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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The value of tumor angiogenesis, EGFR and c-erbB-2 oncoprotein, a long with p 53 protein expression for predicting relapse-free survival was investigated in 110 node-negative breast cancer patients. The grade of neovascularization was assessed by the microvessel density which was obtained by an immunocytochemical staining by factor VIII-related antigen. EGFR, c-erbB-2 oncoprotein and p 53 oncoprotein were also determined by immunocytochemical assay. Univariate analysis showed no statistical significance of EGFR, c-erbB-2 and p53 status as a prognostic indicator. However, the microvessel density was a significant predictor of relapse-free survival. Patients with over 100 counts of factor VIII-RA positive cells per mm2 field in the most active areas of neovascularization showed significantly poorer prognosis compared to those with less than 100 counts (p < 0.005). Multivariate analysis demonstrated that microvessel density was an independent prognostic indicator in node-negative breast cancer patients (p < 0.0005). It was suggested that microvessel density might be of use in selecting the high-risk group in node-negative breast cancer patients needing adjuvant therapies.
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PMID:[Significance of tumor angiogenesis as an independent prognostic factor in axillary node-negative breast cancer]. 753 84

Angiogenesis, the formation of new blood vessels from an existing vasculature, is requisite for tumor growth. It entails intercellular coordination of endothelial and tumor cells through angiogenic growth factor signaling. Interruption of these events has implications in the suppression of tumor growth. PD166285, a broad-spectrum receptor tyrosine kinase (RTK) inhibitor, and PD173074, a selective FGFR1TK inhibitor, were evaluated for their anti-angiogenic activity and anti-tumor efficacy in combination with photodynamic therapy (PDT). To evaluate the anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in vitro tumor cell growth and microcapillary formation assays, in vivo murine angiogenesis and anti-tumor efficacy studies utilizing RTK inhibitors in combination with photodynamic therapy were performed. PD166285 inhibited PDGFR-beta-, EGFR-, and FGFR1TKs and c-src TK by 50% (IC50) at concentrations between 7-85 nM. PD173074 displayed selective inhibitory activity towards FGFR1TK at 26 nM. PD173074 demonstrated (>100 fold) selective growth inhibitory action towards human umbilical vein endothelial cells compared with a panel of tumor cell lines. Both PD166285 and PD173074 (at 10 nM) inhibited the formation of microcapillaries on Matrigel-coated plastic. In vivo anti-angiogenesis studies in mice revealed that oral administration (p.o.) of either PD166285 (1-25 mg/kg) or PD173074 (25-100 mg/kg) generated dose dependent inhibition of angiogenesis. Against a murine mammary 16c tumor, significantly prolonged tumor regressions were achieved with daily p.o. doses of PD166285 (5-10 mg/kg) or PD173074 (30-60 mg/kg) following PDT compared with PDT alone (p<0.001). Many long-term survivors were also noted in combination treatment groups. PD166285 and PD173074 displayed potent anti-angiogenic and anti-tumor activity and prolonged the duration of anti-tumor response to PDT. Interference in membrane signal transduction by inhibitors of specific RTKs (e.g. FGFR1TK) should result in new chemotherapeutic agents having the ability to limit tumor angiogenesis and regrowth following cytoreductive treatments such as PDT.
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PMID:Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy. 1063 83

Therapeutic options for patients with metastatic colorectal cancer have clearly improved during the last years. The regular use of irinotecan and oxaliplatin in first- and second-line treatment led to a clear improvement of median overall survival time. For the first time a new therapeutic concept--the inhibition of tumor angiogenesis--has been realized for clinical use by combining the anti-VEGF monoclonal antibody bevacizumab with an irinotecan-based first-line therapy. The monoclonal antibody cetuximab, targeted against EGFR, offers another new and very effective therapeutic option to patients with advanced irinotecan-refractory colorectal cancer--even those who are already pretreated with oxaliplatin. Further clinical studies are going to evaluate the future role of these new molecular treatment options as part of those therapeutic possibilities which are already available and established for the treatment of colorectal cancer patients with advanced disease (such as the optimal sequencing, the role of orale fluoropyrimidine-based combination therapy with cetuximab or bevacizumab).
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PMID:[Novel molecular approaches in the therapy of advanced colorectal carcinoma]. 1471 46

