Vascular mechanisms regulating breast cancer brain metastasis

摘要 乳腺癌是女性中最常见的癌症类型，经常扩散。在30-40%的患者中 如果乳腺癌进展到晚期，这种疾病将转移到大脑，对目前的治疗没有反应。 尽管在早期发现和治疗原发性乳腺癌和脑外病变方面取得了进展， 乳腺癌脑转移是致命的。拟议的研究将遗传和原位结合在一起， 模型，以检查控制血管完整性作为乳腺癌脑转移调节因子的机制。 在Eliceiri和Felding实验室之间，我们将使用定义的遗传和治疗模型来靶向 血管渗漏的病理生理学相关性、血管正常化和血小板对 脑转移瘤的发生、生长和侵袭。我们的实验设计利用了 和创新的方法，在我们的实验室开发，以调查特定的介质，血管 乳腺癌脑转移正常化。我们合作的独特重点将挑战 在乳腺癌脑定植的确定遗传宿主模型中血管正常化的教条， 转移性病变的进展。该提案未满足的需求和具体挑战是部署 我们的研究小组取得了进展，并研究了src激酶、内皮粘着斑激酶 (FAK)和血小板功能介导脑转移中的脑血管完整性。我们将使用独特的 生物发光模型，以评估血管周围星形胶质细胞和小胶质细胞活化， 细胞外基质成分，以及支持我们遗传模型发现的候选疗法。 目的1将确定Src介导的血管通透性在乳腺癌发生过程中的作用。 癌症脑转移目的2将显示是否通过内皮细胞的增加血管正常化， FAK的特异性缺失保护脑免受乳腺癌转移。目标3将确定血小板如何 影响脑转移和血脑屏障内皮的完整性。这些实验将提供一个 更好地理解脑血管正常化机制的功能基础 控制乳腺癌脑转移本研究结果可进一步证实src、内皮FAK和特异性血小板 作为预防和治疗乳腺癌患者脑转移的关键靶点。

Abstract Breast cancer is the most common cancer type in women that frequently spreads. In 30-40% of patients with advancing breast cancer, the disease will metastasize to the brain and not respond to current therapies. Despite advances in early detection and treatment of primary breast cancer and lesions outside the brain, breast cancer brain metastasis is uniformly fatal. The proposed studies bring together genetic and orthotopic models to examine mechanisms that control vascular integrity as a regulator of breast cancer brain metastasis. Between the Eliceiri and Felding labs, we will use defined genetic and therapeutic models to target the pathophysiological relevance of vascular leak, vascular normalization and the contribution of platelets to the initiation, growth and invasion of brain metastatic lesions. Our experimental design exploits the complementary and innovative approaches developed in our laboratories to investigate specific mediators of vascular normalization in breast cancer brain metastasis. The unique focus of our collaboration will challenge the dogma of vascular normalization in defined genetic host models of breast cancer brain colonization and progression of metastatic lesions. The unmet need and specific challenge of this proposal is to deploy advances developed in our groups and examine contributions of src kinase, endothelial focal adhesion kinase (FAK), and platelet functions to mediate cerebral vascular integrity in brain metastasis. We will use unique bioluminescence models to assess peri-vascular astrocyte and microglial activation, signaling mediated by extracellular matrix components, and candidate therapeutics that support the findings from our genetic models. Aim 1 will determine the role of Src-mediated vascular permeability in the host compartment during breast cancer brain metastasis. Aim 2 will show whether an increase in vascular normalization through endothelial- specific deletion of FAK protects the brain from breast cancer metastasis. Aim 3 will determine how platelets affect brain metastasis and endothelial integrity of the blood brain barrier. These experiments will provide a functional basis for a better understanding of mechanisms through which cerebral vascular normalization controls breast cancer brain metastasis. The results may validate src, endothelial FAK and specific platelet functions as key targets for prevention and treatment of brain metastasis in breast cancer patients.