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 language | English |
|---|---|
| Pages (from-to) | 1362-1373 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 71 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 15 2011 |
Fingerprint
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 journal › Article
}
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 -