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      Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases

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          Abstract

          The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of inducing angiogenesis, some cancers vascularize by the non-angiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option prevails in human breast cancer liver metastases, a setting where results with anti-angiogenic therapy have been disappointing. In our preclinical mechanistic studies, we show that cancer cell motility mediated by the Arp2/3 complex is required for vessel co-option in liver metastases in vivo and that combined inhibition of angiogenesis and vessel co-option is more effective than inhibiting angiogenesis alone in this setting. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option may be a warranted therapeutic strategy.

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          Most cited references 66

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          Statistical methods for assessing agreement between two methods of clinical measurement.

          In clinical measurement comparison of a new measurement technique with an established one is often needed to see whether they agree sufficiently for the new to replace the old. Such investigations are often analysed inappropriately, notably by using correlation coefficients. The use of correlation is misleading. An alternative approach, based on graphical techniques and simple calculations, is described, together with the relation between this analysis and the assessment of repeatability.
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            STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT

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              Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.

              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

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                27 October 2016
                17 October 2016
                November 2016
                17 April 2017
                : 22
                : 11
                : 1294-1302
                Affiliations
                [1 ]Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
                [2 ]The Royal Marsden, London, UK
                [3 ]McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada
                [4 ]Translational Cancer Research Unit, Gasthuis Zusters Antwerpen Hospitals St. Augustinus, Antwerp, Belgium
                [5 ]Breast Cancer Now Histopathology Core Facility, The Royal Marsden, London, UK
                [6 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
                [7 ]Breast Cancer Now Unit, Guy's Hospital, King's College London School of Medicine, London, UK
                [8 ]Cancer Genomics Center-Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Uppsalalaan 8, Utrecht 3584CT, Netherlands
                [9 ]Department of Surgical and Perioperative Sciences, Umeå University, Umea, Sweden
                [10 ]The University of Texas MD Anderson Cancer Center, Houston, TX, USA
                Author notes
                Lead correspondong author: Andrew Reynolds, andrew.reynolds@ 123456icr.ac.uk
                Co-corresponding authors: Peter Metrakos, peter.metrakos@ 123456mcgill.ca , David Cunningham, David.Cunningham@ 123456rmh.nhs.uk
                [12]

                Co-senior authors.

                EMS69950
                10.1038/nm.4197
                5104270
                27748747

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