MT-MMP/DDR cross talk at the tumor cell-matrix interface and cancer progression

肿瘤细胞-基质界面处的 MT-MMP/DDR 串扰和癌症进展

• 批准号: 8846055
• 负责人: Rafael A. Fridman
• 金额: $ 26.04万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-06 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846055
• 关键词: 3-Dimensional; Address; Adhesives; Architecture; Basement membrane; Biochemical; Biological Assay; Biological Models; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Breast Carcinoma; Breast Epithelial Cells; Cancer Control; Cancerous; Carcinoma; Cells; Cleaved cell; Collagen; Collagen Receptors; DDR1 gene; DDR2 gene; Data; Development; Diagnostic; Distant Metastasis; Down-Regulation; Engineering; Enzymes; Epithelial; Epithelium; Experimental Models; Extracellular Matrix; Family; Funding; Human; In Situ; In Vitro; Invaded; Knowledge; Ligands; Light; MMP14 gene; MT3 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Membrane; Mesenchymal; Modeling; Molecular; Morphogenesis; Mus; Neoplasm Metastasis; Outcome; Patients; Phenotype; Phosphotransferases; Play; Process; Proteolysis; Receptor Activation; Receptor Cross-Talk; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Role; Signal Transduction; Structure-Activity Relationship; Supporting Cell; System; Testing; Therapeutic; Time; Tissues; base; breast cancer diagnosis; cancer cell; cell behavior; cell motility; cohort; design; discoidin receptor; human MMP14 protein; human tissue; improved; in vivo; information gathering; insight; malignant breast neoplasm; malignant phenotype; member; membrane-type matrix metalloproteinase; neoplastic cell; novel; programs; public health relevance; receptor; response; therapeutic target; tumor; tumor progression

The long term of our studies is to understand the functional contribution of proteolytic systems to cancer progression. We have focused on the action of membrane type- matrix metalloproteinases (MT-MMPs) known to promote pro-invasive activity through tissue barriers, particularly MT1-MMP (MMP14). We now show a novel interaction between three members of the MT-MMP family, MT1- (MMP14), MT2- (MMP15), and MT3- (MP16) MP (refered here to as MT-MMPs), and the discoidin domain receptors (DDRs), a unique set of receptor tyrosine kinases (RTKs) that are specifically activated in response to collagen, which together with MT-MMPs' collagenolytic activity may orchestrate the proteolytic and adhesive programs during tumor cell dissemination. Preliminary data show a unique functional and specific relationship between MT-MMPs and DDRs that leads to downregulation of collagen-evoked DDR (DDR1 and DDR2) activation in a process that goes beyond receptor cleavage. Indeed, MT-MMPs selectively cleave DDR1 but not DDR2. We also report a gradual loss of DDR1 expression in invasive breast carcinomas suggesting a role for DDR1 in the transition from in situ to invasive carcinoma. Since DDR1 has been implicated in maintenance of normal mammary epithelial function and DDR2 may be associated with mesenchymal- like phenotypes, we posit that a differential regulation of DDRs by MT-MMPs may contribute to the disruption of normal breast tissue architecture and function that leads to malignant cancer. To test this hypothesis we propose thre Specific Aims: 1) To investigate the structural bases, molecular mechanisms, and functional consequences of DDR/MT-MMP interactions, 2) To investigate the expression of DDRs and MT1-MMP in human breast cancer tissues, and 3) To Investigate the DDR/MT1-MMP interplay in experimental models of breast epithelial-matrix interactions. The studies in this application will fill a wide gap of knowledge on our understanding of DDR regulation and function, and wil shed light on how their interactions with MT-MMPs influence cell behavior in normal and malignant breast epithelium. We hope that this new knowledge will help to develop better therapeutic and diagnostic strategies to improve survival in breast cancer patients.