Prostate cancer is the most common non-skin cancer affecting men in United States and the second leading cause of death after lung cancer. The clinical course of patients after given diagnosis of prostate cancer is highly variable and the underlying reasons for such variability remain elusive. To better understand the pathophysiology of prostate cancer, there has been a push to elucidate the molecular mechanisms that mediate the development and progression of prostate cancer. Recent literature has pointed that a complex interplay between various cytokines, growth factors, and androgen receptors regulate the growth and functions of the prostate gland. Amongst the currently implicated anomalous pathways involved in prostate oncogenesis, the IGF-IGFBP axis has been demonstrated to play a very important role, although the precise molecular events regulated by IGF remain to be elucidated. The tumor promoting functions of VEGF has been defined in tumor angiogenesis and currently remains the central focus of anti-angiogenesis therapy in prostate cancer. Another key cytokine, TGF-beta has tumor-suppressor functions in normal prostate gland, but its pleiotropic functions in prostate cancer are influenced by the hormonal state of the disease. In partnership with other deregulated growth factor signaling, the TGF-beta cascade has also been implicated in the spread of prostate cancer. Lastly, members of the EGFR family, particularly the HER2 receptor, have also been recognized as crucial elements of aberrant signal transduction pathways, which induce activation of downstream signaling, involved in cellular proliferation, cell survival, and angiogenesis. The abnormal function of a number of growth factors in prostate cancer biology explains the heterogeneity of its histologic grade, mode of presentation and disease prognosis. At the same time, continued research in this field allows for the potential development of drug therapies against a diverse pool of cancer causing targets.
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PMID:Growth factors involved in prostate carcinogenesis. 1576 31

Receptor and non-receptor protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes and signal transduction pathways that regulate cell growth, differentiation, migration and metabolism by catalyzing protein phosphorylation and dephosphorylation. In recent years, different tyrosine kinase receptors were identified as regulators of tumor or tumor vessel growth. Their inhibition by specific tyrosine kinase inhibitors and antibodies targeting growth factors and their receptors were recently shown to constitute a new modality for treating cancers. The pathognomonic role of the inhibited tyrosine kinase defines the way of action, whereas the amount of expression in tumor tissue is thought to define the indication for the tumor entity. Various compounds targeting PTKs are under clinical investigation in phase I-III trials or are already approved. This review describes new drugs targeting BCR-Abl, c-kit, EGFR (epidermal growth factor receptor), tumor angiogenesis via VEGF (vascular endothelial growth factor), HER2/neu and "multitarget" tyrosine kinase inhibitors.
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PMID:Receptor tyrosine kinases and anticancer therapy. 1585 62

Epidermal growth factor (EGF) receptor family members are expressed by tumor cells and contribute to tumor progression. The expression and activity of EGF receptors in endothelial cells are less well characterized. Analysis of tumor-derived endothelial cells showed that they express EGFR, ErbB2, and ErbB4, whereas their normal counterparts express ErbB2, ErbB3, and ErbB4. The gain in expression of EGFR and the loss of ErbB3 expression in tumor vasculature was also observed in vivo. As a consequence of their expressing EGFR, tumor endothelial cells responded to EGF and other EGF family members by activating both EGFR and ErbB2, by activating the downstream mitogen-activated protein kinase pathway, and by enhanced proliferation. On the other hand, normal endothelial cells did not respond to EGF but instead were responsive to neuregulin (NRG), a ligand for ErbB3 and ErbB4. NRG activated ErbB3 in normal endothelial cells and inhibited growth of these cells. In contrast, tumor endothelial cells, which do not express ErbB3, were not growth inhibited by NRG. Furthermore, due to their expression of EGFR, tumor endothelial cells, unlike normal endothelial cells, are direct targets for EGFR kinase inhibitors. These low-molecular-weight compounds block EGF-induced EGFR activation and proliferation of tumor endothelial cells. These results suggest that a gain of EGF-induced endothelial cell proliferation, and loss of NRG-induced growth inhibition in tumor endothelial cells constitutes a switch that promotes tumor angiogenesis. In addition, these results suggest that EGFR kinase inhibitors may be effective for antiangiogenesis therapy by specifically targeting the tumor, but not the normal, vasculature.
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PMID:Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. 1648 18

Vandetanib (ZD6474; ZACTIMA, AstraZeneca) is a once-daily, orally available agent with potential for use in a number of solid tumor types. Vandetanib targets key signaling pathways in cancer by inhibiting VEGFR-dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation and survival. Phase I studies showed vandetanib to be generally well tolerated at doses of < or = 300 mg/day, with a pharmacokinetic profile that supports once-daily oral administration. Phase II evaluation of vandetanib in patients with advanced refractory NSCLC has demonstrated improvements in progression-free survival both as monotherapy (versus gefitinib) and in combination with docetaxel (versus docetaxel alone). These positive outcomes have led to the initiation of Phase III trials of vandetanib in advanced NSCLC. Clinical development is also ongoing in other tumor types and encouraging evidence of antitumor activity has been reported in patients with metastatic hereditary medullary thyroid cancer.
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PMID:Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. 1724 44

