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Angiogenesis and antiangiogenic agents in cervical cancer.

ABSTRACT: Standard treatment of cervical cancer (CC) consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1?. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF). Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC.

SUBMITTER: Tomao F

PROVIDER: S-EPMC4259513 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Angiogenesis and antiangiogenic agents in cervical cancer.

Tomao Federica F Papa Anselmo A Rossi Luigi L Zaccarelli Eleonora E Caruso Davide D Zoratto Federica F Benedetti Panici Pierluigi P Tomao Silverio S

OncoTargets and therapy 20141203

Standard treatment of cervical cancer (CC) consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the de ...[more]

PMID: 25506227

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Project description:PurposeIntegrins are critical to cancer progression. Integrin alpha 5 (ITGA5) is correlated with the prognosis of cervical cancer patients. However, whether ITGA5 plays an active role in cervical cancer progression or not remains unknown.MethodsITGA5 protein expression was detected in 155 human cervical cancer tissues by immunohistochemistry. Data from The Cancer Genome Atlas were utilized to identify risk factors for the overall survival of cervical cancer patients and ITGA5-associated differentially expressed genes. Analyses of single-cell RNA-seq based on Gene Expression Omnibus datasets were performed to show the coexpression of ITGA5 and angiogenesis factors. Tube formation assay, 3D spheroid sprout assay, qRT-PCR, Western Blotting, ELISA, and immunofluorescence were conducted to explore the angiogenic function of ITGA5 in vitro and underlying mechanisms.ResultsHigh ITGA5 level was significantly correlated with increased risk in terms of overall survival and advanced disease stage in cervical cancer patients. ITGA5-associated differentially expressed genes linked ITGA5 to angiogenesis, and immunohistochemistry showed a positive correlation between ITGA5 and microvascular density in cervical cancer tissues. Moreover, tumor cells transfected with ITGA5-targeting siRNA decreased ability to promote endothelial tube formation in vitro. ITGA5/VEGFA coexpression was observed in a tumor cell subpopulation and the decreased endothelial angiogenesis by downregulating ITGA5 could be reversed by VEGFA. Bioinformatics analysis highlighted the PI3K-Akt signaling pathway as downstream of ITGA5. Downregulation of ITGA5 in tumor cells significantly decreased p-AKT and VEGFA levels. Fibronectin (FN1) coated cells or transfected with FN1-targeting siRNA showed fibronectin may play a critical role on ITGA5-mediated angiogenesis.ConclusionITGA5 promotes angiogenesis and possibly be a potential predictive biomarker for poor survival of patients in cervical cancer.

Dataset Information

Angiogenesis and antiangiogenic agents in cervical cancer.

Publications

Angiogenesis and antiangiogenic agents in cervical cancer.

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