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

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... Full description

Journal Title: Nature Medicine 2016-11, Vol.22 (11), p.1294-1302
Main Author: Frentzas, Sophia
Other Authors: Simoneau, Eve , Bridgeman, Victoria L , Vermeulen, Peter B , Foo, Shane , Kostaras, Eleftherios , Nathan, Mark R , Wotherspoon, Anew , Gao, Zu-Hua , Shi, Yu , Van den Eynden, Gert , Daley, Frances , Peckitt, Clare , Tan, Xianming , Salman, Ayat , Lazaris, Anthoula , Gazinska, Patrycja , Berg, Tracy J , Eltahir, Zak , Ritsma, Laila , van Rheenen, Jacco , Khashper, Alla , Brown, Gina , Nyström, Hanna , Sund, Malin , Van Laere, Steven , Loyer, Evelyne , Dirix, Luc , Cunningham, David , Metrakos, Peter , Reynolds, Anew R
Format: Electronic Article Electronic Article
Language: English
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Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
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title: Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
format: Article
creator:
  • Frentzas, Sophia
  • Simoneau, Eve
  • Bridgeman, Victoria L
  • Vermeulen, Peter B
  • Foo, Shane
  • Kostaras, Eleftherios
  • Nathan, Mark R
  • Wotherspoon, Anew
  • Gao, Zu-Hua
  • Shi, Yu
  • Van den Eynden, Gert
  • Daley, Frances
  • Peckitt, Clare
  • Tan, Xianming
  • Salman, Ayat
  • Lazaris, Anthoula
  • Gazinska, Patrycja
  • Berg, Tracy J
  • Eltahir, Zak
  • Ritsma, Laila
  • van Rheenen, Jacco
  • Khashper, Alla
  • Brown, Gina
  • Nyström, Hanna
  • Sund, Malin
  • Van Laere, Steven
  • Loyer, Evelyne
  • Dirix, Luc
  • Cunningham, David
  • Metrakos, Peter
  • Reynolds, Anew R
subjects:
  • 11 Medical And Health Sciences
  • 3 Complex
  • Actin
  • Actin-Related Protein 2-3 Complex - genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis
  • Angiogenesis Inhibitors
  • Angiogenesis Inhibitors - therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols
  • Antineoplastic Combined Chemotherapy Protocols - therapeutic use
  • Article
  • Bevacizumab
  • Bevacizumab - therapeutic use
  • Biochemistry
  • Biochemistry & Molecular Biology
  • Breast
  • Breast Neoplasms
  • Breast Neoplasms - pathology
  • Cancer and Oncology
  • Cancer och onkologi
  • Carcinoma
  • Carcinoma - blood supply
  • Carcinoma - drug therapy
  • Carcinoma - secondary
  • Carcinoma, Ductal, Breast - secondary
  • Carcinoma, Lobular - secondary
  • Cell Biology
  • Cell Movement
  • Cell Movement - genetics
  • Clinical Medicine
  • Colorectal Neoplasms
  • Colorectal Neoplasms - drug therapy
  • Colorectal Neoplasms - pathology
  • Coronary vessels
  • Drug Resistance
  • Drug Resistance, Neoplasm
  • Drug therapy
  • Ductal
  • Female
  • Gene Knockdown Techniques
  • Genetics
  • HT29 Cells
  • Humans
  • Immunology
  • Journal Article
  • Klinisk medicin
  • Life Sciences & Biomedicine
  • Liver cancer
  • Liver Neoplasms
  • Liver Neoplasms - blood supply
  • Liver Neoplasms - drug therapy
  • Liver Neoplasms - secondary
  • Lobular
  • Male
  • Medical and Health Sciences
  • Medicin och hälsovetenskap
  • Medicine
  • Medicine(all)
  • Metastasis
  • Middle Aged
  • Molecular Biology(all)
  • Neoplasm
  • Neoplasm Grading
  • Neovascularization
  • Neovascularization, Pathologic - drug therapy
  • over
  • Pathologic
  • Patient outcomes
  • Related Protein 2
  • Research & Experimental
  • Research & Experimental Medicine
  • Science & Technology
  • Tumour angiogenesis
