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Classical VEGF, Notch and Ang signalling in cancer angiogenesis, alternative approaches and future directions

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      Abstract

      Angiogenesis is the formation of new vessels starting from pre-existing vasculature. Tumour environment is characterized by ‘aberrant angiogenesis’, whose main features are tortuous and permeable blood vessels, heterogeneous both in their structure and in efficiency of perfusion and very different from normal vessels. Therapeutic strategies targeting the three pathways chiefly involved in tumour angiogenesis, VEGF, Notch and Ang signalling, have been identified to block the vascular supply to the tumour. However, phenomena of toxicity, development of primary and secondary resistance and hypoxia significantly blunted the effects of anti-angiogenic drugs in several tumour types. Thus, different strategies aimed to overcome these problems are imperative. The focus of the present review was some principal ‘alternative’ approaches to classic antiangiogenic therapies, including the cyclooxygenase-2 (COX-2) blockade, the use of oligonucleotide complementary to the miRNA to compete with the mRNA target (antimiRs) and the inhibition of matrix metalloproteinases (MMPs). The role of blood soluble VEGFA as a predictive biomarker during antiangiogenic therapy in gastric, ovarian and colorectal cancer was also examined.

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        No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society
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          Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer. Copyright 2004 Massachusetts Medical Society
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            Author and article information

            Affiliations
            Department of Biomedical and Biotechnological Sciences, University of Catania, I-95123 Catania, Italy
            Author notes
            Correspondence to: Professor Carmelina Daniela Anfuso, Department of Biomedical and Biotechnological Sciences, University of Catania, Biological Tower, via S. Sofia 97, I-95123 Catania, Italy, E-mail: daniela.anfuso@ 123456unict.it
            [*]

            Contributed equally

            Journal
            Mol Med Rep
            Mol Med Rep
            Molecular Medicine Reports
            D.A. Spandidos
            1791-2997
            1791-3004
            October 2017
            07 August 2017
            07 August 2017
            : 16
            : 4
            : 4393-4402
            28791360
            5646999
            10.3892/mmr.2017.7179
            mmr-16-04-4393
            Copyright: © Caporarello et al.

            This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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