ROLE OF CYSTATIN M IN BREAST TUMOR PROGRESSION

胱抑素 M 在乳腺肿瘤进展中的作用

• 批准号: 6348441
• 负责人: J. Michael Mathis
• 金额: $ 9.99万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-14 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6348441
• 关键词: SCID mouse; antineoplastics; breast neoplasms; cell line; cell migration; complementary DNA; cysteine endopeptidases; extracellular matrix; matrigel; metastasis; neoplasm /cancer invasiveness; neoplastic process; protease inhibitor; recombinant proteins; transfection

Loss of cell-cell interactions, degradation of the basement membrane and invasion of the underlying stromal tissue by malignant epithelial cells are key events in the progression of a primary breast tumor to local and distant metastases. There is increasing evidence that proteolytic enzymes, or proteases, are involved in tumor progression. In recent years several endosomal/lysosomal cysteine proteases have been cloned and shown to be overexpressed in cancer tissues. However, despite the enormous potential for development of novel therapeutics, we still understand little about the regulation of their proteolytic activity. Cystatins such as cystatin M are potent endogenous protein inhibitors of endosomal/lysosomal cysteine proteases. Cystatin M is expressed in primary human breast cancer but is downregulated in metastatic breast tissue and many cancer cell lines and could therefore represent a novel metastasis suppressor gene. The long-term objective of our studies is to define the critical steps controlled by cystatin M during tumor growth, invasion and metastasis. Our working hypothesis is that cystatin M maintains primary breast tumors in a dormant and non-invasive phase. Tumor progression in vivo is complex in nature. We will therefore begin our work with established in vitro models to determine: 1. whether cystatin M is able to inhibit tumor cell-mediated matrix degradation and invasion. The first specific aim will be addressed using recombinant cystatin M as well as engineering human breast cancer cell lines with altered expression of cystatin M. These in vitro studies should greatly help the principal investigator in designing and performing studies for specific aim 2 that will analyze the suppressing function(s) of cystatin M on primary tumor growth, invasion and metastasis in SCID mice. The new insights that should be generated by the overall research of this project may lead to the design of novel drugs for the treatment of primary invasive human breast cancers and/or their metastases.

细胞间相互作用的丧失、基底膜的降解以及恶性上皮细胞对底层基质组织的侵袭是原发性乳腺肿瘤进展为局部和远处转移的关键事件。 越来越多的证据表明蛋白水解酶或蛋白酶参与肿瘤进展。 近年来，几种内体/溶酶体半胱氨酸蛋白酶已被克隆，并显示在癌症组织中过度表达。 然而，尽管开发新疗法具有巨大潜力，但我们对其蛋白水解活性的调节仍然知之甚少。 胱抑素如胱抑素 M 是内体/溶酶体半胱氨酸蛋白酶的有效内源性蛋白质抑制剂。胱抑素 M 在原发性人类乳腺癌中表达，但在转移性乳腺组织和许多癌细胞系中表达下调，因此可能代表一种新型转移抑制基因。我们研究的长期目标是确定肿瘤生长、侵袭和转移过程中由胱抑素 M 控制的关键步骤。 我们的工作假设是胱抑素 M 使原发性乳腺肿瘤维持在休眠和非侵袭性阶段。 体内肿瘤进展本质上是复杂的。 因此，我们将从建立的体外模型开始，以确定： 1. 半胱氨酸蛋白酶抑制剂 M 是否能够抑制肿瘤细胞介导的基质降解和侵袭。 第一个具体目标将通过使用重组半胱氨酸蛋白酶抑制剂 M 以及工程化改变半胱氨酸蛋白酶抑制剂 M 表达的人乳腺癌细胞系来实现。这些体外研究应极大地帮助主要研究者设计和执行具体目标 2 的研究，该目标将分析抑制胱抑素 M 对 SCID 小鼠原发性肿瘤生长、侵袭和转移的功能。 该项目的整体研究应产生的新见解可能会导致设计用于治疗原发性侵袭性人类乳腺癌和/或其转移瘤的新药物。