ispartof: Nature Medicine, 2016-11, Vol.22 (11), p.1294-1302
description: 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
  • 1546-170X
url: Link


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titleVessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
creatorFrentzas, Sophia ; Simoneau, Eve ; Bridgeman, Victoria L ; Vermeulen, Peter B ; Foo, Shane ; Kostaras, Eleftherios ; Nathan, Mark R ; Wotherspoon, Anew ; Gao, Zu-Hua ; Shi, Yu ; Van den Eynden, Gert ; Daley, Frances ; Peckitt, Clare ; Tan, Xianming ; Salman, Ayat ; Lazaris, Anthoula ; Gazinska, Patrycja ; Berg, Tracy J ; Eltahir, Zak ; Ritsma, Laila ; van Rheenen, Jacco ; Khashper, Alla ; Brown, Gina ; Nyström, Hanna ; Sund, Malin ; Van Laere, Steven ; Loyer, Evelyne ; Dirix, Luc ; Cunningham, David ; Metrakos, Peter ; Reynolds, Anew R
creatorcontribFrentzas, Sophia ; Simoneau, Eve ; Bridgeman, Victoria L ; Vermeulen, Peter B ; Foo, Shane ; Kostaras, Eleftherios ; Nathan, Mark R ; Wotherspoon, Anew ; Gao, Zu-Hua ; Shi, Yu ; Van den Eynden, Gert ; Daley, Frances ; Peckitt, Clare ; Tan, Xianming ; Salman, Ayat ; Lazaris, Anthoula ; Gazinska, Patrycja ; Berg, Tracy J ; Eltahir, Zak ; Ritsma, Laila ; van Rheenen, Jacco ; Khashper, Alla ; Brown, Gina ; Nyström, Hanna ; Sund, Malin ; Van Laere, Steven ; Loyer, Evelyne ; Dirix, Luc ; Cunningham, David ; Metrakos, Peter ; Reynolds, Anew R
descriptionThe 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.
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subject11 Medical And Health Sciences ; 3 Complex ; Actin ; Actin-Related Protein 2-3 Complex - genetics ; Adult ; Aged ; Aged, 80 and over ; Angiogenesis ; Angiogenesis Inhibitors ; Angiogenesis Inhibitors - therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Article ; Bevacizumab ; Bevacizumab - therapeutic use ; Biochemistry ; Biochemistry & Molecular Biology ; Breast ; Breast Neoplasms ; Breast Neoplasms - pathology ; Cancer and Oncology ; Cancer och onkologi ; Carcinoma ; Carcinoma - blood supply ; Carcinoma - drug therapy ; Carcinoma - secondary ; Carcinoma, Ductal, Breast - secondary ; Carcinoma, Lobular - secondary ; Cell Biology ; Cell Movement ; Cell Movement - genetics ; Clinical Medicine ; Colorectal Neoplasms ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - pathology ; Coronary vessels ; Drug Resistance ; Drug Resistance, Neoplasm ; Drug therapy ; Ductal ; Female ; Gene Knockdown Techniques ; Genetics ; HT29 Cells ; Humans ; Immunology ; Journal Article ; Klinisk medicin ; Life Sciences & Biomedicine ; Liver cancer ; Liver Neoplasms ; Liver Neoplasms - blood supply ; Liver Neoplasms - drug therapy ; Liver Neoplasms - secondary ; Lobular ; Male ; Medical and Health Sciences ; Medicin och hälsovetenskap ; Medicine ; Medicine(all) ; Metastasis ; Middle Aged ; Molecular Biology(all) ; Neoplasm ; Neoplasm Grading ; Neovascularization ; Neovascularization, Pathologic - drug therapy ; over ; Pathologic ; Patient outcomes ; Related Protein 2 ; Research & Experimental ; Research & Experimental Medicine ; Science & Technology ; Tumour angiogenesis
ispartofNature Medicine, 2016-11, Vol.22 (11), p.1294-1302
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22Brown, Gina
23Nyström, Hanna
24Sund, Malin
25Van Laere, Steven
26Loyer, Evelyne
27Dirix, Luc
28Cunningham, David
29Metrakos, Peter
30Reynolds, Anew R
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descriptionThe 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.
