engleski

The role of Vascular Factors in Tumor Growth

Although it has been observed for decades that neoplastic tissues are more vascular than related normal tissues, it is only since Folkman proposed his anti-angiogenesis hypothesis that it is recognized that tumors require a vascular supply for progressive growth. Because of its central role in pathogenesis of neoplasia, tumor angiogenesis is now considered one of the most important factors of tumor biology. Consequently, the tumor vasculature has become an important target in cancer treatment and an area of intensive research. The regulation of tumor-associated angiogenesis is a complex process involving many factors. In last few years, there have been dramatic advances in our understanding of angiogenesis and in knowledge of factors regulating this process. It is now well accepted that controlling angiogenesis is critical to clinically control cancer and other angiogenesis-dependent diseases. The list of known angiogenic stimulators and inhibitors is continuously increasing. There are now many well-characterized pro-angiogenic and anti-angiogenic agents and factors. Pro-angiogenic agents can be further divided into several categories: growth factors, proteases, trace elements, oncogenes, cytokines, signal transduction molecules, and endogenous inducers. Some of the most potent pro-angiogenic factors include: vascular endothelial growth factor/vascular permeability factor (VEGF/VPF); basic fibroblast growth factor (bFGF); and hepatocyte growth factor/scatter factor (HGF/SF). Other positive regulators of angiogenesis include: angiopoietin-1; angiotropin; angiogenin; epidermalgrowth factor (EGF); granulocyte colony-stimulating factor (G-CSF); interleukin-1 (IL-1); IL-6; IL-8; platelet derived growth factor (PDGF); and tumor necrosis factor-alpha (TNF-alpha). In addition, matrix proteins (such as collagen and fibrin) and cell surface molecules (especially the integrins) are extremely important regulators of the angiogenesis process. Finally, proteolytic enzymes are also considered to be key regulators of angiogenesis. Those include: cathepsins; urokinase-type plasminogen activator; and several matrix metalloproteinases (especially gelatinase A/B, and stromelysis). Angiogenesis can be physiologically suppressed by several recently characterized endogenous inhibitors such as angiopoietin-2, angiostatin, endostatin, interferon-alpha (INF-alpha), platelet factor-4 (PF-4), prolactin (16kD fragment), thrombospondin, the tissue inhibitors of metalloproteins (TIMP-1, TIMP-2 and TIMP-3), and troponin I. Endogenous inhibitors also include caveolin-1 and –2. These molecules are highly expressed in endothelial cells where they mediate action of endogenous and exogenous factors regulating angiogenesis. Hence, several angiogenic growth factors (bFGF, HGF/SF, VEGF) down-regulate expression of caveolin, while several angiogenesis inhibitors (angiostatin, fumagillin, and thalidomide) up-regulate caveolin expression. For certain factors, exact role played in the angiogenesis process is obscure or variable. Therefore, TNF-alpha, transforming growth factor-beta (TGF-beta), or IL-4 are bifunctional modulators - these molecules are either stimulators or inhibitors depending on several factors such as local concentration, location, microenvironment, or presence of other cytokines. In addition to the recent characterization of these pro- and anti-angiogenic agents, research efforts have focused on molecular mechanisms underlying tumor-associated angiogenesis. A good illustration is investigation linking p53 to the angiogenesis process. Inactivating mutations of the p53 gene occurs in more than half of all human cancers and is also frequent in animal tumors. The mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and malignant progression. Exogenous expression of wild type p53 inhibits angiogenesis in vivo resulting in formation of dormant tumors. By inhibiting angiogenesis, p53 indirectly induces apoptosis in vivo but not in vitro and can revert tumors to a dormant phenotype. It has been shown that using fibroblasts, these cells become fully angiogenic in two steps. Firstly, there is loss of both alleles of wild-type p53, which causes a 20-fold drop in secreted thrombospondin and a fourfold increase in secreted VEGF. Secondly, angiogenic activity increases further following activation of the ras oncogene. Thus, there is a step-wise change in the angiogenic phenotype in response to oncogene activation and tumor suppressor gene loss, resulting in decreased secretion of angiogenesis inhibitors and sequential up-regulation of angiogenesis inducers. Search for efficacious anti-angiogenic therapies is currently a major focus of many pharmaceutical companies and academic institutions, and results from clinical trials are very promising. However, more effort will be required to identify selective and potent inhibitors, to appropriately find the optimal combinations between angiosuppressive and cytotoxic therapies, and to design optimal formulations, routes of administration, and dosing schedules. References are available upon request.

vascular factors; tumor

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