title: Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.
abstract: Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel co-option could mediate resistance to anti-angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co-option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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 (TCRU), GZA 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: 2nd Institute of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bilecz
authors.affiliation: Breast Cancer Now Histopathology Core Facility, The Royal Marsden, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Daley
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 R
authors.initials: MR
authors.lastname: Nathan
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: Elaine
authors.initials: E
authors.lastname: Wan
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: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schweiger
authors.affiliation: Department of Thoracic Surgery, Ruhrlandklinik Essen, University Hospital of University Duisburg-Essen, Germany.|MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Konrad
authors.initials: K
authors.lastname: Hoetzenecker
authors.affiliation: Department of Thoracic Surgery, Semmelweis University-National Institute of Oncology, Budapest, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Renyi-Vamos
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kuczynski
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.|Cancer Research UK Centre, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, UK.
authors.forename: Naveen S
authors.initials: NS
authors.lastname: Vasudev
authors.affiliation: The Royal Marsden, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.affiliation: The Royal Marsden, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Harold F
authors.initials: HF
authors.lastname: Dvorak
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.|Tumour Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
authors.forename: Sandor
authors.initials: S
authors.lastname: Paku
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.|Department of Thoracic Surgery, Semmelweis University-National Institute of Oncology, Budapest, Hungary.|National Koranyi Institute of Pulmonology, Budapest, Hungary.|Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria.
authors.forename: Balazs
authors.initials: B
authors.lastname: Dome
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: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002196:Capillaries / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007211:Indoles / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology*; D011758:Pyrroles / Q000627:therapeutic use; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: angiogenesis; anti-angiogenic therapy; drug resistance; lung metastasis; sunitinib; vessel co-option