我们长期的研究是了解蛋白水解物的功能贡献 癌症进展的系统。我们关注的是膜型的作用-- 基质金属蛋白酶(MT-MMPs)通过以下途径促进侵袭活性 组织屏障，特别是MT1-MMP(MMP14)。我们现在展示一种新的交互方式 在MT-MMP家族的三个成员之间，MT1-(MMP14)，MT2-(MMP15)，和 MT3-(MP16)MP(这里称为MT-MMPs)和Discoidin结构域 受体(DDR)，一组独特的受体酪氨酸激酶(RTK)，它们是特异性的 胶原蛋白的激活与MT-MMPs的胶原酶活性 可能在肿瘤细胞扩散过程中协调蛋白分解和黏附程序。 初步数据显示MT-MMP之间存在独特的功能和特异性关系 以及导致胶原蛋白诱导的DDR(DDR1和DDR2)下调的DDR 激活超越受体裂解的过程。的确，MT-MMPs 有选择地切割DDR1，但不切割DDR2。我们还报告了DDR1的逐渐丧失 在浸润性乳腺癌中的表达提示DDR1在这一转变中的作用 从原位癌到浸润性癌。由于DDR1被牵连到 正常乳腺上皮功能和DDR2可能与间充质病变有关。 与表型相似，我们假设MT-MMP对DDR的不同调控可能 会破坏正常的乳房组织结构和功能，导致 恶性肿瘤。为了验证这一假设，我们提出了三个具体目标：1) 研究其结构基础、分子机制和功能后果 DDR/MT-MMP的相互作用，2)研究DDR和MT1-MMP在卵巢癌组织中的表达 3)研究DDR/MT1-MMP3在乳腺癌组织中的相互作用。 乳腺上皮-基质相互作用的实验模型。这方面的研究 应用将填补我们在了解DDR规则和 功能，并将阐明它们与MT-MMPs的相互作用如何影响细胞 正常和恶性乳腺上皮的行为。我们希望这一新知识 将有助于开发更好的治疗和诊断策略，以提高患者的存活率 乳腺癌患者。

项目成果

Assessment of gelatinases (MMP-2 and MMP-9) by gelatin zymography.

• DOI: 10.1007/978-1-61779-854-2_8
• 发表时间: 2012-01-01
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Toth, Marta;Sohail, Anjum;Fridman, Rafael
• 通讯作者: Fridman, Rafael

Assessment of Gelatinases (MMP-2 and MMP-9 by Gelatin Zymography.

• DOI: 10.1385/1-59259-136-1:163
• 发表时间: 2001-01-01
• 期刊: Methods in molecular medicine
• 作者: Toth, M;Fridman, R
• 通讯作者: Fridman, R

Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells.

• 发表时间: 1999-12
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Gangyong Li;R. Fridman;Hyeong‐Reh Choi Kim

A potent gelatinase inhibitor with anti-tumor-invasive activity and its metabolic disposition.

• DOI: 10.1111/j.1747-0285.2008.00750.x
• 发表时间: 2009-02
• 期刊: Chemical biology & drug design
• 影响因子: 3
• 作者: Lee M;Celenza G;Boggess B;Blase J;Shi Q;Toth M;Bernardo MM;Wolter WR;Suckow MA;Hesek D;Noll BC;Fridman R;Mobashery S;Chang M
• 通讯作者: Chang M

Synthesis and biological evaluation in U87MG glioma cells of (ethynylthiophene)sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors.

• DOI: 10.1016/j.ejmech.2011.03.033
• 发表时间: 2011-07
• 期刊: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 6.7
• 作者: Nuti, Elisa;Casalini, Francesca;Santamaria, Salvatore;Gabelloni, Pamela;Bendinelli, Sara;Da Pozzo, Eleonora;Costa, Barbara;Marinelli, Luciana;La Pietra, Valeria;Novellino, Ettore;Bernardo, M. Margarida;Fridman, Rafael;Da Settimo, Federico;Martini, Claudia;Rossello, Armando
• 通讯作者: Rossello, Armando