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      Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy

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          Abstract

          Background:

          We examine how changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy.

          Methods:

          In metastatic renal cancer patients treated with anti-angiogenic tyrosine kinase inhibitors, arterial phase contrast-enhanced computed tomography was used to simultaneously measure changes in: (a) tumour size, and (b) tumour enhancement (a surrogate marker of tumour vessel density) within individual lesions.

          Results:

          No correlation between baseline tumour enhancement and lesion shrinkage was observed, but a reduction in tumour enhancement on treatment was strongly correlated with reduction in lesion size ( r=0.654, P<0.0001). However, close examination of individual metastases revealed different types of response: (1) good vascular response with significant tumour shrinkage, (2) good vascular response with stabilisation of disease, (3) poor vascular response with stabilisation of disease and (4) poor vascular response with progression. Moreover, contrasting responses between different lesions within the same patient were observed. We also assessed rebound vascularisation in tumours that acquired resistance to treatment. The amplitude of rebound vascularisation was greater in lesions that had a better initial response to therapy ( P=0.008).

          Interpretation:

          Changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. The data provide insight into the mechanisms that underlie response and resistance to this class of agent.

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          Most cited references45

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          Antiangiogenic therapy: impact on invasion, disease progression, and metastasis.

          Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following antiangiogenic therapy is different to classic cytotoxic therapies-in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future antiangiogenic drug discovery and development. © 2011 Macmillan Publishers Limited. All rights reserved
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            Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma.

            Antiangiogenic therapy leads to devascularization that limits tumor growth. However, the benefits of angiogenesis inhibitors are typically transient and resistance often develops. In this study, we explored the hypothesis that hypoxia caused by antiangiogenic therapy induces tumor cell autophagy as a cytoprotective adaptive response, thereby promoting treatment resistance. Hypoxia-induced autophagy was dependent on signaling through the hypoxia-inducible factor-1α (HIF-1α)/AMPK pathway, and treatment of hypoxic cells with autophagy inhibitors caused a shift from autophagic to apoptotic cell death in vitro. In glioblastomas, clinically resistant to the VEGF-neutralizing antibody bevacizumab, increased regions of hypoxia and higher levels of autophagy-mediating BNIP3 were found when compared with pretreatment specimens from the same patients. When treated with bevacizumab alone, human glioblastoma xenografts showed increased BNIP3 expression and hypoxia-associated growth, which could be prevented by addition of the autophagy inhibitor chloroquine. In vivo targeting of the essential autophagy gene ATG7 also disrupted tumor growth when combined with bevacizumab treatment. Together, our findings elucidate a novel mechanism of resistance to antiangiogenic therapy in which hypoxia-mediated autophagy promotes tumor cell survival. One strong implication of our findings is that autophagy inhibitors may help prevent resistance to antiangiogenic therapy used in the clinic. ©2012 AACR.
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              Rapid vascular regrowth in tumors after reversal of VEGF inhibition.

              Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less alpha-SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                03 September 2013
                06 August 2013
                : 109
                : 5
                : 1230-1242
                Affiliations
                [1 ]Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research , London SW3 6JB, UK
                [2 ]Paul Strickland Scanner Centre, Mount Vernon Hospital , Northwood HA6 2RN, UK
                [3 ]Royal Marsden Hospital , London SW3 6JJ, UK
                [4 ]Department of Medical Oncology, Mount Vernon Cancer Centre , Northwood, HA6 2RN, UK
                Author notes
                [5]

                Current address: Cancer Research UK Centre, Leeds Institute of Cancer Studies and Pathology, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.

                [6]

                Current address: Division of Imaging Sciences and Biomedical Engineering, King's College London, London SE1 7EH, UK.

                Article
                bjc2013429
                10.1038/bjc.2013.429
                3778288
                23922108
                f2555587-5b2d-40e9-bf0b-eb9da7b431ea
                Copyright © 2013 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 24 January 2013
                : 30 June 2013
                : 04 July 2013
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                angiogenesis,metastasis,tyrosine kinase inhibitor,resistance,renal cell carcinoma

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