title: Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma.
abstract: The matrix metalloproteinases (MMPs) are endopeptidases which break down the extracellular matrix and regulate cytokine and growth factor activity. Several MMPs have been implicated in the promotion of invasion and metastasis in a broad range of tumours including urothelial carcinoma. In this study, RNA from 132 normal bladder and urothelial carcinoma specimens was profiled for each of the 24 human MMPs, the four endogenous tissue inhibitors of MMPs (TIMPs) and several key growth factors and their receptors using quantitative real time RT-PCR. Laser capture microdissection (LCM) of RNA from 22 tumour and 11 normal frozen sections was performed allowing accurate RNA extraction from either stromal or epithelial compartments. This study confirms the over expression in bladder tumour tissue of well-documented MMPs and highlights a range of MMPs which have not previously been implicated in the development of urothelial cancer. In summary, MMP-2, MT1-MMP and the previously unreported MMP-28 were very highly expressed in tumour samples while MMPs 1, 7, 9, 11, 15, 19 and 23 were highly expressed. There was a significant positive correlation between transcript expression and tumour grade for MMPs 1, 2, 8, 10, 11, 12, 13, 14, 15 and 28 (P < 0.001). At the same confidence interval, TIMP-1 and TIMP-3 also correlated with increasing tumour grade. LCM revealed that most highly expressed MMPs are located primarily within the stromal compartment except MMP-13 which localised to the epithelial compartment. This work forms the basis for further functional studies, which will help to confirm the MMPs as potential diagnostic and therapeutic targets in early bladder cancer.
authors.affiliation: Department of Oncology, Hutchison MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK. mjw38@cam.ac.uk
authors.forename: M J
authors.initials: MJ
authors.lastname: Wallard
authors.forename: C J
authors.initials: CJ
authors.lastname: Pennington
authors.forename: A
authors.initials: A
authors.lastname: Veerakumarasivam
authors.forename: G
authors.initials: G
authors.lastname: Burtt
authors.forename: I G
authors.initials: IG
authors.lastname: Mills
authors.forename: A
authors.initials: A
authors.lastname: Warren
authors.forename: H Y
authors.initials: HY
authors.lastname: Leung
authors.forename: G
authors.initials: G
authors.lastname: Murphy
authors.forename: D R
authors.initials: DR
authors.lastname: Edwards
authors.forename: D E
authors.initials: DE
authors.lastname: Neal
authors.forename: J D
authors.initials: JD
authors.lastname: Kelly
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D020869:Gene Expression Profiling; D006801:Humans; D020782:Matrix Metalloproteinases / Q000032:analysis* / Q000096:biosynthesis* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D020782:Matrix Metalloproteinases