Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas

Studies have suggested that an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to the malignant phenotype of gliomas. In this study, we have undertaken a detailed analysis of expression of the TIMP family in normal human brain and malignant gliomas at both the mRNA and protein level. Reverse transcription-PCR (RT-PCR) analyses of total RNA from surgical tumour specimens revealed unique expression patterns for the 4 members of the TIMP family, with TIMP-1 and -4 showing positive and negative correlations, respectively, with glioma malignancy. By RT-PCR, TIMP-2 and TIMP-3 expression did not change with tumour grade. In situ hybridization localized TIMP-1 to glial tumour cells and also to the surrounding tumour vasculature. TIMP-4 transcripts were predominantly localized to tumour cells, though minor expression was found in vessels. Recombinant TIMP-4 reduced invasion of U251 glioma cells through Matrigel, and U87 clones overexpressing TIMP-4 showed reduced invasive capacity in vitro. TIMP-4, but not TIMP-1, blocked Membrane Type-1-MMP-mediated progelatinase-A (MMP-2) activation in human umbilical vein endothelial cells. The differential expression and localization of individual TIMPs may contribute to the pathophysiology of human malignant gliomas, particularly with regard to tumour vascularization. © 2001 Cancer Research Campaign http://www.bjcancer.co

An IL13Rα2 peptide exhibits therapeutic activity against metastatic colorectal cancer

36 p.-6 fig.BACKGROUND:Interleukin 13 receptor α2 (IL13Rα2) is overexpressed in metastatic colorectal cancer. Here, we have developed novel strategies to block IL-13 binding to IL13Rα2 in order to reduce metastatic spread.METHODS:Synthetic IL13Rα2 D1 peptide (GSETWKTIITKN) was tested for the inhibition of IL-13 binding to IL13Rα2 using ELISA and different cellular assays. Peptide blocking effects on different cell signalling mediators were determined by western blot. An enantiomer version of the peptide (D-D1) was prepared to avoid proteolytic digestion. Nude mice were used for tumour growth and survival analysis after treatment with IL13Rα2 peptides.RESULTS:IL13Rα2 D1 peptide inhibited migration, invasion, and proliferation in metastatic colorectal and glioblastoma cancer cells treated with IL-13. Residues 82K, 83T, 85I and 86T were essential for blocking IL-13. IL13Rα2 peptide abolished ligand-mediated receptor internalisation and degradation, and substantially decreased IL-13 signalling capacity through IL13Rα2 to activate the FAK, PI3K/AKT and Src pathways as well as MT1-MMP expression. In addition, D1 significantly inhibited IL-13-mediated STAT6 activation through IL13Rα1. Nude mice treated with the enantiomer D-D1 peptide showed a remarkable survival increase.CONCLUSIONS:We propose that the D-D1 peptide from IL13Rα2 represents a promising therapeutic agent to inhibit metastatic progression in colorectal cancer and, likely, other solid tumours.This research was supported by grants BIO2015-66489-R from the MINECO, Foundation Ramón Areces and PRB2 (IPT13/0001-ISCIII-SGEFI/FEDER).Peer reviewe

New functions for the matrix metalloproteinases in cancer progression

Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic