Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer

被引：49

作者：

Cunha, Sara I. ^{[1
,2
]}

Bocci, Matteo ^{[3
]}

Lovrot, John ^{[4
]}

Eleftheriou, Nikolas ^{[3
]}

Roswall, Pernilla ^{[2
]}

Cordero, Eugenia ^{[3
]}

Lindstrom, Linda ^{[4
]}

Bartoschek, Michael ^{[3
]}

Haller, B. Kristian ^{[2
]}

Pearsall, R. Scott ^{[5
]}

Mulivor, Aaron W. ^{[5
]}

Kumar, Ravindra ^{[5
]}

Larsson, Christer ^{[3
]}

Bergh, Jonas ^{[4
]}

Pietras, Kristian ^{[2
,3
]}

机构：

[1] Ludwig Inst Canc Res, S-75124 Uppsala, Sweden

[2] Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden

[3] Lund Univ, Div Translat Canc Res, Dept Lab Med, Medicon Village, SE-22381 Lund, Sweden

[4] Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden

[5] Acceleron Pharma, Cambridge, MA USA

来源：

CANCER RESEARCH | 2015年 / 75卷 / 12期

基金：

瑞典研究理事会; 欧洲研究理事会;

关键词：

ANTIANGIOGENIC THERAPY; MONOCLONAL-ANTIBODY; MOLECULAR-ORIGINS; GROWTH-FACTOR; TGF-BETA; ANGIOGENESIS; SUNITINIB; TUMORS; STAGE;

D O I：

10.1158/0008-5472.CAN-14-3706

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case-control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer. (C) 2015 AACR.

引用

页码：2445 / 2456

页数：12

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