Integrin Activation in Breast Cancer Metastasis

描述：(申请人提供)转移性疾病的并发症为 人类乳腺癌的主要死因。因此，从长远来看， 这个项目的目标是了解决定乳房的机制。 癌症转移。中心假设是黏附的稳定表达 处于功能激活状态的受体整合素avbeta3促进 乳腺癌细胞的转移表型。整合素Alphavbeta3在这里 被定义为激活，如果它支持乳腺癌细胞与 血液流动过程中的血小板，从而介导乳腺癌细胞停滞，以及 如果它能促进乳腺癌细胞的迁移。具体目标是：1. 分析表达活化的αvbeta3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 转移瘤。这将在一个新的乳腺癌细胞模型中进行测试，在该模型中，细胞 变异体稳定表达激活或非激活的alphavbeta3，并且 基因上贴上了荧光标签。它们的命运和分布 将在免疫缺陷小鼠身上追踪肿瘤细胞变异；2.分析乳房 由活化的乳腺癌细胞控制的癌细胞功能 整合素αvbeta3，与转移活性有关。这个 有待检验的假设是激活的avbeta3支持特定的配体 乳腺癌细胞具有结合、黏附、迁移和侵袭的功能 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细胞模型的 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 已经讨论很久了，激活的alphavbeta3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，从而阻止肿瘤细胞的生长。血小板对乳房的贡献 癌症转移将在一种新的小鼠模型中进行决定性的测试，该模型缺乏 循环中的血小板和接受人类肿瘤细胞移植物。团结在一起， 拟议的研究将有助于理解特定的粘合剂 由乳腺癌细胞整合素激活控制的机制，以及 支持从久坐不动的转移瘤转变为传播性转移瘤 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.