Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

Charlotte Anderberg; Sara I. Cunha; Zhenhua Zhai; Eliane Cortez; Evangelia Pardali; Jill R. Johnson; Marcela Franco; Marta Páez-Ribes; Ross Cordiner; Jonas Fuxe; Bengt R. Johansson; Marie José Goumans; Oriol Casanovas; Peter ten Dijke; Helen M. Arthur; Kristian Pietras

doi:10.1084/jem.20120662

Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

Charlotte Anderberg, Sara I. Cunha, Zhenhua Zhai, Eliane Cortez, Evangelia Pardali, Jill R. Johnson, Marcela Franco, Marta Páez-Ribes, Ross Cordiner, Jonas Fuxe, Bengt R. Johansson, Marie José Goumans, Oriol Casanovas, Peter ten Dijke, Helen M. Arthur, Kristian Pietras^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.

Original language	English
Pages (from-to)	563-579
Number of pages	17
Journal	Journal of Experimental Medicine
Volume	210
Issue number	3
DOIs	https://doi.org/10.1084/jem.20120662
Publication status	Published - 11 Feb 2013

Bibliographical note

© 2013 Anderberg et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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jem_20120662
© 2013 Anderberg et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
Final published version, 4.06 MBLicence: CC BY-NC-SA 3.0

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Anderberg, C., Cunha, S. I., Zhai, Z., Cortez, E., Pardali, E., Johnson, J. R., Franco, M., Páez-Ribes, M., Cordiner, R., Fuxe, J., Johansson, B. R., Goumans, M. J., Casanovas, O., Dijke, P. T., Arthur, H. M., & Pietras, K. (2013). Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. Journal of Experimental Medicine , 210(3), 563-579. https://doi.org/10.1084/jem.20120662

@article{92deecfb55374f678ab78cd67b14afcc,

title = "Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination",

abstract = "Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.",

author = "Charlotte Anderberg and Cunha, {Sara I.} and Zhenhua Zhai and Eliane Cortez and Evangelia Pardali and Johnson, {Jill R.} and Marcela Franco and Marta P{\'a}ez-Ribes and Ross Cordiner and Jonas Fuxe and Johansson, {Bengt R.} and Goumans, {Marie Jos{\'e}} and Oriol Casanovas and Dijke, {Peter ten} and Arthur, {Helen M.} and Kristian Pietras",

note = "{\textcopyright} 2013 Anderberg et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).",

year = "2013",

month = feb,

day = "11",

doi = "10.1084/jem.20120662",

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Anderberg, C, Cunha, SI, Zhai, Z, Cortez, E, Pardali, E, Johnson, JR, Franco, M, Páez-Ribes, M, Cordiner, R, Fuxe, J, Johansson, BR, Goumans, MJ, Casanovas, O, Dijke, PT, Arthur, HM & Pietras, K 2013, 'Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination', Journal of Experimental Medicine , vol. 210, no. 3, pp. 563-579. https://doi.org/10.1084/jem.20120662

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T1 - Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

AU - Anderberg, Charlotte

AU - Cunha, Sara I.

AU - Zhai, Zhenhua

AU - Cortez, Eliane

AU - Pardali, Evangelia

AU - Johnson, Jill R.

AU - Franco, Marcela

AU - Páez-Ribes, Marta

AU - Cordiner, Ross

AU - Fuxe, Jonas

AU - Johansson, Bengt R.

AU - Goumans, Marie José

AU - Casanovas, Oriol

AU - Dijke, Peter ten

AU - Arthur, Helen M.

AU - Pietras, Kristian

N1 - © 2013 Anderberg et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

PY - 2013/2/11

Y1 - 2013/2/11

N2 - Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.

AB - Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.

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SN - 0022-1007

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EP - 579

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 3

ER -

Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

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