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 - 细胞相互作用的丧失，基底膜的降解以及通过恶性上皮细胞侵袭了基础基质组织，这是原发性乳腺肿瘤向局部和遥远转移酶的进展中的关键事件。 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被克隆并显示在癌组织中过表达。 然而，尽管开发了新型治疗剂的潜力巨大，但我们仍然对它们的蛋白水解活性的调节知之甚少。 伴半胱氨酸蛋白酶的囊肿是内源性/溶酶体半胱氨酸蛋白酶的有效内源性蛋白抑制剂。胱抑素M在原发性人乳腺癌中表达，但在转移性乳腺组织和许多癌细胞系中被下调，因此可以代表一种新型的转移抑制基因。我们研究的长期目标是定义肿瘤生长，侵袭和转移过程中抑制蛋白M控制的关键步骤。 我们的工作假设是，抑制蛋白M在休眠和非侵入性期保持原发性乳腺肿瘤。 体内肿瘤进展本质上很复杂。 因此，我们将开始使用已建立的体外模型开始我们的工作，以确定：1。胱抑素M是否能够抑制肿瘤细胞介导的基质降解和侵袭。 第一个具体目的将使用重组囊蛋白M以及与伴半胱氨酸蛋白酶的表达改变的人类乳腺癌细胞系进行解决。这些体外研究应大大帮助首席研究者在设计和执行特定目的的研究和进行特定目的的研究中，分析伴有对原发性肿瘤生长，侵袭和转移，sciD s scid Miese的抑制功能的抑制功能。 该项目的整体研究应产生的新见解可能会导致设计新型药物，以治疗主要的侵入性人类乳腺癌和/或其转移。