The alpha2beta1 Integrin and Tumor Metastasis

描述（由申请人提供）：本提案的目标是确定α 2 <$1整联蛋白在肿瘤转移中的作用，特别关注恶性乳腺上皮细胞和肿瘤微环境之间的相互作用。 整合素介导的肿瘤细胞与其微环境之间的相互作用是肿瘤进展和转移所必需的。 我们最早的来自人类病理标本的数据表明，α 2 <$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。 我们现在提出了新的和令人兴奋的初步数据，缺乏α 2 <$1整合素表达促进肿瘤转移的自发性乳腺癌的体内模型。 虽然原发肿瘤的发病率和潜伏期相似，但相对于野生型MMTV-c-neu同窝对照，缺乏α 2 <$1整联蛋白的转基因MMTV-c-neu小鼠的转移频率是野生型MMTV-c-neu同窝对照的两倍。 因此，α 2 <$1整合素可能作为转移抑制基因发挥作用，改变转移率，但不影响肿瘤的发生。 转移性疾病不仅依赖于恶性上皮细胞，而且同样受到肿瘤微环境的影响。 当用刘易斯肺癌细胞静脉内注射野生型和α 2-缺失动物时，α 2-缺失动物具有显著增加的转移性疾病。 这些来自静脉注射肿瘤细胞的数据表明，增加的转移是影响肿瘤转移过程的后续步骤的宿主因素的结果。 在自发转移模型中，我们不能排除α 2缺失肿瘤细胞的额外贡献。 基于这些数据，我们提出了以下假设，并旨在解决这些假设：1）α 2 <$1整联蛋白是一种转移抑制基因，并改变肿瘤的进展和转移表型; 2）α 2 <$1整联蛋白修饰肿瘤微环境，作为转移效率修饰基因。 目标1：明确α 2 <$1整合素在肿瘤细胞单独表达、肿瘤微环境单独表达或肿瘤和微环境共同表达时对肿瘤转移的抑制作用。 焦点-肿瘤细胞和微环境的相互作用。 目标2：明确α 2 <$1整合素在肿瘤细胞中表达调节肿瘤进展的作用并确定其分子机制。 专注于肿瘤细胞。 目的#3：确定α 2 <$1整联蛋白改变宿主微环境以抑制肿瘤转移的作用。 该目标将特别关注肺和内渗、细胞存活、停滞和定殖的步骤。 病灶-肺转移部位的微环境。

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.