Impact of TIMP-1 in the host microenvironment on modification of the new prognostic marker L1CAM during liver metastasis

宿主微环境中TIMP-1对肝转移过程中新预后标志物L1CAM修饰的影响

• 批准号: 122660502
• 负责人: Professor Dr. Achim Krüger
• 金额: --
• 依托单位: Institut für Molekulare Immunologie und Experimentelle Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/122660502?language=en
• 关键词: Impact; TIMP; host; microenvironment; modification

In this project we aim for establishing a functional relationship between the cell adhesion molecule L1CAM, the natural metalloprotease inhibitor TIMP-1 and the Sheddase ADAM-10. High expression levels of L1CAM on tumor cells and high systemic levels of TIMP-1 in the host are associated with bad prognosis of cancer patients and promotion of tumor cell metastasis. ADAM-10 is a known sheddase of L1CAM and was found to be inhibited by TIMP-1. On this basis we hypothesize that elevated systemic levels of TIMP-1, which then are present also in the microenvironment of the tumor cell, contribute to increase of the metastatic potential of tumor cells by stabilizing the cell surface presence of L1CAM on the tumor cell surface by inhibiting the sheddase function of ADAM-10. First, we aim to investigate in vitro whether exposure of tumor cells to exogenous recombinant TIMP-1 induces L1CAM protein, via inhibition of ADAM-10, at the tumor cell surface. In the next step, we aim to elevate TIMP-1 levels systemically in the host and investigate, whether the previously observed promotion of experimental metastasis correlates with L1CAM expression on the tumor cells. Further, we aim to investigate whether inhibition of ADAM-10 by TIMP-1 leads to compensation by increasing the expression and functional activity of the alternative L1CAM sheddases, ADAM-17 and Plasmin, which are not inhibited by TIMP-1 and whether this compensation within the complex proteolytic network has consequences in vivo. Since metastasis seems to almost always rely on the increased activity of the HGF/Met signalling pathway and we found that this pathway mediates the metastasis-promoting effect of elevated exogenous TIMP-1 levels in the organism, we aim to elucidate a possible regulation of L1CAM on the gene expression level. The TIMP-1-induced stabilization of Met at the cell surface that we had previously found may trigger gene expression of L1CAM. Elucidation of the interplay between TIMP-1 and L1CAM during metastasis will provide important hints for the development of new therapies of malignant tumors.

在这个项目中，我们的目标是建立细胞粘附分子L1 CAM，天然金属蛋白酶抑制剂TIMP-1和脱落酶ADAM-10之间的功能关系。肿瘤细胞上L1 CAM的高表达水平和宿主中TIMP-1的高全身水平与癌症患者的不良预后和促进肿瘤细胞转移相关。ADAM-10是已知的L1 CAM的脱落酶，并且被发现被TIMP-1抑制。在此基础上，我们假设TIMP-1的升高的全身水平（其随后也存在于肿瘤细胞的微环境中）通过抑制ADAM-10的脱落酶功能来稳定肿瘤细胞表面上L1 CAM的细胞表面存在，从而有助于增加肿瘤细胞的转移潜能。首先，我们的目的是研究在体外是否暴露的肿瘤细胞外源性重组TIMP-1诱导L1 CAM蛋白，通过抑制ADAM-10，在肿瘤细胞表面。在下一步中，我们的目标是提高TIMP-1在宿主中的系统水平，并研究先前观察到的实验转移的促进是否与肿瘤细胞上的L1 CAM表达相关。此外，我们的目的是研究是否通过TIMP-1抑制ADAM-10导致补偿，通过增加替代L1 CAM脱落酶，ADAM-17和纤溶酶，这是不受TIMP-1抑制的表达和功能活性，以及是否在复杂的蛋白水解网络内的这种补偿在体内有后果。由于转移似乎几乎总是依赖于HGF/Met信号通路的活性增加，并且我们发现该通路介导生物体中外源性TIMP-1水平升高的转移促进作用，因此我们的目的是阐明L1 CAM在基因表达水平上的可能调节。TIMP-1诱导的Met在细胞表面的稳定性，我们以前发现可能触发L1 CAM的基因表达。阐明TIMP-1和L1 CAM在肿瘤转移过程中的相互作用，将为恶性肿瘤新的治疗方法的开发提供重要的线索。

项目成果

Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization, and metastatic growth

• DOI: 10.1007/s10585-013-9613-6
• 发表时间: 2013
• 期刊: Clinical & Experimental Metastasis
• 影响因子: 4
• 作者: Dirk Weinspach;Bastian Seubert;Susanne Schaten;Katja Honert;S. Sebens;P. Altevogt;A. Krüger