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      Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration

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          Abstract

          Background:

          Bevacizumab (Bev), a monoclonal antibody to vascular endothelial growth factor (VEGF), is used in combination with chemotherapy for the treatment of metastatic colorectal cancer (CRC). The effects of Bev on angiogenesis have been well described, but the direct effect of Bev on tumour cells is unknown. This study was carried out to determine the molecular and phenotypic changes in CRC cells after chronic Bev exposure in vitro.

          Methods:

          Human CRC cell lines were chronically exposed (3 months) to Bev in vitro to develop Bev-adapted (Bev-A) cell lines. Vascular endothelial growth factor family members were determined by reverse transcription–polymerase chain reaction and western blotting. Migration and invasion was determined using standard in vitro assays. Intravenous injection of tumour cells was carried out to evaluate metastatic potential in mice.

          Results:

          Bevacizumab-adapted cells were found to be more migratory and invasive than control cells ( P<0.001). Bevacizumab-adapted cells showed higher levels of VEGF-A, -B, -C, placental growth factor (PlGF), VEGF receptor-1 (VEGFR-1) and phosphorylation of VEGFR-1. Furthermore, treatment with SU5416, a VEGFR protein tyrosine kinase inhibitor, led to significantly decreased cell migration in vitro ( P<0.001). Bevacizumab-adapted cells were more metastatic in vivo ( P<0.05).

          Conclusion:

          Chronic exposure of CRC cells to Bev (1) increased expression of VEGF-A, -B, -C, PlGF, VEGFR-1 and VEGFR-1 phosphorylation, (2) increased tumour cell migration and invasion, and (3) metastatic potential in vivo. Our study shows the functional significance of autocrine VEGF signalling in CRC cells.

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          Most cited references 17

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          Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.

          To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.
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            Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.

            New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.
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              Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.

              Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible "metastatic conditioning" in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                12 April 2011
                15 March 2011
                : 104
                : 8
                : 1270-1277
                Affiliations
                [1 ]Department of Cancer Biology, The University of Texas MD Anderson Cancer Center , Unit 173, PO Box 301402, Houston, TX 77030-1402, USA
                [2 ]Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center , Unit 173, PO Box 301402, Houston, TX 77030-1402, USA
                Author notes
                Article
                bjc201181
                10.1038/bjc.2011.81
                3078594
                21407219
                Copyright © 2011 Cancer Research UK
                Categories
                Translational Therapeutics

                Oncology & Radiotherapy

                metastasis, resistance, bevacizumab, vegf, colorectal cancer, migration

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