肿瘤侵袭和转移课件.pptVIP

MMP mainly involved in metastasis are different in some tumors MMP induction by cell-cell interaction and emmprin Emmprin(extracellular matrix metalloproteinase inducer) The cDNA for human emmprin encodes a 269 amino acid residue A signal peptide of 21 aa A 185-aa extracellular domain consisting of two regions characteristic of the immunoglobulin (Ig) superfamily A 24-aa transmembrane domain A 39-aa cytoplasmic domain Induction and activation of MMP Emmprin is a surface molecule on tumor cells that stimulates nearly fibroblasts to produce collagenase, GelA and stromelysin-1 Emmprin also stimulates the production of proGelA activators,MT1-and MT2-MMP,by fibroblasts At the invasion front where tumor cells contact fibroblasts, emmprin stimulates pericellular proteolysis of ECM through activation of proGelA on the cell surface (3) Regulation of MMP activity Transcriptional regulation Pro-enzyme regulation MMps are synthesized as pre-proenzymes, which are secreted from cell as proenzymes. Step-wise activation Cell surface activation by another MMP MT1-MMP(MMP-14) forms a complex with TIMP-2, and subsequently activates pro MMP-2(pro GelA) Intracellular activation MMP-11 contains an additional 10 aa in the propeptide end, It is activated by a Golgi –associated proteinase and secreted as an active enzyme. TIMP inhibition: TIMPs play a key role in maintaining the balance between ECM deposition and its degradation by binding tightly to and regulating MMP actions four isoforms: TIMP 1-4 (4) Tumor cell migration and MMP Cell migration plays a key role in tumor invasion and metastasis, and degradation of ECM by MMP is assumed to be a prerequisite for the cells to migrate into native or provisional tissue matrix Types of tumor cell migration Single cell locomotion Cohort migration ②Expression of MMP during cell migration In SCL, each migrating cell expresses MT1-MMP mRNA and the translated proteins are localized preferentially at the leading edges In cohort type