Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression.
Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression.
复制标题
DOI：
10.1002/path.4217
复制
发表时间：
2013-09
影响因子：
7.3
通讯作者：
Di Vizio, Dolores
中科院分区：
文献类型：
--
作者：
Ayala, Gustavo;Morello, Matteo;Frolov, Anna;You, Sungyong;Li, Rile;Rosati, Fabiana;Bartolucci, Gianluca;Danza, Giovanna;Adam, Rosalyn M.;Thompson, Timothy C.;Lisanti, Michael P.;Freeman, Michael R.;Di Vizio, Dolores
在前列腺癌进展过程中，肿瘤上皮细胞中的小窝蛋白-1（Cav-1）水平增加。相反，在晚期和转移性前列腺癌中，间质中的Cav-1表达可以下降。在724例前列腺癌的大队列中，我们观察到基质Cav-1水平显著降低，与Gleason评分增加一致（p = 0.012）。重要的是，间质中Cav-1表达的降低与无复发生存期的降低相关（p = 0.009），表明间质Cav-1在抑制晚期疾病中的作用。在WPMY-1前列腺成纤维细胞中通过shRNA沉默Cav-1导致Akt磷酸化上调，并显著改变参与血管生成、侵袭和转移的基因的表达，包括TGF-β1和γ-突触核蛋白（SNCG）基因表达增加> 2.5倍。此外，沉默的Cav-1诱导前列腺癌细胞迁移时，基质细胞作为引诱剂。Akt的药理学抑制引起TGF-β1和SNCG的下调，表明基质中Cav-1的缺失可以影响肿瘤微环境中Akt介导的信号传导。Cav-1耗竭的基质细胞表现出细胞内胆固醇水平升高，胆固醇是雄激素生物合成的前体，类固醇生成酶和睾酮。这些发现表明，肿瘤微环境中Cav-1的缺失通过涉及通过Akt活化上调TGF-β1和SNCG的机制促进肿瘤细胞的转移行为。他们还表明，雄激素的内分泌生产，与去势抵抗相关的过程，可能发生在间质中。
Levels of caveolin-1 (Cav-1) in tumour epithelial cells increase during prostate cancer progression. Conversely, Cav-1 expression in the stroma can decline in advanced and metastatic prostate cancer. In a large cohort of 724 prostate cancers, we observed significantly decreased levels of stromal Cav-1 in concordance with increased Gleason score (p = 0.012). Importantly, reduced expression of Cav-1 in the stroma correlated with reduced relapse-free survival (p = 0.009), suggesting a role for stromal Cav-1 in inhibiting advanced disease. Silencing of Cav-1 by shRNA in WPMY-1 prostate fibroblasts resulted in up-regulation of Akt phosphorylation, and significantly altered expression of genes involved in angiogenesis, invasion, and metastasis, including a > 2.5-fold increase in TGF-β1 and γ-synuclein (SNCG) gene expression. Moreover, silencing of Cav-1 induced migration of prostate cancer cells when stromal cells were used as attractants. Pharmacological inhibition of Akt caused down-regulation of TGF-β1 and SNCG, suggesting that loss of Cav-1 in the stroma can influence Akt-mediated signalling in the tumour microenvironment. Cav-1-depleted stromal cells exhibited increased levels of intracellular cholesterol, a precursor for androgen biosynthesis, steroidogenic enzymes, and testosterone. These findings suggest that loss of Cav-1 in the tumour microenvironment contributes to the metastatic behaviour of tumour cells by a mechanism that involves up-regulation of TGF-β1 and SNCG through Akt activation. They also suggest that intracrine production of androgens, a process relevant to castration resistance, may occur in the stroma.
登录
查看更多内容
影响因子：
5.3
作者：
Cecchi C;Rosati F;Pensalfini A;Formigli L;Nosi D;Liguri G;Dichiara F;Morello M;Danza G;Pieraccini G;Peri A;Serio M;Stefani M
通讯作者：
Stefani M
影响因子：
4.2
作者：
Amsterdam, Abraham;Shezen, Elias;Melzer, Ehud
通讯作者：
Melzer, Ehud
影响因子：
5
作者：
Fitchev, Philip P.;Wcislak, Susan M.;Doll, Jennifer A.
通讯作者：
Doll, Jennifer A.
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Evangelista C;Kim IF;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Holko M;Ayanbule O;Yefanov A;Soboleva A
通讯作者：
Soboleva A
影响因子：
11.2
作者：
Di Vizio D;Kim J;Hager MH;Morello M;Yang W;Lafargue CJ;True LD;Rubin MA;Adam RM;Beroukhim R;Demichelis F;Freeman MR
通讯作者：
Freeman MR