Integrin Activation in Breast Cancer Metastasis

描述：（由申请人提供）转移性疾病的并发症是 人类乳腺癌的主要死因。因此，从长远来看， 本项目的目的是了解决定乳腺癌的机制， 癌症转移中心假设是粘附的稳定表达 受体整联蛋白α v β 3在功能活化状态下， 乳腺癌细胞的转移表型。整合素α v β 3 定义为激活，如果它支持乳腺癌细胞与 血小板在血液流动过程中，从而介导乳腺癌细胞停滞，和 如果它增强乳腺癌细胞迁移。具体目标是1. 分析表达活化的alphavbeta 3的乳腺癌细胞是否具有 在肿瘤生长过程中的选择性优势，并代表恶性细胞， 转移这将在一种新的乳腺癌细胞模型中进行测试， 变体稳定表达活化或非活化的α v β 3， 用荧光标记进行遗传标记。它们的命运和分布 将在免疫缺陷小鼠中追踪肿瘤细胞变体; 2.分析乳房 癌细胞功能由激活的乳腺癌细胞控制 整联蛋白α v β 3，并且其有助于转移活性。的 待检验假设是活化的Δ V β 3支持特异性配体 结合，粘附，迁移和侵袭乳腺癌细胞的功能， 在乳腺癌转移过程中是必需的。这将在体外进行测试， 与乳腺癌细胞模型的功能变体和与原发性 来自乳腺癌患者的转移细胞; 3.阐明血小板是否发挥作用 在乳腺癌转移中的作用。血小板在肿瘤转移中的作用已被证实。 长期以来一直在讨论，激活的α v β 3在 转移性乳腺癌细胞是为了支持与血小板的相互作用， 血液流动，从而阻止肿瘤细胞。血小板对乳腺的贡献 癌症转移将在一种新的小鼠模型中进行明确测试，该模型缺乏 循环血小板并接受人类肿瘤细胞移植物。统称 建议的研究将有助于了解特定的粘合剂 机制，由乳腺癌细胞整合素激活控制， 支持从久坐型到扩散型转移性 表型

DESCRIPTION: (provided by applicant) Complications from metastatic disease are the primary cause of death in human breast cancer. Therefore, the long term objective of this project is to understand mechanisms that determine breast cancer metastasis. The central hypothesis is that stable expression of adhesion receptor integrin avbeta3 in a functionally activated state, promotes the metastatic phenotype in breast cancer cells. Integrin alphavbeta3 is here defined as activated, if it supports breast cancer cell interaction with platelets during blood flow, thereby mediating breast cancer cell arrest, and if it enhances breast cancer cell migration. The specific aims are to 1. Analyze whether breast cancer cells expressing activated alphavbeta3 have a selective advantage during tumor growth, and represent the malignant cells that metastasize. This will be tested in a new breast cancer cell model, where cell variants stably express either activated or non-activated alphavbeta3, and are genetically tagged with fluorescent labels. The fate and distribution of these tumor cell variants will be tracked in immune deficient mice; 2. Analyze breast cancer cell functions that are controlled by activated breast cancer cell integrin alphavbeta3, and that contribute to the metastatic activity. The hypothesis to be tested is that activated avbeta3 supports specific ligand binding, adhesive, migratory and invasive breast cancer cell functions, that are required during breast cancer metastasis. This will be tested in vitro, with functional variants of the breast cancer cell model and with primary metastatic cells from breast cancer patients; 3. Clarify whether platelets play a role in breast cancer metastasis. A role of platelets in tumor metastasis has long been discussed, and a prominent function of activated alphavbeta3 in metastatic breast cancer cells is, to support interaction with platelets during blood flow and thereby tumor cell arrest. A contribution of platelets to breast cancer metastasis will be tested definitively in a new mouse model, that lacks circulating platelets and accepts human tumor cell grafts. Together, the proposed studies will contribute to an understanding of specific adhesive mechanisms, that are controlled by breast cancer cell integrin activation, and that support the change from a sedentary to a disseminating metastatic phenotype.