國家衛生研究院 NHRI:Item 3990099045/8209
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    题名: Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression
    作者: Chen, JY;Li, CF;Kuo, CC;Tsai, K;Hou, MF;Hung, WC
    贡献者: National Institute of Cancer Research;Institute of Cellular and Systems Medicine
    摘要: IntroductionExpression of indoleamine 2, 3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, clinical significance of stromal IDO and the regulation of stromal IDO are unclear.MethodsMetabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) up-regulates IDO expression. Associations of stromal IDO with clinicopathological parameters were tested in tumor specimens. Orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth.ResultsKynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells up-regulates IDO expression in fibroblasts through an EP4/ Signal transducer and activator of transcription 3 (STAT3)-dependent pathway. On the other hand, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that up-regulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo.ConclusionIntegration of metabolomics, molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2 and IDO promotes tumor progression and predicts poor patient survival.
    日期: 2014-07
    關聯: Breast Cancer Research. 2014 Jul;16(4):Article number 410.
    Link to: http://dx.doi.org/10.1186/s13058-014-0410-1
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1465-542X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000344310300018
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84906834688
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    [郭呈欽] 期刊論文

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