Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models

Victoria L. Bridgeman, Peter B. Vermeulen, Shane Foo, Agnes Bilecz, Frances Daley, Eleftherios Kostaras, Mark R. Nathan, Elaine Wan, Sophia Frentzas, Thomas Schweiger, Balazs Hegedus, Konrad Hoetzenecker, Ferenc Renyi-Vamos, Elizabeth A. Kuczynski, Naveen S. Vasudev, James Larkin, Martin Gore, Harold F. Dvorak, Sandor Paku, Robert S. KerbelBalazs Dome, Andrew R. Reynolds

Research output: Contribution to journalArticleResearchpeer-review

63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)362-374
Number of pages13
JournalJournal of Pathology
Volume241
Issue number3
DOIs
Publication statusPublished - 1 Feb 2017
Externally publishedYes

Keywords

  • angiogenesis
  • anti-angiogenic therapy
  • drug resistance
  • lung metastasis
  • sunitinib
  • vessel co-option

Cite this

Bridgeman, V. L., Vermeulen, P. B., Foo, S., Bilecz, A., Daley, F., Kostaras, E., ... Reynolds, A. R. (2017). Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. Journal of Pathology, 241(3), 362-374. https://doi.org/10.1002/path.4845
Bridgeman, Victoria L. ; Vermeulen, Peter B. ; Foo, Shane ; Bilecz, Agnes ; Daley, Frances ; Kostaras, Eleftherios ; Nathan, Mark R. ; Wan, Elaine ; Frentzas, Sophia ; Schweiger, Thomas ; Hegedus, Balazs ; Hoetzenecker, Konrad ; Renyi-Vamos, Ferenc ; Kuczynski, Elizabeth A. ; Vasudev, Naveen S. ; Larkin, James ; Gore, Martin ; Dvorak, Harold F. ; Paku, Sandor ; Kerbel, Robert S. ; Dome, Balazs ; Reynolds, Andrew R. / Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. In: Journal of Pathology. 2017 ; Vol. 241, No. 3. pp. 362-374.
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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.",
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author = "Bridgeman, {Victoria L.} and Vermeulen, {Peter B.} and Shane Foo and Agnes Bilecz and Frances Daley and Eleftherios Kostaras and Nathan, {Mark R.} and Elaine Wan and Sophia Frentzas and Thomas Schweiger and Balazs Hegedus and Konrad Hoetzenecker and Ferenc Renyi-Vamos and Kuczynski, {Elizabeth A.} and Vasudev, {Naveen S.} and James Larkin and Martin Gore and Dvorak, {Harold F.} and Sandor Paku and Kerbel, {Robert S.} and Balazs Dome and Reynolds, {Andrew R.}",
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Bridgeman, VL, Vermeulen, PB, Foo, S, Bilecz, A, Daley, F, Kostaras, E, Nathan, MR, Wan, E, Frentzas, S, Schweiger, T, Hegedus, B, Hoetzenecker, K, Renyi-Vamos, F, Kuczynski, EA, Vasudev, NS, Larkin, J, Gore, M, Dvorak, HF, Paku, S, Kerbel, RS, Dome, B & Reynolds, AR 2017, 'Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models', Journal of Pathology, vol. 241, no. 3, pp. 362-374. https://doi.org/10.1002/path.4845

Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. / Bridgeman, Victoria L.; Vermeulen, Peter B.; Foo, Shane; Bilecz, Agnes; Daley, Frances; Kostaras, Eleftherios; Nathan, Mark R.; Wan, Elaine; Frentzas, Sophia; Schweiger, Thomas; Hegedus, Balazs; Hoetzenecker, Konrad; Renyi-Vamos, Ferenc; Kuczynski, Elizabeth A.; Vasudev, Naveen S.; Larkin, James; Gore, Martin; Dvorak, Harold F.; Paku, Sandor; Kerbel, Robert S.; Dome, Balazs; Reynolds, Andrew R.

In: Journal of Pathology, Vol. 241, No. 3, 01.02.2017, p. 362-374.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models

AU - Bridgeman, Victoria L.

AU - Vermeulen, Peter B.

AU - Foo, Shane

AU - Bilecz, Agnes

AU - Daley, Frances

AU - Kostaras, Eleftherios

AU - Nathan, Mark R.

AU - Wan, Elaine

AU - Frentzas, Sophia

AU - Schweiger, Thomas

AU - Hegedus, Balazs

AU - Hoetzenecker, Konrad

AU - Renyi-Vamos, Ferenc

AU - Kuczynski, Elizabeth A.

AU - Vasudev, Naveen S.

AU - Larkin, James

AU - Gore, Martin

AU - Dvorak, Harold F.

AU - Paku, Sandor

AU - Kerbel, Robert S.

AU - Dome, Balazs

AU - Reynolds, Andrew R.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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.

AB - 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.

KW - angiogenesis

KW - anti-angiogenic therapy

KW - drug resistance

KW - lung metastasis

KW - sunitinib

KW - vessel co-option

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