TUMOR CELL STROMAL INTERACTIONS IN CANCER

癌症中肿瘤细胞间质的相互作用

• 批准号: 6784432
• 负责人: BRYAN P TOOLE
• 金额: $ 27.97万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784432
• 关键词: athymic mouse; cell cell interaction; connective tissue cells; enzyme induction /repression; glycoproteins; metalloendopeptidases; metastasis; neoplastic cell; protein structure function

DESCRIPTION: (adapted from the investigator's abstract) One of the crucial steps in tumor growth and metastasis is proteolytic modification of the extracellular matrix surrounding tumor cells. A major class of proteases that mediates this process is the matrix metalloproteinases (MMPs); inhibition of these enzymes has been shown to prevent tumor progression. Although it was originally thought that tumor MMPs were produced by tumor cells themselves, it is now clear that, in vivo, most tumor MMPs are produced by stromal cells associated with tumors. The tumor cell surface glycoprotein, EMMPRIN, stimulates production of several MMPs by fibroblasts and endothelial cells. Also, EMMPRIN is enriched in malignant tumors relative to normal tissues and elevated expression of EMMPRIN leads to increased tumor growth in vivo. Thus EMMPRIN may be an important regulator of MMP production that serves a crucial role in cancer. Consequently, the focus of this proposal will be the structure, function and mechanism of action of EMMPRIN in tumorigenesis. The role of EMMPRIN in various aspects of tumor progression will be tested by overexpression, by antisense inhibition of expression, and by testing susceptibility of EMMPRIN-null mice to tumor growth. The potential significance of EMMPRIN stimulation of endothelial MMP production in augmenting tumor angiogenesis, and of EMMPRIN stimulation of fibroblast MMP production in tumor cell growth and invasiveness will be explored. The fibroblast/endothelial cell receptor responsible for transduction of EMMPRIN stimulation of MMP production will be isolated and characterized. Finally, the region of EMMPRIN responsible for interacting with stromal cells and stimulating MMP production will be mapped, and reagents will be designed to facilitate examination of the functions of EMMPRIN and is putative receptor. The results obtained should determine definitively whether or not EMMPRIN is a crucial element in malignancy, and they should begin to resolve the mechanisms whereby its action is regulated and transmitted. Interference with EMMPRIN action may then be an effective way to inhibit tumor progression patients.

描述：（改编自研究者的摘要）关键之一 肿瘤生长和转移的步骤是蛋白水解修饰 肿瘤细胞周围的细胞外基质。一类主要的蛋白酶 介导这一过程的是基质金属蛋白酶（MMP）；抑制 这些酶已被证明可以预防肿瘤进展。虽然那是 最初认为肿瘤MMPs是由肿瘤细胞自身产生的，但 现在已经清楚，在体内，大多数肿瘤 MMP 是由基质细胞产生的 与肿瘤有关。肿瘤细胞表面糖蛋白 EMMPRIN 刺激成纤维细胞和内皮细胞产生多种 MMP。 此外，相对于正常组织，EMMPRIN 在恶性肿瘤中含量丰富，并且 EMMPRIN 表达升高导致体内肿瘤生长增加。因此 EMMPRIN 可能是 MMP 产生的重要调节因子，具有重要的作用 在癌症中的作用。因此，该提案的重点将是结构， EMMPRIN 在肿瘤发生中的功能和作用机制。的作用 EMMPRIN 在肿瘤进展各个方面的作用将通过 过表达，通过表达的反义抑制，并通过测试 EMMPRIN缺失小鼠对肿瘤生长的易感性。潜在意义 EMMPRIN 刺激内皮 MMP 产生以增强肿瘤的作用 血管生成以及 EMMPRIN 刺激肿瘤中成纤维细胞 MMP 的产生 将探讨细胞生长和侵袭性。成纤维细胞/内皮细胞 负责转导 EMMPRIN 刺激 MMP 产生的受体 将被隔离和表征。最后，EMMPRIN 负责的区域 与基质细胞相互作用并刺激 MMP 产生 映射，并且将设计试剂以方便检查 EMMPRIN 的功能，是推定的受体。所得结果应 明确确定EMMPRIN是否是一个关键元素 恶性肿瘤，他们应该开始解决其作用的机制 受到监管和传播。干扰 EMMPRIN 的作用可能是 抑制患者肿瘤进展的有效方法。