Therapies targeted on cell signal pathways that control cell division and tumor angiogenesis have been developed over the last five years for non small cell lung cancer (NSCLC) with some amazing results, in subgroups of selected patients, predicting more significant success in the upcoming years. Compounds targeted on EGF tyrosine kinase receptor have been tested in large clinical phase 2 and 3 trials including thousands of patients. Their efficacy has been proved, in second and third line trials, after first line cisplatin-based chemotherapy for non-mucinous adenocarcinoma in non-smokers, women and Asian patients. Response rates vary from 10% in non selected Caucasian patients to 40% in non-smoking Asian patients with long survivals. Therapeutic targeting improves success rates, either relying on EGFR gene amplification detection by FISH, or search for EGFR tyrosine kinase domain mutations. Commercial kits are available for routine molecular diagnosis of domain mutations potentially enabling molecular targeting in addition to clinical targeting. Angiogenesis inhibitors, especially monoclonal antibody to VEGF, bevacizumab, have also been developed in the last few years. Bevacizumab associated with classical cytotoxic chemotherapy led, in selected patients (with non squamous cell lung cancer and no past history of cardiovascular disease) to an increase of median survival to more than 12 months with tolerable toxicity. Other drugs that have both anti-EGFR activity and anti-angiogenic properties will be soon developed, since future bioactive anti-cancer drugs will probably be multi-targeted drugs.
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PMID:[New biological treatments for lung cancer]. 1745 80

Expression of cyclooxygenase-2 (COX-2) has been linked to many cancers and may contribute to malignant phenotypes, including enhanced proliferation, angiogenesis, and resistance to cytotoxic therapies. Malignant gliomas are highly aggressive brain tumors that display many of these characteristics. One prominent molecular abnormality discovered in these astrocytic brain tumors is alteration of epidermal growth factor (EGF) receptor (EGFR) through gene amplification and/or mutation resulting in excessive signaling from this receptor. We found that EGF-mediated stimulation of EGFR tyrosine kinase in human glioma cell lines induces expression of both COX-2 mRNA and protein. The p38 mitogen-activated protein kinase (p38-MAPK) pathway was a strong downstream factor in this activation with inhibition of this pathway leading to strong suppression of COX-2 induction. The p38-MAPK pathway can activate the Sp1/Sp3 transcription factors and this seems necessary for EGFR-dependent transactivation of the COX-2 promoter. Analysis of COX-2 promoter/luciferase constructs revealed that transcriptional activation of the COX-2 promoter by EGFR requires the Sp1 binding site located at -245/-240. Furthermore, Sp1/Sp3 binding to this site in the promoter is enhanced by EGFR activation both in vitro and in vivo. Enhanced DNA binding by Sp1/Sp3 requires p38-MAPK activity and correlates with increased phosphorylation of the Sp1 transcription factor. Thus, EGFR activation in malignant gliomas can transcriptionally activate COX-2 expression in a process that requires p38-MAPK and Sp1/Sp3. Finally, treatment of glioma cell lines with prostaglandin E2, the predominant product of COX-2 activity, results in increased vascular endothelial growth factor expression, thus potentially linking elevations in COX-2 expression with tumor angiogenesis in malignant gliomas.
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PMID:EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas. 1761 68

Osteopontin (OPN) is a secreted protein that is overexpressed in a number of human cancers, and has been associated with increased metastatic burden and poor prognosis in breast cancer patients. The OPN protein contains several conserved structural elements including heparin- and calcium-binding domains, a thrombin-cleavage site, a CD44 binding site, and two integrin-binding sites. Experimental studies have shown that the ability of OPN to interact with a diverse range of factors, including cell surface receptors (integrins, CD44), secreted proteases (matrix metalloproteinases, urokinase plasminogen activator), and growth factor/receptor pathways (TGFalpha/EGFR, HGF/Met) is central to its role in malignancy. These complex signaling interactions can result in changes in gene expression, which ultimately lead to alterations in cell properties involved in malignancy such as adhesion, migration, invasion, enhanced tumor cell survival, tumor angiogenesis, and metastasis. Therefore, OPN is not merely associated with cancer, but rather it plays a multi-faceted functional role via complex molecular cross-talk with other factors. This review will focus on the role of OPN in breast cancer, in particular on the malignancy-promoting aspects of OPN that may reveal opportunities for new approaches to the clinical management of breast cancer.
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PMID:Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management. 1772 86


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