The alpha2beta1 Integrin and Tumor Metastasis

α2β1整合素与肿瘤转移

• 批准号: 8403773
• 负责人: MARY M. ZUTTER
• 金额: $ 29.04万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403773
• 关键词: Address; Animal Model; Animals; Behavior; Breast Cancer Cell; Burn injury; Cancer Etiology; Cell Survival; Cells; Cessation of life; Clinical; Collagen; Data; Disease; Environment; Epithelial; Epithelial Cells; Genes; Goals; Health; Human; Incidence; Integration Host Factors; Integrin alpha2beta1; Integrins; Laboratories; Laminin Receptor; Lead; Lewis Lung Carcinoma; Lung; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary gland; Mediating; Metastasis Suppression; Metastasis Suppressor Genes; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Phenotype; Primary Neoplasm; Proteins; Relative (related person); Role; Sampling; Severities; Site; Soil; Specimen; Tail; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Proteins; Veins; Xenograft Model; base; cancer cell; cell type; in vivo; in vivo Model; interest; intravenous injection; malignant breast neoplasm; metastatic process; neoplastic cell; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): The goal of this proposal is to define the role of the a2¿1 integrin in tumor metastasis, with specific interest on the interplay between malignant mammary epithelial cells and the tumor microenvironment. Integrin-mediated interactions between tumor cells and their microenvironment are required for tumor progression and metastasis. Our earliest data derived from human pathological specimens demonstrated that the a2¿1 integrin was highly expressed on normal epithelial cells but was diminished or lost in cancer in a manner that correlated with cancer progression. We now present new and exciting preliminary data that lack of the a2¿1 integrin expression promotes tumor metastasis in an in vivo model of spontaneous breast cancer. Although primary tumor incidence and latency were similar, metastases were twice as frequent in transgenic MMTV-c-neu mice lacking the a2¿1 integrin relative to wild type MMTV-c-neu littermate controls. Thus, the a2¿1 integrin may function as a metastasis suppressor gene that alters the rate of metastasis but not tumor initiation. Metastatic disease is not solely dependent on the malignant epithelial cell, but is equally influenced by the tumor microenvironment. When wild type and a2-null were injected intravenously with Lewis Lung carcinoma cells, the a2-null animals harbored significantly increased metastatic disease. These data from the intravenous injection of tumor cells suggest that increased metastasis is a consequence of host factors influencing the later steps of the tumor metastatic process. We cannot exclude additional contributions from the a2-null tumor cells in the spontaneous metastasis model. Based on these data we propose the following hypotheses and aims to address the hypotheses: 1) The a2¿1 integrin is a metastasis suppressor gene and alters tumor progression and the metastatic phenotype; 2) the a2¿1 integrin modifies the tumor micro-environment to serve as a metastasis efficiency modifier gene. AIM #1: To define the independent or cooperative contributions mediated by the a2¿1 integrin when expressed by tumor cells alone, by the tumor microenvironment alone, or by both tumor and microenvironment that leads to suppression of metastasis. Focus - the interaction of the tumor cells and the microenvironment. AIM #2: To define the role and determine the molecular mechanisms by which the a2¿1 integrin expression by the tumor cells regulates tumor progression. Focus - the tumor cells. AIM #3: To determine the role of the a2¿1 integrin modifies the host microenvironment to suppress tumor metastasis. This aim will focus specifically on the lung and the steps of intravasation, cell survival, arrest and colonization. Focus - the microenvironment of the metastatic site in the lung.

描述（由申请人提供）：本提案的目标是确定 a2¿1 整合素在肿瘤转移中的作用，特别关注恶性乳腺上皮细胞与肿瘤微环境之间的相互作用。 肿瘤进展和转移需要整合素介导的肿瘤细胞与其微环境之间的相互作用。 我们从人类病理标本中获得的最早数据表明，a2¿1 整合素在正常上皮细胞上高度表达，但在癌症中以与癌症进展相关的方式减少或丢失。 我们现在提供了令人兴奋的新初步数据，表明缺乏 a2¿1 整合素表达会促进自发性乳腺癌体内模型中的肿瘤转移。 尽管原发肿瘤发生率和潜伏期相似，但缺乏 a2¿1 整合素的转基因 MMTV-c-neu 小鼠的转移频率是野生型 MMTV-c-neu 同窝对照小鼠的两倍。 因此，a2¿1整合素可能充当转移抑制基因，改变转移率但不改变肿瘤起始。 转移性疾病不仅依赖于恶性上皮细胞，还同样受到肿瘤微环境的影响。 当野生型和a2缺失动物静脉注射Lewis肺癌细胞时，a2缺失动物的转移性疾病显着增加。 来自静脉注射肿瘤细胞的这些数据表明，转移增加是影响肿瘤转移过程后期步骤的宿主因素的结果。 我们不能排除自发转移模型中a2缺失肿瘤细胞的额外贡献。 基于这些数据，我们提出以下假设并旨在解决这些假设：1）a2¿1整合素是一种转移抑制基因，改变肿瘤进展和转移表型； 2）a2¿1整合素改变肿瘤微环境，作为转移效率调节基因。 目标#1：定义当肿瘤细胞单独表达、肿瘤微环境单独表达或肿瘤和微环境两者表达时，a2¿1 整合素介导的独立或协同作用，从而抑制转移。 焦点——肿瘤细胞与微环境的相互作用。 目标#2：定义肿瘤细胞表达的 a2¿1 整合素调节肿瘤进展的作用并确定分子机制。 焦点——肿瘤细胞。 目标#3：确定 a2¿1 整合素在改变宿主微环境以抑制肿瘤转移方面的作用。 这一目标将特别关注肺部以及内渗、细胞存活、停滞和定植的步骤。 焦点 - 肺部转移部位的微环境。