Munoz O, Fend F, de Beaumont R, Husson H, Astier A, Freedman A S
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Leukemia. 2004 Dec;18(12):2015-25. doi: 10.1038/sj.leu.2403485.
We have previously reported an overexpression of Smad1 in follicular lymphoma (FL) cells, which are characterized by the t(14;18) bcl2/IgH translocation. Smad1 is commonly involved in bone morphogenetic protein but not in tumor-transforming growth factor beta (TGFbeta) signaling pathways. This study focuses on Smad1 signaling pathway in non-Hodgkin lymphoma cells including follicular or large-cell lymphoma cells. Our results support the notion that phosphorylation of Smad1 is mediated by TGFbeta present in the microenvironment and occurs in FL in vivo. Using an in vitro coculture system mimicking interactions between stroma cells and FL cells, we found that both the cell partners release TGFbeta at a sufficient concentration to activate Smad pathways in the malignant cells. This Smad1 activation involves TGFbetaRII but not ALK-1 receptors, and does not compete with the Smad2 pathway. Moreover, proliferation assays performed on lymphoma cells expressing wild-type or mutated Smad1, or in which endogenous Smad1 level was decreased by gene silencing, strongly supported that overexpression and activation of Smad1 modifies the biological response of lymphoma B cells to TGFbeta family members. This work opens new insights into aberrant Smad pathways and their pathophysiological role in FL and in other non-Hodgkin lymphomas.
我们之前报道过，在以t(14;18) bcl2/IgH易位为特征的滤泡性淋巴瘤(FL)细胞中，Smad1存在过表达。Smad1通常参与骨形态发生蛋白信号通路，但不参与肿瘤转化生长因子β (TGFβ)信号通路。本研究聚焦于非霍奇金淋巴瘤细胞（包括滤泡性或大细胞淋巴瘤细胞）中的Smad1信号通路。我们的结果支持以下观点：Smad1的磷酸化由微环境中存在的TGFβ介导，且在体内的滤泡性淋巴瘤中发生。使用模拟基质细胞与滤泡性淋巴瘤细胞之间相互作用的体外共培养系统，我们发现两种细胞伙伴均释放足够浓度的TGFβ以激活恶性细胞中的Smad信号通路。这种Smad1激活涉及TGFβRII而非ALK-1受体，并且不与Smad2信号通路竞争。此外，对表达野生型或突变型Smad1的淋巴瘤细胞，或通过基因沉默使内源性Smad1水平降低的淋巴瘤细胞进行增殖分析，有力地支持了Smad1的过表达和激活改变了淋巴瘤B细胞对TGFβ家族成员的生物学反应。这项工作为滤泡性淋巴瘤和其他非霍奇金淋巴瘤中异常的Smad信号通路及其病理生理作用提供了新的见解。
