Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) is a powerful mitogenic and/or anti-apoptotic peptide produced by many cancer cells. To evaluate the potential role of the endothelin system in glioblastoma we first determined the cellular distribution of the mRNA and proteins of the components of the endothelin system, preproendothelin-1 (PPET-1), endothelin-converting enzyme-1 (ECE-1), and ET(A) and ET(B) receptors in human glioblastoma tissue and glioblastoma cell lines. PPET-1, ECE-1, and ET(A) receptor were highly expressed in glioblastoma vessels and in some scattered glioblastoma areas whereas ET(B) receptor was mainly found in cancer cells. This suggests that glioblastoma vessels constitute an important source of ET-1 that acts on cancer cells via the ET(B) receptor. Four human glioblastoma cell lines expressed mRNA for all of the components of the ET-1 pathway. Bosentan, a mixed ET(A) and ET(B) receptor antagonist, induced apoptosis in these cell lines in a dose-dependent manner. Apoptosis was potentiated by Fas Ligand (APO-1L, CD95L), a pro-apoptotic peptide, only in LNZ308 cells, corresponding to the known functional Fas expression in these cell lines. LNZ308 cells also expressed the long and short forms of the cellular FLICE/caspase-8 inhibitory protein (FLIP). Bosentan and a protein kinase C inhibitor down-regulated short FLIP in these cells. ET-1 induced transient phosphorylation of extracellular signal-regulated kinase but did not induce long-term thymidine incorporation in LNZ308 glioblastoma cells. These results suggest that, in glioblastoma cells, ET-1, mainly acting via the ET(B) receptor, is a survival/antiapoptotic factor produced by tumor vasculature, but not a proliferation factor, involving protein kinase C and extracellular signal-regulated kinase pathways, and stabilization of the short form of FLIP.
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PMID:The endothelin system in human glioblastoma. 1109 28

In the last decades, the active research in the field of tumor angiogenesis has led to the development of a class of agents providing an effective inhibition of neo-vessel formation through the blockade of VEGF related pathways. More recently, the identification of other factors involved in tumor angiogenesis, such as platelet-derived growth factor, fibroblast growth factor and Angiopoietins has emphasized the need to develop agents targeting multiple pro-angiogenic pathways. Although contrasting data are currently available regarding the clinical efficacy of multikinase inhibitors, Sunitinib, Sorafenib and Pazopanib have displayed encouraging results, and have fuelled further evaluations. Moreover, definitive data are also eagerly awaited regarding the clinical role of angiopoietins inhibitors. On the other hand, the existence of morphological, functional and architectural differences between normal and tumor vasculature has provided solid basis for the development of a novel class of compounds, known as Vascular Disrupting Agents (VDAs) able to selectively disrupt existing tumor vessels. After initial concerns related to the potential development of severe cardiovascular toxicities, further clinical investigations have shown a safe toxicity profile for these agents. Moreover, despite the discouraging data on dolostatin-10 and ASA404, several VDAs, including CAP4, Ombrabulin and Pinabulin have already shown promising activity in phase I-II clinical trials warranting more advanced evaluations. In this review we aimed at summarizing the most relevant VEGF-independent strategies targeting tumor vasculature, focusing on the clinical development of novel antiangiogenic agents including multikinase and angiopoietins inhibitors as well as VDAs.
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PMID:Novel VEGF-independent strategies targeting tumor vasculature: clinical aspects. 2239 Jul 58