title: Global gene expression profiling in mouse plasma cell tumor precursor and bystander cells reveals potential intervention targets for plasma cell neoplasia.
abstract: Tumor progression usually proceeds through several sequential stages, any of which could be targets for interrupting the progression process if one understood these steps at the molecular level. We extracted nascent plasma cell tumor (PCT) cells from within inflammatory oil granulomas (OG) isolated from IP pristane-injected BALB/c.iMyc(Eμ) mice at 5 different time points during tumor progression. We used laser capture microdissection to collect incipient PCT cells and analyzed their global gene expression on Affymetrix Mouse Genome 430A microarrays. Two independent studies were performed with different sets of mice. Analysis of the expression data used ANOVA and Bayesian estimation of temporal regulation. Genetic pathway analysis was performed using MetaCore (GeneGo) and IPA (Ingenuity). The gene expression profiles of PCT samples and those of undissected OG samples from adjacent sections showed that different genes and pathways were mobilized in the tumor cells during tumor progression, compared with their stroma. Our analysis implicated several genetic pathways in PCT progression, including biphasic (up- and then down-regulation) of the Spp1/osteopontin-dependent network and up-regulation of mRNA translation/protein synthesis. The latter led to a biologic validation study that showed that the AMPK-activating diabetes drug, metformin, was a potent specific PCT inhibitor in vitro.
authors.affiliation: Molecular Genetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: LeGrand
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Shalu
authors.initials: S
authors.lastname: Gupta
authors.forename: James D
authors.initials: JD
authors.lastname: Owens
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Nelson
authors.forename: Wendy
authors.initials: W
authors.lastname: DuBois
authors.forename: Thomas
authors.initials: T
authors.lastname: Bair
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.forename: J Frederic
authors.initials: JF
authors.lastname: Mushinski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006104:Granuloma, Plasma Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D054219:Neoplasms, Plasma Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C506896:Spp1 protein, mouse; D053495:Osteopontin; D008687:Metformin