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.
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Abbreviations
- MMP:
-
matrix metalloprotease
- MT1-MMP:
-
membrane type-MMP
- STR:
-
short tandem repeat
- TCC:
-
transitional cell carcinoma
- TIMP:
-
tissue inhibitor of metalloprotease
References
DG Skinner JP Stein G Lieskovsky et al. (1998) ArticleTitle25-year experience in the management of invasive bladder cancer by radical cystectomy Eur Urol 33 IssueID4 25–6 Occurrence Handle10.1159/000052260
K Inoue JW Slaton P Perrotte et al. (2000) ArticleTitlePaclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma Clin Cancer Res 6 IssueID12 4874–84 Occurrence Handle11156247
D Raghavan WU Shipley MB Garnick et al. (1990) ArticleTitleBiology and management of bladder cancer N Engl J Med 322 IssueID16 1129–38 Occurrence Handle2181313
JA Smith WF Whitmore (1981) ArticleTitleRegional lymph node metastasis from bladder cancer J Urol 126 IssueID5 591–3 Occurrence Handle7299915
L Sengelov C Kamby H Maase Particlevon der (1996) ArticleTitlePattern of metastases in relation to characteristics of primary tumor and treatment in patients with disseminated urothelial carcinoma J Urol 155 IssueID1 111–4 Occurrence Handle10.1097/00005392-199601000-00041 Occurrence Handle7490804
RJ Babaian DE Johnson L Llamas et al. (1980) ArticleTitleMetastases from transitional cell carcinoma of urinary bladder Urology 16 IssueID2 142–4 Occurrence Handle10.1016/0090-4295(80)90067-9 Occurrence Handle7404907
A Wallmeroth U Wagner H Moch et al. (1999) ArticleTitlePatterns of metastasis in muscle-invasive bladder cancer (pT2–4): An autopsy study on 367 patients Urol Int 62 IssueID2 69–75 Occurrence Handle10.1159/000030361 Occurrence Handle10461106
TE Ahlering L Dubeau PA Jones (1987) ArticleTitleA new in vivo model to study invasion and metastasis of human bladder carcinoma Cancer Res 47 IssueID24 6660–5 Occurrence Handle3677100
CP Dinney R Fishbeck RK Singh et al. (1995) ArticleTitleIsolation and characterization of metastatic variants from human transitional cell carcinoma passaged by orthotopic implantation in athymic nude mice J Urol 154 IssueID4 1532–8 Occurrence Handle10.1097/00005392-199510000-00087 Occurrence Handle7658585
U Flatow AB Rabson AS Rabson (1987) ArticleTitleTumorigenicity of T24 urinary bladder carcinoma cell sublines Int J Cancer 40 IssueID2 240–5 Occurrence Handle3301693
JA Heaney EP Ornellas JJ Daly et al. (1978) ArticleTitle In vivo growth of human bladder cancer cell lines Invest Urol 15 IssueID5 380–4 Occurrence Handle640800
D Theodorescu I Cornil BJ Fernandez et al. (1990) ArticleTitleOverexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma Proc Natl Acad Sci USA 87 IssueID22 9047–51 Occurrence Handle2247480
BA Barut JE Klaunig (1986) ArticleTitleIsolation and characterization of metastatic sublines from a murine transitional cell bladder carcinoma Clin Exp Metastasis 4 IssueID1 1–11 Occurrence Handle10.1007/BF00053468 Occurrence Handle3698364
BU Pauli SN Anderson VA Memoli et al. (1980) ArticleTitleDevelopment of an in vitro and in vivo epithelial tumor model for the study of invasion Cancer Res 40 IssueID12 4571–80 Occurrence Handle7438091
MJ Seraj MA Harding JJ Gildea et al. (2000) ArticleTitleThe relationship of BRMS1 and RhoGDI2 gene expression to metastatic potential in lineage related human bladder cancer cell lines Clin Exp Metastasis 18 IssueID6 519–25 Occurrence Handle10.1023/A:1011819621859 Occurrence Handle11592309
S Bellusci G Moens JP Thiery et al. (1994) ArticleTitleA scatter factor-like factor is produced by a metastatic variant of a rat bladder carcinoma cell line J Cell Sci 107 IssueID5 1277–87 Occurrence Handle7929634
BE Nicholson HF Frierson MR Conaway et al. (2004) ArticleTitleProfiling the evolution of human metastatic bladder cancer Cancer Res 64 IssueID21 7813–21 Occurrence Handle15520187
IJ Fidler ML Kripke (1977) ArticleTitleMetastasis results from preexisting variant cells within a malignant tumor Science 197 IssueID4306 893–5 Occurrence Handle887927
IJ Fidler (1999) ArticleTitleCritical determinants of cancer metastasis: Rationale for therapy Cancer Chemother Pharmacol 43 S3–10 Occurrence Handle10.1007/s002800051091 Occurrence Handle10357552
