title: Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.
abstract: The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic 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 is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.|The Royal Marsden, London, UK.
authors.forename: Sophia
authors.initials: S
authors.lastname: Frentzas
authors.affiliation: McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada.
authors.forename: Eve
authors.initials: E
authors.lastname: Simoneau
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bridgeman
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.|Translational Cancer Research Unit, Gasthuis Zusters Antwerpen Hospitals St. Augustinus, Antwerp, Belgium.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Vermeulen
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: Foo
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Kostaras
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Nathan
authors.affiliation: The Royal Marsden, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada.
authors.forename: Zu-Hua
authors.initials: ZH
authors.lastname: Gao
authors.affiliation: McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Translational Cancer Research Unit, Gasthuis Zusters Antwerpen Hospitals St. Augustinus, Antwerp, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Van den Eynden
authors.affiliation: Breast Cancer Now Histopathology Core Facility, The Royal Marsden, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Daley
authors.affiliation: The Royal Marsden, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Tan
authors.affiliation: McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada.
authors.forename: Ayat
authors.initials: A
authors.lastname: Salman
authors.affiliation: McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada.
authors.forename: Anthoula
authors.initials: A
authors.lastname: Lazaris
authors.affiliation: Breast Cancer Now Unit, Guy's Hospital, King's College London School of Medicine, London, UK.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Gazinska
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Berg
authors.affiliation: The Royal Marsden, London, UK.
authors.forename: Zak
authors.initials: Z
authors.lastname: Eltahir
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Uppsalalaan 8, Utrecht 3584CT, Netherlands.
authors.forename: Laila
authors.initials: L
authors.lastname: Ritsma
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Uppsalalaan 8, Utrecht 3584CT, Netherlands.
authors.forename: Jacco
authors.initials: J
authors.lastname: Van Rheenen
authors.affiliation: McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada.
authors.forename: Alla
authors.initials: A
authors.lastname: Khashper
authors.affiliation: The Royal Marsden, London, UK.
authors.forename: Gina
authors.initials: G
authors.lastname: Brown
authors.affiliation: Department of Surgical and Perioperative Sciences, Umeå University, Umea, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Nystrom
authors.affiliation: Department of Surgical and Perioperative Sciences, Umeå University, Umea, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Sund
authors.affiliation: Translational Cancer Research Unit, Gasthuis Zusters Antwerpen Hospitals St. Augustinus, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Laere
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Loyer
authors.affiliation: Translational Cancer Research Unit, Gasthuis Zusters Antwerpen Hospitals St. Augustinus, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: The Royal Marsden, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: McGill University Health Centre, Royal Victoria Hospital - Glen Site, Montreal, Quebec, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Metrakos
authors.affiliation: Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Reynolds
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000473:pathology; D002277:Carcinoma / Q000098:blood supply* / Q000188:drug therapy / Q000556:secondary; D018270:Carcinoma, Ductal, Breast / Q000556:secondary; D018275:Carcinoma, Lobular / Q000556:secondary; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic / Q000188:drug therapy*
chemical_list: C517043:ARPC3 protein, human; D051376:Actin-Related Protein 2-3 Complex; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab