Altered TGF-β signaling in a subpopulation of human stromal cells promotes prostatic carcinogenesis.
Altered TGF-β signaling in a subpopulation of human stromal cells promotes prostatic carcinogenesis.
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DOI：
10.1158/0008-5472.can-10-3142
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发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Hayward SW
中科院分区：
文献类型：
--
作者：
Franco OE;Jiang M;Strand DW;Peacock J;Fernandez S;Jackson RS 2nd;Revelo MP;Bhowmick NA;Hayward SW
癌相关成纤维细胞（CAF）在恶性进展中发挥着关键作用。前列腺基质中TGF-β受体II(TGF-βR2)的丧失与前列腺肿瘤发生相关。为了确定由于TGFβR2的缺失导致的基质异质性可能导致癌症进展的机制，我们在肿瘤进展模型中减弱了永生化人前列腺成纤维细胞亚群中的TGF-β信号传导。在组织重组模型中，50％的基质细胞群中TGF6R2功能的丧失导致非致瘤性人前列腺上皮细胞系BPH1的恶性转化。混合表达空载体和显性失活TGFβR2的成纤维细胞通过TGF-β1的升高和Akt途径的激活增加肌成纤维细胞分化标记物的表达[波形蛋白和α平滑肌肌动蛋白(αSMA)的共表达]。结合起来，这两个基质细胞群再现了 CAF 的肿瘤诱导活性。体外培养的混合基质细胞群中的TGF-βR2活性引起已知促进肿瘤进展的因子的分泌，包括TGF-β1、SDF1/CXCL12以及FGF和BMP家族的成员。在体内，过表达TGF-β1和SDF1/CXCL12的成纤维细胞的组织重组不仅诱导BPH1细胞的转化，而且还促进高度侵袭性细胞的强劲生长，类似于CAF产生的效果。虽然体内特定基质细胞群体的精确性质和/或起源仍然未知，但这些发现将TGF-β信号传导的异质性与肿瘤基质细胞的肿瘤促进密切相关。
Carcinoma-associated fibroblasts (CAFs) play a critical role in malignant progression. Loss of TGF-ϐ receptor II (TGFϐR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity due to loss of TGFϐR2 might contribute to cancer progression, we attenuated TGF-ϐ signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFϐR2 function in 50% of the stromal cell population resulted in malignant transformation of the non-tumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFϐR2 increased the expression of markers of myofibroblast differentiation [co-expression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-ϐ1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFϐR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-ϐ1, SDF1/CXCL12, and members of the FGF and BMP families. In vivo, tissue recombination of fibroblasts overexpressing TGF-ϐ1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-ϐ signaling to tumor promotion by tumor stromal cells.