title: Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays.
abstract: To explore molecular mechanisms of prostate cancer progression, we applied tissue microarrays (TMAs) to analyze expression of candidate gene targets discovered by cDNA microarray analysis of the CWR22 xenograft model system. A TMA with 544 clinical specimens from different stages of disease progression was probed by mRNA in situ hybridization and protein immunohistochemistry. There was an excellent correlation (r = 0.96; n = 16) between the expression levels of the genes in the xenografts by cDNA microarray and mRNA in situ hybridization on a TMA. One of the most highly overexpressed genes in hormone-refractory CWR22R xenografts was the S100P gene. This gene, coding for a calcium signaling molecule implicated in the loss of senescence, was also significantly associated with progression in clinical tumors by TMA analysis (P < 0.001), suggesting dysregulation of this pathway in hormone-refractory and metastatic prostate cancers. Conversely, two genes that were down-regulated during tumor progression in the CWR22 model system were validated in vivo: crystallin mu (CRYM) and a LIM-domain protein LMO4 both showed significantly lower mRNA levels in hormone-refractory tumors as compared with primary tumors (P < 0.001). These results illustrate a strategy for rapid clinical validation at the mRNA and protein level of gene targets found to be differentially expressed in cDNA microarray experiments of model systems of cancer.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Urs
authors.initials: U
authors.lastname: Wagner
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.forename: Juha
authors.initials: J
authors.lastname: Kononen
authors.forename: Robert
authors.initials: R
authors.lastname: Cornelison
authors.forename: Natalie
authors.initials: N
authors.lastname: Goldberger
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Niels
authors.initials: N
authors.lastname: Willi
authors.forename: Pasi
authors.initials: P
authors.lastname: Koivisto
authors.forename: William
authors.initials: W
authors.lastname: Ferhle
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Guito
authors.initials: G
authors.lastname: Sauter
authors.forename: Olli-P
authors.initials: OP
authors.lastname: Kallioniemi
mesh_terms: D000818:Animals; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000090803:mu-Crystallins
chemical_list: C000716469:CRYM protein, human; C000716470:Crym protein, mouse; D012333:RNA, Messenger; D000090803:mu-Crystallins