Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.
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PMID:Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction. 1207 78

The first generation of clinically useful antiangiogenic agents focused on VEGF and targets in the VEGF pathway. The strengths and limitations of these therapeutics are now clear. Some tumors do not respond to VEGF-directed therapies de novo and others become non-responsive or resistant over time by switching to other angiogenic pathways. The next generation of angiogenesis-directed therapeutics will expand the field beyond the VEGF pathway and become more disease selective. Placental growth factor, a protein closely related to VEGF, is induced as tumors lose responsiveness to VEGF-directed therapies. Angiopoietins 1 and 2 are being targeted with a unique peptibody, a human recombinant Fc constant region fused to peptides, in clinical trials. The HGF/c-Met pathway is upregulated in some tumors as an alternate angiogenic pathway. The CXCL12 (SDF-1)/CXCR4 pathway represents a stromal chemokine axis involved in tumor angiogenesis. CXCR2 is a G-protein coupled receptor with several ligands including interleukin-8 and other angiogenic cytokines and may represent a useful target for antiangiogenic agents. The notch pathway is being investigated as a target in the setting of tumor angiogenesis. Sphingosine-1-phosphate is a bioactive lipid that can be neutralized with a monoclonal antibody. The anti-S-1-P antibody is under investigation as an antiangiogenic agent. Finally, several multi-targeted kinase inhibitors each with a unique pattern of inhibitory potency are in clinical trial with a focus on antiangiogenic activity. The expansion of the scope of potential antiangiogenic agents in or entering clinical trial should allow the development of antiangiogenic combination regimens and single agents that address diseases refractory to VEGF-directed therapeutics.
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PMID:Antiangiogenic agents and targets: A perspective. 2092 Apr 81