TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer
TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer
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DOI：
10.1038/onc.2013.527
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发表时间：
2015-01-02
期刊：
影响因子：
8
通讯作者：
Landberg, G.
中科院分区：
文献类型：
--
作者：
Busch, S.;Acar, A.;Landberg, G.
转化生长因子-β（TGF-β）是一种多效性细胞因子，具有根据细胞环境作为肿瘤抑制因子或肿瘤促进因子的能力。TGF-β受体2型（TGFBR 2）是TGF-β家族所有成员的配体结合受体。来自小鼠模型实验的数据表明，乳腺成纤维细胞中Tgfbr 2表达的丧失与肿瘤的发生和转移有关。我们使用一项随机的他莫昔芬试验队列，共包括564例浸润性乳腺癌，检查了癌症相关成纤维细胞（CAF）中TGFBR 2的表达（n = 252）和下游靶点SMAD 2（pSMAD 2）的磷酸化水平（n = 319），并评估了与临床病理标志物、预后和治疗预测值的联系。该研究显示，CAF特异性TGFBR 2表达与改善的无复发生存率相关。多因素分析证实CAF-TGFBR 2是独立的预后指标（多因素考克斯回归，危险比：0.534，95%（CI）：0.360-0.793，P = 0.002）。然而，CAF特异性pSMAD 2水平与生存结局无关。在实验上，使用TGF-β配体和抑制剂或通过慢病毒短发夹RNA介导的TGFBR 2特异性敲低来调节成纤维细胞中的TGF-β信号传导。为了确定成纤维细胞TGF-β通路对乳腺癌细胞的作用，我们使用了细胞接触依赖性细胞生长和克隆形成试验，其显示CAFs中TGFBR 2的敲低导致细胞生长、增殖和克隆形成存活增加。此外，在小鼠模型中，将转染的CAF与MCF 7共注射，并监测肿瘤重量和比例。我们发现，包含TGFBR 2敲低成纤维细胞的小鼠异种移植肿瘤略大，并显示出增加的肿瘤细胞能力。总的来说，我们的数据表明，成纤维细胞相关的生物标志物具有临床相关的信息，成纤维细胞赋予乳腺癌细胞的生长和存活的影响。通过成纤维细胞TGF-β途径调节肿瘤-基质串扰可能取决于成纤维细胞表型，强调了肿瘤微环境亚型的重要性。
Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-beta family. Data from mouse model experiments demonstrated that loss of Tgfbr2 expression in mammary fibroblasts was linked to tumour initiation and metastasis. Using a randomised tamoxifen trial cohort including in total 564 invasive breast carcinomas, we examined TGFBR2 expression (n = 252) and phosphorylation level of downstream target SMAD2 (pSMAD2) (n = 319) in cancer-associated fibroblasts (CAFs) and assessed links to clinicopathological markers, prognostic and treatment-predictive values. The study revealed that CAF-specific TGFBR2 expression correlated with improved recurrence-free survival. Multivariate analysis confirmed CAF-TGFBR2 to be an independent prognostic marker (multivariate Cox regression, hazard ratio: 0.534, 95% (Cl): 0.360-0.793, P = 0.002). CAF-specific pSMAD2 levels, however, did not associate with survival outcome. Experimentally, TGF-beta signalling in fibroblasts was modulated using a TGF-beta ligand and inhibitor or through lentiviral short hairpin RNA-mediated TGFBR2-specific knockdown. To determine the role of fibroblastic TGF-beta pathway on breast cancer cells, we used cell contact-dependent cell growth and clonogenicity assays, which showed that knockdown of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival. Further, in a mouse model transfected CAFs were co-injected with MCF7 and tumour weight and proportion was monitored. We found that mouse xenograft tumours comprising TGFBR2 knockdown fibroblasts were slightly bigger and displayed increased tumour cell capacity. Overall, our data demonstrate that fibroblast-related biomarkers possess clinically relevant information and that fibroblasts confer effects on breast cancer cell growth and survival. Regulation of tumour-stromal cross-talk through fibroblastic TGF-beta pathway may depend on fibroblast phenotype, emphasising the importance to characterise tumour microenvironment subtypes.