Activation of tumor cell integrin αvβ3 controls angiogenesis and metastatic growth in the brain
Activation of tumor cell integrin αvβ3 controls angiogenesis and metastatic growth in the brain
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DOI：
10.1073/pnas.0903035106
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发表时间：
2009-06-30
影响因子：
11.1
通讯作者：
Felding-Habermann, Brunhilde
中科院分区：
文献类型：
--
作者：
Lorger, Mihaela;Krueger, Joseph S.;Felding-Habermann, Brunhilde
脑转移的发病率正在上升，并提出了一个严重的临床问题，因为我们缺乏有效的治疗和知识的机制，控制转移生长的大脑。在这里，我们证明了高亲和力肿瘤细胞整合素α（v）β（3）在脑转移瘤生长和血管募集中的关键作用。虽然alpha（v）beta（3）在原发性脑肿瘤和脑归巢癌的转移性病变中经常上调，但我们表明，alpha（v）beta（3）激活状态对脑病变生长至关重要。在常氧条件下，活化而非非非活化的肿瘤细胞α（v）β（3）通过持续上调血管内皮生长因子（VEGF）蛋白支持有效的脑转移生长。在携带活化的α（v）β（3）的转移性脑病变中，VEGF表达在转录后水平受到控制，并涉及翻译抑制因子4 E结合蛋白（4 E-BP 1）的磷酸化和抑制。相反，具有非活化的alpha（v）beta（3）的肿瘤细胞依赖于缺氧来诱导VEGF，导致血管生成减少、肿瘤细胞凋亡和颅内生长效率低下。重要的是，微环境严重影响激活的肿瘤细胞α（v）β（3）对肿瘤细胞生长的影响。虽然它强烈促进颅内生长，受体的激活状态并不影响肿瘤生长的乳腺脂肪垫作为一个主要网站。因此，我们确定了一种机制，通过这种机制，转移细胞在脑微环境中茁壮成长，并使用高亲和力形式的粘附受体来生长和确保宿主支持增殖。靶向这种分子机制可能被证明对抑制脑转移有价值。
The incidence of brain metastasis is rising and poses a severe clinical problem, as we lack effective therapies and knowledge of mechanisms that control metastatic growth in the brain. Here we demonstrate a crucial role for high-affinity tumor cell integrin alpha(v)beta(3) in brain metastatic growth and recruitment of blood vessels. Although alpha(v)beta(3) is frequently up-regulated in primary brain tumors and metastatic lesions of brain homing cancers, we show that it is the alpha(v)beta(3) activation state that is critical for brain lesion growth. Activated, but not non-activated, tumor cell alpha(v)beta(3) supports efficient brain metastatic growth through continuous up-regulation of vascular endothelial growth factor (VEGF) protein under normoxic conditions. In metastatic brain lesions carrying activated alpha(v)beta(3), VEGF expression is controlled at the post-transcriptional level and involves phosphorylation and inhibition of translational respressor 4E-binding protein (4E-BP1). In contrast, tumor cells with non-activated alpha(v)beta(3) depend on hypoxia for VEGF induction, resulting in reduced angiogenesis, tumor cell apoptosis, and inefficient intracranial growth. Importantly, the microenvironment critically influences the effects that activated tumor cell alpha(v)beta(3) exerts on tumor cell growth. Although it strongly promoted intracranial growth, the activation state of the receptor did not influence tumor growth in the mammary fat pad as a primary site. Thus, we identified a mechanism by which metastatic cells thrive in the brain microenvironment and use the high-affinity form of an adhesion receptor to grow and secure host support for proliferation. Targeting this molecular mechanism could prove valuable for the inhibition of brain metastasis.