H Ueno H Nakamura M Inoue et al. (1997) ArticleTitleExpression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas Cancer Res 57 IssueID10 2055–60 Occurrence Handle9158005
IJ Fidler (2002) ArticleTitleCritical determinants of metastasis Semin Cancer Biol 12 IssueID2 89–96 Occurrence Handle10.1006/scbi.2001.0416 Occurrence Handle12027580
SM Goldman AA Fajardo RC Naraval et al. (1979) ArticleTitleMetastatic transitional cell carcinoma from the bladder: Radiographic manifestions Am J Roentgenol 132 IssueID3 419–25
A Bokhoven Particlevan M Varella-Garcia C Korch et al. (2001) ArticleTitleTSU-Pr1 and JCA-1 cells are derivatives of T24 bladder carcinoma cells and are not of prostatic origin Cancer Res 61 IssueID17 6340–4 Occurrence Handle11522622
D Djakiew BR Pflug R Delsite et al. (1993) ArticleTitleChemotaxis and chemokinesis of human prostate tumor cell lines in response to human prostate stromal cell secretory proteins containing a nerve growth factor-like protein Cancer Res 53 IssueID6 1416–20 Occurrence Handle8443820
P Skehan R Storeng D Scudiero et al. (1990) ArticleTitleNew colorimetric cytotoxicity assay for anticancer-drug screening J Natl Cancer Inst 82 IssueID13 1107–12
JA Sharp M Waltham ED Williams et al. (2004) ArticleTitleTransfection of MDA-MB-231 human breast carcinoma cells with bone sialoprotein (BSP) stimulates migration and invasion in vitro and growth of primary and secondary tumors in nude mice Clin Exp Metastasis 21 IssueID1 19–29 Occurrence Handle10.1023/B:CLIN.0000017167.17065.61 Occurrence Handle15065599
MM Tomayko CP Reynolds (1989) ArticleTitleDetermination of subcutaneous tumor size in athymic (nude) mice Cancer Chemother Pharmacol 24 IssueID3 148–54 Occurrence Handle10.1007/BF00300234 Occurrence Handle2544306
MA Lafleur AF Drew EL Sousa Particlede et al. (2004) ArticleTitleUpregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: A major induction of stromal MMP-13 Int J Cancer 114 544–54 Occurrence Handle10.1002/ijc.20763
AF Drew TJ Blick MA Lafleur et al. (2004) ArticleTitleCorrelation of tumor- and stromal-derived MT1-MMP expression with progression of human ovarian tumors in SCID mice Gynecol Oncol 95 IssueID3 437–48 Occurrence Handle10.1016/j.ygyno.2004.08.032 Occurrence Handle15581944
A Bokhoven Particlevan M Varella-Garcia C Korch et al. (2001) ArticleTitleWidely used prostate carcinoma cell lines share common origins Prostate 47 IssueID1 36–51 Occurrence Handle10.1002/pros.1045 Occurrence Handle11304728
Y Pan WO Lui N Nupponen et al. (2001) ArticleTitle5q11, 8p11, and 10q22 are recurrent chromosomal breakpoints in prostate cancer cell lines Genes Chromosomes Cancer 30 IssueID2 187–95 Occurrence Handle10.1002/1098-2264(2000)9999:9999<::AID-GCC1075>3.3.CO;2-8 Occurrence Handle11135436
AJ Keen MA Knowles (1994) ArticleTitleDefinition of two regions of deletion on chromosome 9 in carcinoma of the bladder Oncogene 9 IssueID7 2083–8 Occurrence Handle8208555
F Kimura AR Florl HH Seifert et al. (2001) ArticleTitleDestabilization of chromosome 9 in transitional cell carcinoma of the urinary bladder Br J Cancer 85 IssueID12 1887–93
H Nishiyama T Takahashi Y Kakehi et al. (1999) ArticleTitleHomozygous deletion at the 9q32–33 candidate tumor suppressor locus in primary human bladder cancer Genes Chromosomes Cancer 26 IssueID2 171–5 Occurrence Handle10.1002/(SICI)1098-2264(199910)26:2<171::AID-GCC10>3.0.CO;2-B Occurrence Handle10469456
LA Takle MA Knowles (1996) ArticleTitleDeletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer Oncogene 12 IssueID5 1083–7 Occurrence Handle8649800
M Muscheck F Sukosd T Pesti et al. (2000) ArticleTitleHigh density deletion mapping of bladder cancer localizes the putative tumor suppressor gene between loci D8S504 and D8S264 at chromosome 8p23.3 Lab Invest 80 IssueID7 1089–93 Occurrence Handle10908154
C Choi MH Kim SW Juhng et al. (2000) ArticleTitleLoss of heterozygosity at chromosome segments 8p22 and 8p11.2–21.1 in transitional-cell carcinoma of the urinary bladder Int J Cancer 86 IssueID4 501–5 Occurrence Handle10.1002/(SICI)1097-0215(20000515)86:4<501::AID-IJC9>3.0.CO;2-# Occurrence Handle10797262
T Iizumi T Yazaki S Kanoh et al. (1987) ArticleTitleEstablishment of a new prostatic carcinoma cell line (TSU-Pr1) J Urol 137 IssueID6 1304–6 Occurrence Handle3586177
