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首页> 外文期刊>The Journal of Experomental Medicine >Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
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Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis

机译：激活素受体样激酶1的遗传和药理靶向削弱肿瘤的生长和血管生成。

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Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-β and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.
机译：转化生长因子β（TGF-β）家族的成员已与胚胎发生过程中的血管形成遗传相关。然而，有关TGF-β和其他已报道血管功能的家族成员（例如骨形态发生蛋白（BMP）9）在生理和病理性血管生成中的作用的相互矛盾的研究使得对机理研究的需求显而易见。我们通过遗传和药理学方法证明，TGF-β和BMP9受体激活素受体样激酶（ALK）1代表了肿瘤血管生成的新治疗靶标。在多步肿瘤发生的转基因小鼠模型中，减少ALK1基因剂量或用ALK1-Fc融合蛋白RAP-041进行全身治疗可通过抑制血管生成来延缓肿瘤的生长和进展。此外，RAP-041显着削弱了对血管内皮生长因子A和碱性成纤维细胞生长因子的体外和体内血管生成反应。在寻找观察到的效应的机制时，我们发现了TGF-β和BMP9之间意想不到的信号协同作用，通过这两种因素的联合作用增强了内皮细胞对血管生成刺激的反应。我们描述了在肿瘤血管生成中由TGF-β家族成员进行信号传导的决定性作用，并为即将在肿瘤学中阻断ALK1的药物的临床开发提供了机理性见解。

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