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8Angiogenesis Inhibitors
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10Antineoplastic Combined Chemotherapy Protocols
11Antineoplastic Combined Chemotherapy Protocols - therapeutic use
12Article
13Bevacizumab
14Bevacizumab - therapeutic use
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16Biochemistry & Molecular Biology
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18Breast Neoplasms
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21Cancer och onkologi
22Carcinoma
23Carcinoma - blood supply
24Carcinoma - drug therapy
25Carcinoma - secondary
26Carcinoma, Ductal, Breast - secondary
27Carcinoma, Lobular - secondary
28Cell Biology
29Cell Movement
30Cell Movement - genetics
31Clinical Medicine
32Colorectal Neoplasms
33Colorectal Neoplasms - drug therapy
34Colorectal Neoplasms - pathology
35Coronary vessels
36Drug Resistance
37Drug Resistance, Neoplasm
38Drug therapy
39Ductal
40Female
41Gene Knockdown Techniques
42Genetics
43HT29 Cells
44Humans
45Immunology
46Journal Article
47Klinisk medicin
48Life Sciences & Biomedicine
49Liver cancer
50Liver Neoplasms
51Liver Neoplasms - blood supply
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59Medicine(all)
60Metastasis
61Middle Aged
62Molecular Biology(all)
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65Neovascularization
66Neovascularization, Pathologic - drug therapy
67over
68Pathologic
69Patient outcomes
70Related Protein 2
71Research & Experimental
72Research & Experimental Medicine
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titleVessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
authorFrentzas, Sophia ; Simoneau, Eve ; Bridgeman, Victoria L ; Vermeulen, Peter B ; Foo, Shane ; Kostaras, Eleftherios ; Nathan, Mark R ; Wotherspoon, Anew ; Gao, Zu-Hua ; Shi, Yu ; Van den Eynden, Gert ; Daley, Frances ; Peckitt, Clare ; Tan, Xianming ; Salman, Ayat ; Lazaris, Anthoula ; Gazinska, Patrycja ; Berg, Tracy J ; Eltahir, Zak ; Ritsma, Laila ; van Rheenen, Jacco ; Khashper, Alla ; Brown, Gina ; Nyström, Hanna ; Sund, Malin ; Van Laere, Steven ; Loyer, Evelyne ; Dirix, Luc ; Cunningham, David ; Metrakos, Peter ; Reynolds, Anew R
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56Medical and Health Sciences
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68Pathologic
69Patient outcomes
70Related Protein 2
71Research & Experimental
72Research & Experimental Medicine
73Science & Technology
74Tumour angiogenesis
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6Nathan, Mark R
7Wotherspoon, Anew
8Gao, Zu-Hua
9Shi, Yu
10Van den Eynden, Gert
11Daley, Frances
12Peckitt, Clare
13Tan, Xianming
14Salman, Ayat
15Lazaris, Anthoula
16Gazinska, Patrycja
17Berg, Tracy J
18Eltahir, Zak
19Ritsma, Laila
20van Rheenen, Jacco
21Khashper, Alla
22Brown, Gina
23Nyström, Hanna
24Sund, Malin
25Van Laere, Steven
26Loyer, Evelyne
27Dirix, Luc
28Cunningham, David
29Metrakos, Peter
30Reynolds, Anew R
formatjournal
genrearticle
ristypeJOUR
atitleVessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
jtitleNature Medicine
addtitleNat Med
date2016-11
risdate2016
volume22
issue11
spage1294
epage1302
pages1294-1302
issn
01078-8956
11546-170X
eissn1546-170X
notesCo-senior authors.
abstractThe 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.
copUnited States
pubNature Publishing Group
pmid27748747
doi10.1038/nm.4197
tpages9
orcidid
0https://orcid.org/0000-0002-0214-2008
1https://orcid.org/0000-0002-5478-2269
oafree_for_read