M Katoh (2002) ArticleTitleWNT and FGF gene clusters (review) Int J Oncol 21 IssueID6 1269–73 Occurrence Handle12429977
R Simon K Struckmann P Schraml et al. (2002) ArticleTitleAmplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer Oncogene 21 IssueID16 2476–83 Occurrence Handle10.1038/sj.onc.1205304 Occurrence Handle11971182
A Okada JP Bellocq N Rouyer et al. (1995) ArticleTitleMembrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas Proc Natl Acad Sci USA 92 IssueID7 2730–4 Occurrence Handle7708715
T Etoh H Inoue Y Yoshikawa et al. (2000) ArticleTitleIncreased expression of collagenase-3 (MMP-13) and MT1-MMP in oesophageal cancer is related to cancer aggressiveness Gut 47 IssueID1 50–6 Occurrence Handle10.1136/gut.47.1.50 Occurrence Handle10861264
KB Hotary ED Allen PC Brooks et al. (2003) ArticleTitleMembrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix Cell 114 IssueID1 33–45 Occurrence Handle10.1016/S0092-8674(03)00513-0 Occurrence Handle12859896
KV Lu KA Jong AK Rajasekaran et al. (2004) ArticleTitleUpregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line Lab Invest 84 IssueID1 8–20 Occurrence Handle10.1038/sj.labinvest.3700003 Occurrence Handle14631378
AS Mellick D Blackmore SR Weinstein et al. (2003) ArticleTitleAn assessment of MMP and TIMP gene expression in cell lines and stroma–tumour differences in microdissected breast cancer biopsies Tumour Biol 24 IssueID5 258–70 Occurrence Handle10.1159/000076140 Occurrence Handle15001838
H Ueno H Nakamura M Inoue et al. (1997) ArticleTitleExpression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas Cancer Res 57 2055–60 Occurrence Handle9158005
R Ria G Loverro A Vacca et al. (2002) ArticleTitleAngiogenesis extent and expression of matrix metalloproteinase-2 and -9 agree with progression of ovarian endometriomas Eur J Clin Invest 32 199–200 Occurrence Handle10.1046/j.1365-2362.2002.00960.x Occurrence Handle11895472
G Murphy MI Cockett RV Ward et al. (1991) ArticleTitleMatrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP) Biochem J 277 277–9 Occurrence Handle1649600
JF Woessner SuffixJr (1991) ArticleTitleMatrix metalloproteinases and their inhibitors in connective tissue remodeling FASEB J 5 2145–54 Occurrence Handle1850705
M Egeblad Z Werb (2002) ArticleTitleNew functions for the matrix metalloproteinases in cancer progression Nat Rev Cancer 2 IssueID3 161–74 Occurrence Handle10.1038/nrc745 Occurrence Handle11990853
R Fridman M Toth I Chvyrkova et al. (2003) ArticleTitleCell surface association of matrix metalloproteinase-9 (gelatinase B) Cancer Metastasis Rev 22 IssueID2–3 153–66 Occurrence Handle10.1023/A:1023091214123 Occurrence Handle12784994
BI Carlin GL Andriole (2000) ArticleTitleThe natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma Cancer 88 IssueID12 2989–94 Occurrence Handle10.1002/1097-0142(20000615)88:12+<2989::AID-CNCR14>3.0.CO;2-Q Occurrence Handle10898342
AS Tsingotjidou G Zotalis KR Jackson et al. (2001) ArticleTitleDevelopment of an animal model for prostate cancer cell metastasis to adult human bone Anticancer Res 21 IssueID2A 971–8 Occurrence Handle11396190
JA Nemeth JF Harb U Barroso SuffixJr et al. (1999) ArticleTitleSevere combined immunodeficient-hu model of human prostate cancer metastasis to human bone Cancer Res 59 IssueID8 1987–93 Occurrence Handle10213511
T Kubota (1994) ArticleTitleMetastatic models of human cancer xenografted in the nude mouse: The importance of orthotopic transplantation J Cell Biochem 56 IssueID1 4–8 Occurrence Handle10.1002/jcb.240560103 Occurrence Handle7806591
LE Allen PA Maher (1993) ArticleTitleExpression of basic fibroblast growth factor and its receptor in an invasive bladder carcinoma cell line J Cell Physiol 155 IssueID2 368–75 Occurrence Handle10.1002/jcp.1041550218 Occurrence Handle8387074
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Chaffer, C.L., Dopheide, B., McCulloch, D.R. et al. Upregulated MT1-MMP/TIMP-2 axis in the TSU-Pr1-B1/B2 model of metastatic progression in transitional cell carcinoma of the bladder. Clin Exp Metastasis 22, 115–125 (2005). https://doi.org/10.1007/s10585-005-5141-3
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DOI: https://doi.org/10.1007/s10585-005-5141-3