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

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

Y1 - 2011

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.

KW - Animals

KW - Humans

KW - Cells, Cultured

KW - Mice

KW - Drug Synergism

KW - Mice, SCID

KW - Xenograft Model Antitumor Assays

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Signal Transduction/drug effects

KW - Activin Receptors, Type II/antagonists & inhibitors

KW - Angiogenesis Inhibitors/administration & dosage/therapeutic use

KW - Down-Regulation/drug effects

KW - Drug Resistance, Neoplasm/drug effects/genetics

KW - Molecular Targeted Therapy/methods

KW - Neoplasms/blood supply/drug therapy/pathology

KW - Neovascularization, Pathologic/drug therapy/pathology

KW - Vascular Endothelial Growth Factor A/antagonists & inhibitors

KW - Animals

KW - Humans

KW - Cells, Cultured

KW - Mice

KW - Drug Synergism

KW - Mice, SCID

KW - Xenograft Model Antitumor Assays

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Signal Transduction/drug effects

KW - Activin Receptors, Type II/antagonists & inhibitors

KW - Angiogenesis Inhibitors/administration & dosage/therapeutic use

KW - Down-Regulation/drug effects

KW - Drug Resistance, Neoplasm/drug effects/genetics

KW - Molecular Targeted Therapy/methods

KW - Neoplasms/blood supply/drug therapy/pathology

KW - Neovascularization, Pathologic/drug therapy/pathology

KW - Vascular Endothelial Growth Factor A/antagonists & inhibitors

M3 - SCORING: Journal article

VL - 71

SP - 1362

EP - 1373

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 4

M1 - 4

ER -