Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes.
This study was designed to characterize the expression profiles of nine bladder cancer cell lines (T24, J82, 5637, HT1376, RT4, SCaBER, TCCSUP, UMUC-3, and HT1197) using cDNA microarrays (8976 genes and expressed sequence tags). Novel targets involved in bladder cancer progression of potential clinical relevance were validated by immunohistochemistry using tissue microarrays of primary bladder tumors (n = 193 cases). Hierarchical clustering classified uroepithelial cells based on their histopathogenesis and cell cycle alterations. Keratin 10 and caveolin-1 transcripts were more abundant in tumor cells from squamous and invasive origin. Their combined expression was shown to stratify bladder tumors and define squamous differentiation. To assess the robustness of the clustering analysis, a bootstrap resampling technique was used. This grouped tumor cell lines based on their biological properties, including cell cycle and cell adhesion features. E-cadherin, zyxin, and moesin were identified as genes differentially expressed in these clusters and related to the p53, RB, and INK4A status of the cell lines. Loss of these adhesion molecules was associated with stage and grade in primary tumors (P < 0.05), and moesin expression was also associated with survival (P = 0.01). Deregulation of cell cycle and apoptotic pathways, such as mutations or altered expression of p53, pRB, and INK4A (p16), is necessary for uroepithelial transformation. However, it appears that deregulation of cell adhesion is a common event associated with tumor progression in uroepithelial neoplasms.
Sanchez-Carbayo
Marta
M
Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. sanchezm@mskcc.org
Socci
Nicholas D
ND
Charytonowicz
Elizabeth
E
Lu
Minglan
M
Prystowsky
Michael
M
Childs
Geoffrey
G
Cordon-Cardo
Carlos
C
D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D016000:Cluster Analysis; D003598:Cytoskeletal Proteins; D020869:Gene Expression Profiling; D006023:Glycoproteins; D006801:Humans; D053550:Keratin-10; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D008667:Metalloproteins / Q000096:biosynthesis / Q000235:genetics; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics; D009010:Monte Carlo Method; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060589:Zyxin
D014408:Biomarkers, Tumor; C495540:CAV1 protein, human; D015820:Cadherins; D051242:Caveolin 1; D022461:Caveolins; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; C507493:KRT10 protein, human; D008667:Metalloproteins; D008840:Microfilament Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C092842:ZYX protein, human; D060589:Zyxin; C071058:moesin; D053550:Keratin-10; D007633:Keratins