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Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes.

ABSTRACT: The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment.Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder.The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes.CD90+ prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development.

SUBMITTER: Pascal LE

PROVIDER: S-EPMC2745432 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes.

Pascal Laura E LE Goo Young Ah YA Vêncio Ricardo Zn RZ Page Laura S LS Chambers Amber A AA Liebeskind Emily S ES Takayama Thomas K TK True Lawrence D LD Liu Alvin Y AY

BMC cancer 20090908

<h4>Background</h4>The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment.<h4>Methods</h4>Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sor ...[more]

PMID: 19737398

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Project description:The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. Isolation and characterization of viable populations of the constituent cell types of prostate tumors could provide valuable insight into the biology of cancer. The CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between normal and tumor-associated reactive stromal cells. Reactive stroma is characterized by smooth muscle differentiation, prostate down-regulation of SPOCK3, MSMB, CXCL13, and PAGE4, bladder down-regulation of TRPA1, HSD17B2, IL24, and SALL1, and an up-regulation of CXC-chemokines. This study identified a group of differentially expressed genes in CD90+ reactive stromal cells that are potentially involved in organ development and smooth muscle cell differentiation. Experiment Overall Design: A total of 15 arrays were run for the following sample types obtained from 10 patients: Experiment Overall Design: 2 CD90+ prostate tumor-associated stromal: Experiment Overall Design: Patient 1: CP_Str_08-028_CD90posi Experiment Overall Design: Patient 2: 08-032_CP_strom_CD90posi Experiment Overall Design: 2 CD13+ normal bladder stromal: Experiment Overall Design: Patient 3: 06-125_NB_CD13posi Experiment Overall Design: Patient 4: 06-070_NB_str_CD13posi Experiment Overall Design: 1 CD13+ bladder tumor-associated stromal: Experiment Overall Design: Patient 5: 07-008_CB_str_CD13posi Experiment Overall Design: 5 whole tissue prostate cancer and 5 normal tissue from matched pairs: Experiment Overall Design: Patient 6: 05-206_CaP, 05-206_NP Experiment Overall Design: Patient 7: 05-213_CaP, 05-213_NP Experiment Overall Design: Patient 8: 05-214_CaP, 05-214_NP Experiment Overall Design: Patient 9: 05-218_CaP, 05-218_NP Experiment Overall Design: Patient 10: 05-220_CaP, 05-220_NP Experiment Overall Design: Additionally, 8 arrays were run for the following sample types obtained from 7 patients: Experiment Overall Design: 5 CD49a+ normal prostate stromal (PMID 16638148): Experiment Overall Design: Patient 1: CD49a_01-26-04 Experiment Overall Design: Patient 2: CD49a_03-23-04 Experiment Overall Design: Patient 3: CD49a_03-04-04 Experiment Overall Design: Patient 4: CD49a-1_06-02-04 Experiment Overall Design: Patient 5: CD49a-4_06-02-04 Experiment Overall Design: 3 CD26+ prostate cancer (2 biological replicates, 1 sample run twice): Experiment Overall Design: Patient 6: 05-179_CD26t Experiment Overall Design: Patient 6: 05-179_CD26t_2 Experiment Overall Design: Patient 7: 08-032_CP_epi_CD26posi Experiment Overall Design: The following two prostate cancer samples were also included in the analyses: Experiment Overall Design: CD26+ cancer cell, replicate 1 Experiment Overall Design: CD26+ cancer cell, replicate 2 Experiment Overall Design: The tissue samples consisted of prostate tissue specimens obtained from patients undergoing radical prostatectomy under approval by the University of Washington Institutional Review Board. The same approach was used for both cancer-free and cancer-enriched (where at least 85% of the cells in the corresponding frozen section were of cancer) samples. To obtain bladder stromal cells for analysis, tissue specimens were obtained from cystoprostatectomy surgeries. For cell sorting, the collected specimens were processed within hours. Cell types were sorted using monoclonal antibodies specific for tumor-associated prostate stromal cells (CD90), tumor-associated bladder stromal cells (CD13) and normal bladder stromal cells (CD13) with MACS.

Project description:Little is known about the protective role of inflammatory processes in modulating lipid metabolism in infection. Here we report an intimate link between the innate immune response to infection and regulation of the sterol metabolic network characterized by down-regulation of sterol biosynthesis by an interferon regulatory loop mechanism. In time-series experiments profiling genome-wide lipid-associated gene expression of macrophages, we show a selective and coordinated negative regulation of the complete sterol pathway upon viral infection or cytokine treatment with IFNγ or β but not TNF, IL1β, or IL6. Quantitative analysis at the protein level of selected sterol metabolic enzymes upon infection shows a similar level of suppression. Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output. On the basis of pharmacologic and RNAi inhibition of the sterol pathway we show augmented protection against viral infection, and in combination with metabolite rescue experiments, we identify the requirement of the mevalonate-isoprenoid branch of the sterol metabolic network in the protective response upon statin or IFNβ treatment. Conditioned media experiments from infected cells support an involvement of secreted type 1 interferon(s) to be sufficient for reducing the sterol pathway upon infection. Moreover, we show that infection of primary macrophages containing a genetic knockout of the major type I interferon, IFNβ, leads to only a partial suppression of the sterol pathway, while genetic knockout of the receptor for all type I interferon family members, ifnar1, or associated signaling component, tyk2, completely abolishes the reduction of the sterol biosynthetic activity upon infection. Levels of the proteolytically cleaved nuclear forms of SREBP2, a key transcriptional regulator of sterol biosynthesis, are reduced upon infection and IFNβ treatment at both the protein and de novo transcription level. The reduction in srebf2 gene transcription upon infection and IFN treatment is also found to be strictly dependent on ifnar1. Altogether these results show that type 1 IFN signaling is both necessary and sufficient for reducing the sterol metabolic network activity upon infection, thereby linking the regulation of the sterol pathway with interferon anti-viral defense responses. These findings bring a new link between sterol metabolism and interferon antiviral response and support the idea of using host metabolic modifiers of innate immunity as a potential antiviral strategy.

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Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes.

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Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes.

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