Cancer-associated fibroblasts promote proliferation of endometrial cancer cells.
Cancer-associated fibroblasts promote proliferation of endometrial cancer cells.
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DOI：
10.1371/journal.pone.0068923
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chung I
中科院分区：
文献类型：
--
作者：
Subramaniam KS;Tham ST;Mohamed Z;Woo YL;Mat Adenan NA;Chung I
子宫内膜癌是世界范围内最常见的妇科恶性肿瘤，但对肿瘤微环境，尤其是癌细胞周围的成纤维细胞知之甚少。我们利用抗体偶联磁珠分离技术建立了四种原代培养的人子宫内膜癌组织成纤维细胞(癌相关成纤维细胞，CAF)。这些相对均一的成纤维细胞培养物表达成纤维细胞标志物(CD90、波形蛋白和α-平滑肌肌动蛋白)和激素(雌激素和孕激素)受体。从CAF收集的条件培养液在体外诱导了原代培养的子宫内膜癌细胞和子宫内膜癌细胞系的增殖(175%)，而正常子宫内膜成纤维细胞系(51%)为对照(P<；0.0001)。这些作用在良性子宫内膜增生症组织的成纤维细胞培养中未观察到，表明CAF在影响子宫内膜癌细胞增殖方面具有特异性。为了确定不同成纤维细胞作用的机制，我们比较了正常成纤维细胞和CAFS条件培养液处理后子宫内膜癌细胞中PI3K/Akt和MAPK/Erk通路的激活。Western印迹分析显示，Akt和Erk的磷酸化形式在正常成纤维细胞处理的细胞中表达显著下调，而在CAFS处理的细胞中表达上调/维持。用特定的抑制剂LY294002和U0126治疗逆转了CAFS介导的细胞增殖(P<；0.0001)，表明这些途径在调节子宫内膜癌细胞增殖中起作用。针对PI3K途径下游分子(MTOR)的雷帕霉素也通过诱导细胞凋亡来抑制CAFS诱导的细胞增殖。细胞因子分析显示，与正常成纤维细胞相比，CAF分泌更多的巨噬细胞趋化蛋白(MCP)-1、IL-6、IL-8、RANTES和血管内皮生长因子(VEGF)。我们的数据表明，与正常的成纤维细胞相比，CAF可能在子宫内膜癌的发展过程中表现出促肿瘤作用，PI3K/Akt和MAPK/Erk信号可能代表着子宫内膜癌细胞对微环境的反应的关键调节因子。
Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment.
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影响因子：
6.4
作者：
Dagouassat, Maylis;Suffee, Nadine;Charnaux, Nathalie
通讯作者：
Charnaux, Nathalie
影响因子：
4.8
作者：
Chung, Ivy;Karpf, Adam R.;Trump, Donald L.
通讯作者：
Trump, Donald L.
DOI：
10.1016/b978-0-12-397927-8.00009-9
发表时间：
2012-01-01
期刊：
CURRENT CHALLENGES IN PERSONALIZED CANCER MEDICINE
影响因子：
--
作者：
Franco, Omar E.;Hayward, Simon W.
通讯作者：
Hayward, Simon W.
影响因子：
4.7
作者：
BOKHMAN, JV
通讯作者：
BOKHMAN, JV
影响因子：
2.7
作者：
Classen-Linke, I;Alfer, J;Beier, HM
通讯作者：
Beier, HM