The alpha2beta1 Integrin and Tumor Metastasis

α2β1整合素与肿瘤转移

基本信息

  • 批准号:
    8206619
  • 负责人:
  • 金额:
    $ 30.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-01-01 至 2013-12-31
  • 项目状态:
    已结题

项目摘要

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. PUBLIC HEALTH RELEVANCE: Metastasis is the main cause of cancer death. We have identified a protein that may suppress the incidence and severity of breast cancer metastasis. This proposal will evaluate the way in which this protein suppresses tumor metastasis.
描述(申请人提供):本提案的目标是明确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。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。我们最早从人类病理标本中获得的数据表明,a2?1整合素在正常的上皮细胞上高度表达,但在癌症中以一种与癌症进展相关的方式减少或丢失。我们现在提供新的和令人兴奋的初步数据,在自发性乳腺癌的体内模型中,缺乏a2?1整合素的表达促进了肿瘤的转移。虽然原发肿瘤发病率和潜伏期相似,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对照小鼠的两倍。因此,a2?1整合素可能是一种转移抑制基因,它可以改变转移率,但不能改变肿瘤的起始。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缺失型动物静脉注射Lewis肺癌细胞时,a2缺失型动物的转移性疾病显著增加。这些来自静脉注射肿瘤细胞的数据表明,转移增加是宿主因素影响肿瘤转移过程的后期步骤的结果。我们不能排除自发转移模型中a2缺失的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)a2?1整合素是一个转移抑制基因,改变肿瘤的进展和转移表型;2)a2?1整合素改变肿瘤微环境,作为转移效率修饰物基因。目的1:明确a2?1整合素单独由肿瘤细胞、单独由肿瘤微环境、或由肿瘤与微环境共同表达对肿瘤转移抑制的独立或协同作用。焦点--肿瘤细胞与微环境的相互作用。目的#2:明确a2?1整合素在肿瘤细胞表达调控肿瘤进展中的作用和分子机制。焦点--肿瘤细胞。目的#3:确定a2?1整合素在改变宿主微环境抑制肿瘤转移中的作用。这一目标将特别侧重于肺以及血管内、细胞存活、停滞和定植的步骤。病灶--肺内转移部位的微环境。公共卫生相关性:转移是癌症死亡的主要原因。我们已经确定了一种可能抑制乳腺癌转移发生率和严重程度的蛋白质。这项提案将评估这种蛋白质抑制肿瘤转移的方式。

项目成果

期刊论文数量(0)
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MARY M. ZUTTER其他文献

MARY M. ZUTTER的其他文献

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{{ truncateString('MARY M. ZUTTER', 18)}}的其他基金

Program Leaders
项目负责人
  • 批准号:
    8733554
  • 财政年份:
    2013
  • 资助金额:
    $ 30.9万
  • 项目类别:
Program Leaders
项目负责人
  • 批准号:
    8180520
  • 财政年份:
    2010
  • 资助金额:
    $ 30.9万
  • 项目类别:
Human Tissue Aquisition and Pathology Shared Resource
人体组织采集和病理学共享资源
  • 批准号:
    8180573
  • 财政年份:
    2010
  • 资助金额:
    $ 30.9万
  • 项目类别:
The alpha2beta1 Integrin and Tumor Metastasis
α2β1整合素与肿瘤转移
  • 批准号:
    8403773
  • 财政年份:
    2009
  • 资助金额:
    $ 30.9万
  • 项目类别:
The alpha2beta1 Integrin and Tumor Metastasis
α2β1整合素与肿瘤转移
  • 批准号:
    7744056
  • 财政年份:
    2009
  • 资助金额:
    $ 30.9万
  • 项目类别:
The alpha2beta1 Integrin and Tumor Metastasis
α2β1整合素与肿瘤转移
  • 批准号:
    8009795
  • 财政年份:
    2009
  • 资助金额:
    $ 30.9万
  • 项目类别:
The alpha2beta1 Integrin and Tumor Metastasis
α2β1整合素与肿瘤转移
  • 批准号:
    7576626
  • 财政年份:
    2009
  • 资助金额:
    $ 30.9万
  • 项目类别:
Unexpected Roles for the alpha2beta1 Integrin
α2β1 整合素的意想不到的作用
  • 批准号:
    7389503
  • 财政年份:
    2005
  • 资助金额:
    $ 30.9万
  • 项目类别:
Unexpected Roles for the alpha2beta1 Integrin
α2β1 整合素的意想不到的作用
  • 批准号:
    7585208
  • 财政年份:
    2005
  • 资助金额:
    $ 30.9万
  • 项目类别:
Unexpected Roles for the alpha2beta1 Integrin
α2β1 整合素的意想不到的作用
  • 批准号:
    6959343
  • 财政年份:
    2005
  • 资助金额:
    $ 30.9万
  • 项目类别:

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