PMID- 15313922 OWN - NLM STAT- MEDLINE DCOM- 20040930 LR - 20130603 IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 64 IP - 16 DP - 2004 Aug 15 TI - Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis. PG - 5795-803 AB - Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) regulate the degradation of extracellular matrix components and play important roles in the progression of select neoplastic processes. The locally invasive soft tissue tumor, aggressive fibromatosis (also called desmoid tumor), is caused by mutations resulting in beta-catenin-mediated T-cell factor (tcf)-dependent transcriptional activity. Because beta-catenin can regulate MMP expression, we investigated the expression of several MMPs and TIMPs in aggressive fibromatosis tumors that develop in Apc+/Apc1638N mice. Mmp-3 and Timp-1 were differentially regulated (5-fold and 0.5-fold, respectively) in tumors compared with normal fibrous tissue. Conditioned media from tumor cells showed an increased ability to degrade collagen, and inhibition of MMPs using GM6001 decreased the ability of the tumor cells to invade through Matrigel. Both the treatment of Apc/Apc1638N mice with GM6001 or crossing with a transgenic mouse that overexpresses Timp-1 resulted in a significant reduction in tumor volume. Surprisingly, overexpression of Timp-1 also resulted in a 50% increase in tumor number. Although TIMP-1 can induce growth stimulatory effects in some cell types, we found no difference in proliferation or apoptosis rate in cells from tumors that developed in the Timp-1-transgenic mice compared with mice that did not express the Timp-1 transgene, suggesting that TIMP-1 promotes aggressive fibromatosis tumor formation through an alternate mechanism. These data suggest that MMPs play a crucial role in regulating the invasiveness of mesenchymal cells and in modulating aggressive fibromatosis tumor progression. Because this is a locally invasive tumor, MMP inhibition could slow tumor growth and may prove to be an effective adjuvant therapy. FAU - Kong, Yuan AU - Kong Y AD - Program in Developmental Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Poon, Raymond AU - Poon R FAU - Nadesan, Puviindran AU - Nadesan P FAU - Di Muccio, Tamara AU - Di Muccio T FAU - Fodde, Riccardo AU - Fodde R FAU - Khokha, Rama AU - Khokha R FAU - Alman, Benjamin A AU - Alman BA LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Dipeptides) RN - 0 (Isoenzymes) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide) RN - 0 (Protease Inhibitors) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 9007-34-5 (Collagen) RN - EC 3.4.24.- (Matrix Metalloproteinases) SB - IM MH - Animals MH - Apoptosis/physiology MH - Cell Division/physiology MH - Cell Movement/physiology MH - Collagen/metabolism MH - Dipeptides/pharmacology MH - Fibroma/*enzymology/genetics/metabolism/*pathology MH - Genes, APC MH - Isoenzymes MH - Male MH - Matrix Metalloproteinase Inhibitors MH - Matrix Metalloproteinases/*metabolism MH - Mice MH - Neoplasm Invasiveness MH - Protease Inhibitors/pharmacology MH - Tissue Inhibitor of Metalloproteinase-1/biosynthesis/genetics/metabolism MH - Tumor Cells, Cultured EDAT- 2004/08/18 05:00 MHDA- 2004/10/02 05:00 CRDT- 2004/08/18 05:00 PHST- 2004/08/18 05:00 [pubmed] PHST- 2004/10/02 05:00 [medline] PHST- 2004/08/18 05:00 [entrez] AID - 64/16/5795 [pii] AID - 10.1158/0008-5472.CAN-03-3112 [doi] PST - ppublish SO - Cancer Res. 2004 Aug 15;64(16):5795-803. doi: 10.1158/0008-5472.CAN-03-3112.