title: Upregulated MT1-MMP/TIMP-2 axis in the TSU-Pr1-B1/B2 model of metastatic progression in transitional cell carcinoma of the bladder.
abstract: Muscle invasive transitional cell carcinoma (TCC) of the bladder is associated with a high frequency of metastasis, resulting in poor prognosis for patients presenting with this disease. Models that capture and demonstrate step-wise enhancement of elements of the human metastatic cascade on a similar genetic background are useful research tools. We have utilized the transitional cell carcinoma cell line TSU-Pr1 to develop an in vivo experimental model of bladder TCC metastasis. TSU-Pr1 cells were inoculated into the left cardiac ventricle of SCID mice and the development of bone metastases was monitored using high resolution X-ray. Tumor tissue from a single bone lesion was excised and cultured in vitro to generate the TSU-Pr1-B1 subline. This cycle was repeated with the TSU-Pr1-B1 cells to generate the successive subline TSU-Pr1-B2. DNA profiling and karyotype analysis confirmed the genetic relationship of these three cell lines. In vitro, the growth rate of these cell lines was not significantly different. However, following intracardiac inoculation TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2 exhibited increasing metastatic potential with a concomitant decrease in time to the onset of radiologically detectable metastatic bone lesions. Significant elevations in the levels of mRNA expression of the matrix metalloproteases (MMPs) membrane type 1-MMP (MT1-MMP), MT2-MMP and MMP-9, and their inhibitor, tissue inhibitor of metalloprotease-2 (TIMP-2), across the progressively metastatic cell lines, were detected by quantitative PCR. Given the role of MT1-MMP and TIMP-2 in MMP-2 activation, and the upregulation of MMP-9, these data suggest an important role for matrix remodeling, particularly basement membrane, in this progression. The TSU-Pr1-B1/B2 model holds promise for further identification of important molecules.
authors.affiliation: Bernard O'Brien Institute of Microsurgery, University of Melbourne, Australia.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Chaffer
authors.forename: Bonnie
authors.initials: B
authors.lastname: Dopheide
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McCulloch
authors.forename: Allan B
authors.initials: AB
authors.lastname: Lee
authors.forename: Jane M
authors.initials: JM
authors.lastname: Moseley
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Williams
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000648:ultrastructure; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary* / Q000662:veterinary; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000503:physiopathology* / Q000662:veterinary; D018450:Disease Progression; D020869:Gene Expression Profiling; D007621:Karyotyping; D008297:Male; D053511:Matrix Metalloproteinase 14; D053517:Matrix Metalloproteinase 15; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000503:physiopathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis* / Q000502:physiology*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000503:physiopathology* / Q000662:veterinary
chemical_list: C507098:MMP15 protein, human; C507096:Mmp14 protein, mouse; C507100:Mmp15 protein, mouse; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D053517:Matrix Metalloproteinase 15; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14