Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression.
Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression.
复制标题
DOI：
10.1186/s13058-014-0410-1
复制
发表时间：
2014-07-25
期刊：
影响因子：
--
通讯作者：
Hung WC
中科院分区：
文献类型：
--
作者：
Chen JY;Li CF;Kuo CC;Tsai KK;Hou MF;Hung WC
吲哚胺2，3-双加氧酶（IDO）在原发性乳腺癌中的表达增加肿瘤生长和转移。然而，间质IDO的临床意义和间质IDO的调控尚不清楚。应用代谢组学和酶联免疫吸附试验（ELISA）研究过表达环氧化酶2（考克斯-2）的乳腺癌细胞对共培养的人乳腺成纤维细胞IDO表达的影响。使用生化抑制剂和短发夹RNA（shRNA）来阐明前列腺素E2（PGE 2）如何上调IDO表达。在肿瘤标本中检测间质IDO与临床病理参数的相关性。原位动物模型用于检查考克斯-2和IDO抑制剂对肿瘤生长的影响。犬尿氨酸是IDO产生的代谢物，在与过表达考克斯-2的乳腺癌细胞共培养的成纤维细胞的上清液中增加。由癌细胞释放的PGE 2通过EP 4/信号转导子和转录激活子3（STAT 3）依赖性途径上调成纤维细胞中的IDO表达。相反，成纤维细胞分泌的犬尿氨酸促进E-钙粘蛋白/芳烃受体（AhR）/S期激酶相关蛋白2（Skp 2）复合物的形成，导致E-钙粘蛋白降解，增加乳腺癌的侵袭性。通过与成纤维细胞共培养诱导的乳腺癌细胞运动性的增强被IDO抑制剂1-甲基-色氨酸抑制。病理分析表明间质IDO的上调是一个不良预后因素，并且与考克斯-2的过表达有关。癌症考克斯-2和间质IDO的共表达预测更差的无疾病和无转移生存。最后，考克斯-2和IDO抑制剂在体内抑制肿瘤生长。代谢组学和分子及病理学方法的整合揭示了癌症和基质之间通过考克斯-2的相互作用，IDO促进肿瘤进展并预测患者生存率低。本文的在线版本（doi：10.1186/s13058-014-0410-1）包含补充材料，可供授权用户使用。
Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear. Metabolomics 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) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth. Kynurenine, 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 upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, 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 upregulation 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. Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival. The online version of this article (doi:10.1186/s13058-014-0410-1) contains supplementary material, which is available to authorized users.
登录
查看更多内容
DOI：
10.1186/bcr1678
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Howe LR
通讯作者：
Howe LR
影响因子：
3.6
作者：
Mercier I;Casimiro MC;Wang C;Rosenberg AL;Quong J;Minkeu A;Allen KG;Danilo C;Sotgia F;Bonuccelli G;Jasmin JF;Xu H;Bosco E;Aronow B;Witkiewicz A;Pestell RG;Knudsen ES;Lisanti MP
通讯作者：
Lisanti MP
影响因子：
3.8
作者：
Mansfield AS;Heikkila PS;Vaara AT;von Smitten KA;Vakkila JM;Leidenius MH
通讯作者：
Leidenius MH
DOI：
10.1073/pnas.0401064101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Kuperwasser, C;Chavarria, T;Weinberg, RA
通讯作者：
Weinberg, RA
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A