Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes.
Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes.
复制标题
DOI：
10.1371/journal.pone.0090907
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Aboussekhra A
中科院分区：
文献类型：
--
作者：
Al-Ansari MM;Aboussekhra A
活性的癌相关成纤维细胞（CAF）或肌成纤维细胞不仅在乳腺癌的发生和发展中起重要作用，而且在其预后和治疗中也起重要作用。因此，通过抑制这些细胞的支持性前致癌旁分泌作用来靶向这些细胞对于改善目前主要靶向肿瘤细胞的治疗是强制性的。为此，我们研究了天然的和非生物安全的分子咖啡因对CAF细胞的影响及其各种致癌作用。我们已经发现，咖啡因上调肿瘤抑制蛋白p16、p21、p53和Cav-1，降低各种细胞因子（IL-6、TGF-β、SDF-1和MMP-2）的表达/分泌，并下调α-SMA。此外，咖啡因通过PTEN依赖性Akt/Erk 1/2失活抑制CAF细胞的迁移/侵袭能力。此外，咖啡因降低了CAF细胞对乳腺癌细胞的旁分泌促侵袭/迁移作用。这些结果表明，咖啡因可以抑制乳腺间质肌成纤维细胞。这一点已被证实，咖啡因还通过下调HIF-1α及其下游效应物VEGF-A抑制CAF细胞的旁分泌促血管生成作用。有趣的是，这些效果在没有咖啡因的情况下持续存在。本研究结果提供了一个原则的证据，即乳腺癌肌成纤维细胞可以被灭活，从而咖啡因可以通过抑制活性基质成纤维细胞的致癌作用，提供一种安全有效的预防乳腺肿瘤生长/复发。
Active cancer-associated fibroblasts (CAFs) or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects. We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-β, SDF-1 and MMP-2), and down-regulates α-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN-dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/−migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down-regulating HIF-1αand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine. The present findings provide a proof of principle that breast cancer myofibroblasts can be inactivated, and thereby caffeine may provide a safe and effective prevention against breast tumor growth/recurrence through inhibition of the procarcinogenic effects of active stromal fibroblasts.
登录
查看更多内容
影响因子：
8
作者：
Al-Ansari, M. M.;Hendrayani, S. F.;Shehata, A. I.;Aboussekhra, A.
通讯作者：
Aboussekhra, A.
影响因子：
4.8
作者：
Milanini, J;Viñals, F;Pagès, G
通讯作者：
Pagès, G
影响因子：
0.7
作者：
Aboussekhra, Abdelilah
通讯作者：
Aboussekhra, Abdelilah
影响因子：
7.3
作者：
Franco OE;Shaw AK;Strand DW;Hayward SW
通讯作者：
Hayward SW
影响因子：
4.8
作者：
Foukas, LC;Daniele, N;Shepherd, PR
通讯作者：
Shepherd, PR