Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies

Dana D. Hu-Lowe, Enhong Chen, Lianglin Zhang, Katherine D. Watson, Patrizia Mancuso, Patrick Lappin, Grant Wickman, Jeffrey H. Chen, Jianying Wang, Xin Jiang, Karin Amundson, Ronald Simon, Andreas Erbersdobler, Simon Bergqvist, Zheng Feng, Terri A. Swanson, Brett H. Simmons, John Lippincott, Gerald F. Casperson, Wendy J. LevinCorrado Gallo Stampino, David R. Shalinsky, Katherine W. Ferrara, Walter Fiedler, Francesco Bertolini

Research output: Contribution to journalArticle

Abstract

Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin+ perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.

Original languageEnglish
Pages (from-to)1362-1373
Number of pages12
JournalCancer Research
Volume71
Issue number4
DOIs
Publication statusPublished - Feb 15 2011

Fingerprint

Activin Receptors
Vascular Endothelial Growth Factor A
Carcinogenesis
Vascular Endothelial Growth Factor Receptor
Neoplasms
Blood Vessels
Antibodies
Therapeutics
Pathologic Neovascularization
Lymphatic Vessels
Desmin
Fibroblast Growth Factor 2
Growth
Heterografts
Molecular Biology
Melanoma
Ultrasonography
Blood Cells
Phosphotransferases
Endothelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. / Hu-Lowe, Dana D.; Chen, Enhong; Zhang, Lianglin; Watson, Katherine D.; Mancuso, Patrizia; Lappin, Patrick; Wickman, Grant; Chen, Jeffrey H.; Wang, Jianying; Jiang, Xin; Amundson, Karin; Simon, Ronald; Erbersdobler, Andreas; Bergqvist, Simon; Feng, Zheng; Swanson, Terri A.; Simmons, Brett H.; Lippincott, John; Casperson, Gerald F.; Levin, Wendy J.; Stampino, Corrado Gallo; Shalinsky, David R.; Ferrara, Katherine W.; Fiedler, Walter; Bertolini, Francesco.

In: Cancer Research, Vol. 71, No. 4, 15.02.2011, p. 1362-1373.

Research output: Contribution to journalArticle

Hu-Lowe, DD, Chen, E, Zhang, L, Watson, KD, Mancuso, P, Lappin, P, Wickman, G, Chen, JH, Wang, J, Jiang, X, Amundson, K, Simon, R, Erbersdobler, A, Bergqvist, S, Feng, Z, Swanson, TA, Simmons, BH, Lippincott, J, Casperson, GF, Levin, WJ, Stampino, CG, Shalinsky, DR, Ferrara, KW, Fiedler, W & Bertolini, F 2011, 'Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies', Cancer Research, vol. 71, no. 4, pp. 1362-1373. https://doi.org/10.1158/0008-5472.CAN-10-1451
Hu-Lowe, Dana D. ; Chen, Enhong ; Zhang, Lianglin ; Watson, Katherine D. ; Mancuso, Patrizia ; Lappin, Patrick ; Wickman, Grant ; Chen, Jeffrey H. ; Wang, Jianying ; Jiang, Xin ; Amundson, Karin ; Simon, Ronald ; Erbersdobler, Andreas ; Bergqvist, Simon ; Feng, Zheng ; Swanson, Terri A. ; Simmons, Brett H. ; Lippincott, John ; Casperson, Gerald F. ; Levin, Wendy J. ; Stampino, Corrado Gallo ; Shalinsky, David R. ; Ferrara, Katherine W. ; Fiedler, Walter ; Bertolini, Francesco. / Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. In: Cancer Research. 2011 ; Vol. 71, No. 4. pp. 1362-1373.
@article{bcdeb3c5c40446adb3716ff74e801c3e,
title = "Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies",
abstract = "Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin+ perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.",
author = "Hu-Lowe, {Dana D.} and Enhong Chen and Lianglin Zhang and Watson, {Katherine D.} and Patrizia Mancuso and Patrick Lappin and Grant Wickman and Chen, {Jeffrey H.} and Jianying Wang and Xin Jiang and Karin Amundson and Ronald Simon and Andreas Erbersdobler and Simon Bergqvist and Zheng Feng and Swanson, {Terri A.} and Simmons, {Brett H.} and John Lippincott and Casperson, {Gerald F.} and Levin, {Wendy J.} and Stampino, {Corrado Gallo} and Shalinsky, {David R.} and Ferrara, {Katherine W.} and Walter Fiedler and Francesco Bertolini",
year = "2011",
month = "2",
day = "15",
doi = "10.1158/0008-5472.CAN-10-1451",
language = "English",
volume = "71",
pages = "1362--1373",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "4",

}

TY - JOUR

T1 - Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies

AU - Hu-Lowe, Dana D.

AU - Chen, Enhong

AU - Zhang, Lianglin

AU - Watson, Katherine D.

AU - Mancuso, Patrizia

AU - Lappin, Patrick

AU - Wickman, Grant

AU - Chen, Jeffrey H.

AU - Wang, Jianying

AU - Jiang, Xin

AU - Amundson, Karin

AU - Simon, Ronald

AU - Erbersdobler, Andreas

AU - Bergqvist, Simon

AU - Feng, Zheng

AU - Swanson, Terri A.

AU - Simmons, Brett H.

AU - Lippincott, John

AU - Casperson, Gerald F.

AU - Levin, Wendy J.

AU - Stampino, Corrado Gallo

AU - Shalinsky, David R.

AU - Ferrara, Katherine W.

AU - Fiedler, Walter

AU - Bertolini, Francesco

PY - 2011/2/15

Y1 - 2011/2/15

N2 - Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin+ perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.

AB - Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin+ perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.

UR - http://www.scopus.com/inward/record.url?scp=79951828866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79951828866&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-1451

DO - 10.1158/0008-5472.CAN-10-1451

M3 - Article

C2 - 21212415

AN - SCOPUS:79951828866

VL - 71

SP - 1362

EP - 1373

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 4

ER -