therapies and identify the patients that are more likely to benefit from such treatments. The book edited by Prof. Domenico Ribatti provides a broad overview of the molecular and clinical aspects of angiogenesis and addresses the aforementioned questions. Chapters written by experts in their respective fields will make the reader acquainted with a variety of topics ranging from the role of axon guidance molecules in angiogenesis, the role of circulating endothelial cells in tumorigenesis, to the characterization of novel cellular and pharmacological approaches to inhibit angiogenesis. As such, the volume should be particularly useful to basic investigators, oncologists, opthalmologists and clinicians interested in the latest advances in this exciting field. i Napoleone Ferrara, M.D. Genentech Inc San Francisco, CA USA
ii PREFACE Angiogenesis, the process by which new blood vessels are formed, is an important event in both physiological and pathological conditions. Angiogenic and antiangiogenic molecules released by accessory cells control neovascularization, notably the migration and proliferation of endothelial cells, their morphogenetic differentiation in capillaries and the concurrent remodeling of the extracellular matrix. Under physiological conditions, these steps are tightly controlled, and loss of such control is an important feature of several diseases. Increased production of angiogenic stimuli and/or reduced production of angiogenic inhibitors leads to abnormal neovascularization, such as occurs in cancer, chronic inflammatory diseases, diabetic retinopathy, macular degeneration and cardiovascular disorders. Starting with the hypothesis of Judah Folkman that tumor growth is angiogenesis dependent, this area of research now has a solid scientific foundation. Several clinical studies have shown a positive correlation between the number of vessels in the tumor, metastasis formation and disease prognosis. Many solid and hematologic tumors in advanced stages are not curable with the currently available anticancer treatments, which primarily target the tumor cells. The genetic instability of tumor cells permits the occurrence of multiple genetic alterations that facilitate tumor progression and metastasis, and cell clones with diverse biological aggressiveness may coexist within the same tumor. These two properties allow tumors to acquire resistance to cytotoxic agents, which is still the main cause of treatment failure in cancer patients. Whereas conventional chemotherapy, radiotherapy, and immunotherapy are directed against tumor cells, antiangiogenic therapy is aimed at the vasculature of a tumor and will either cause total tumor regression or keep tumors in a state of dormancy. A number of approaches have been proved to inhibit tumor angiogenesis. Since tumor-associated angiogenesis develops as a physiological mechanism, its inhibition should not lead to emergence of resistance; and since each neovessel supplies hundreds of tumor cells, inhibition of angiogenesis should potentiate the oncostatic effect. By contrast, vascular targeting focused on specific molecular determinants of the neovasculature to be used for local delivering of a toxic effect that leads to a vascular damage and tumor necrosis. Numerous compounds inhibit angiogenesis, but few of them proved effective in vivo and only a couple of agents were able to induce tumor regression. Antiangiogenic tumor therapy has gained much interest in preclinical and clinical assessment. It has been estimated that over 10000 cancer patients worlwide have received experimental form of antiangiogenic therapy. However, the results from these clinical trials have not shown the dramatic antitumor effects which were expected following preclinical studies. This may be because of inadequate trial design in earlier studies. From the results obtained so far in clinical trials it can be concluded that the future clinical success of angiogenesis inhibitors could be related to their use in combination with chemotherapy or radiotherapy. The main problem in the development of antiangiogenic agents is that multiple angiogenic molecules may be produced by tumors, and tumors at different stages of development may depend on different angiogenic factors for their blood supply. Therefore, blocking a single angiogenic molecule was expected to have little or not impact on tumor growth. Currently, most of the FDA-approved drugs as well as those in phase III clinical trials target a
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Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
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Page 12 and 13: 10 Recent Advances in Angiogenesis
Page 16 and 17: The Role of Mesenchymal Stem Cells
Page 22 and 23: Thymus and Angiogenesis Recent Adva
Page 32 and 33: Role of Thymidine Recent Advances i
Page 34 and 35: Role of Stromal Cells Recent Advanc
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

Recent Advances in Angiogenesis and ... - Bentham Science

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