Angiogenesis In Kaposis Sarcoma An Example Of Combined Action Between Angiogenic And Inflammatory Inducers

Kaposi's sarcoma (KS) is a multicentric, highly vascularized neoplasm, probably arising from a monoclonal population of circulating progenitor cells that home to multiple visceral and cutaneous sites (97,98). KS incidence is greatly enhanced in AIDS patients, being detected in about 20% of the affected individuals, who develop a particularly aggressive form (99). Four principal features of KS include the presence of spindle cells, which represent the core of the lesion; an aberrant proliferation of endothelial cells with prominent angiogenesis; the presence of infiltrating mononuclear cells; and increased vascular permeability. The histogenesis of spindle cells is still debated, but recent data, showing the co-expression of endothelial and macrophage antigens, permit speculation that the origin of spindle cells is in a precursor that differentiates in normal tissue in the sinus-lining cells of spleen and lymph nodes (100). The molecular mechanisms regulating the differentiation of a putative precursor into spindle cells are unknown. However, an unbalance of soluble mediator network seems to be pivotal in differentiation and growth of spindle cells, as well as in the recruitment of vascular and lymphomono-nuclear cells. A new herpesvirus, HHV8, has been associated with KS of all origins (101), and some of its genes are homologs to human genes. Among these, there are the homologous of IL-8 receptor (102), IL-6, and macrophage inflammatory protein-1 (103). Human

IL-6 regulates KS proliferation (104), and viral IL-6 can be integrated in an autocrine pathway. HIV-1-Tat is also thought to be the link between increased incidence and aggressiveness of KS in infected patients. Tat is officially the HIV-1 transactivating protein, responsible for viral transcription, but it has a number of extracellular activities relevant for KS pathogenesis. Through the activation of VEGF receptor-2 and -1, Tat promotes, respectively, angiogenesis and monocytes recruitment (105,106). Furthermore, Tat promotes the growth of KS cells (107) and the upregulation of adhesion molecules in endothelium, thus favoring leukocyte infiltration (108).

Besides these viral proteins, the production of autocrine and paracrine human soluble mediators has been demonstrated as relevant in the features of KS lesions. FGF (109), HGF (110), PAF (111), and VEGF-A (112) are instrumental for vascularization; platelet-derived growth factor (PDGF; 113) and TGF-P (114) are instrumental for the maturation of nascent vessels, through the recruitment of pericytes and smooth-muscle cells and the matrix remodeling. KS cells also produce chemokines (115), which, besides VEGF (3) and PAF (71), provide signals for monocytes. Inside the lesion, proteolytic enzymes released by macrophages, PAF, and VEGF participate in the increasing vascular permeability. Furthermore, FGF (109), HGF (110), VEGF (112), PAF (111), IL-1 (116), PDGF (113), TGF-p (114), oncostatin M (117), IL-6 (104), and GM-CSF (118) are also autocrine/paracrine activators of KS spindle cells.

Indeed, KS is an example of co-operation between growth and inflammatory factors supporting the expansion of neoplastic cells, and can represent an appropriate pathological condition to test antiangiogenic compounds in adjuvant therapy of cancer.

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