Consistent loss of functional transforming growth factor β receptor expression in murine plasmacytomas
Consistent loss of functional transforming growth factor β receptor expression in murine plasmacytomas
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DOI：
10.1073/pnas.95.1.189
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发表时间：
1998-01-06
影响因子：
11.1
通讯作者：
Letterio, JJ
中科院分区：
文献类型：
--
作者：
Amoroso, SR;Huang, NH;Letterio, JJ
小鼠浆细胞瘤是可在遗传易感的BALB/c小鼠中诱导的Ig分泌性浆细胞的肿瘤。c-myc原癌基因的失调是浆细胞瘤（Pers）发展中的一个关键致癌事件，尽管它不足以导致其恶性转化。我们已经证明，PCTs在体外产生活性转化生长因子β（TGF-β）。由于TGF-β是B淋巴细胞增殖和分化的有效负调节因子，我们通过比较非肿瘤性浆细胞和PCT对TGF-β的反应性来研究其在浆细胞生成中的作用。在白细胞介素6转基因小鼠中积累的未转化的浆细胞在用TGF-β处理后经历加速的凋亡，但是所研究的15种PCT，包括原发性和移植肿瘤以及建立的细胞系，对TGF-β介导的生长抑制和凋亡是难治的。尽管PCT缺乏功能性TGF-β受体，如通过与放射性标记的TGF-β 1的化学交联所证明的，尽管如此，它们含有I型和II型TGF-β受体的mRNA和蛋白质，提示受体运输或加工中的潜在缺陷。结果清楚地显示了浆细胞瘤细胞中TGF-β受体的一致失活，首次证明了肿瘤抑制途径的中断有助于浆细胞瘤的发生。
Murine plasmacytomas are tumors of Ig-secreting plasma cells that can be induced in genetically susceptible BALB/c mice. The deregulation of the c-myc protooncogene is a critical oncogenic event in the development of plasmacytomas (Pers) although it is not sufficient for their malignant transformation. We have demonstrated that PCTs produce active transforming growth factor beta (TGF-beta) in vitro. Because TGF-beta is a potent negative regulator of the proliferation and differentiation of B lymphocytes, we examined its role in plasmacytomagenesis by comparing responsiveness to TGF-beta of nonneoplastic plasma cells and PCTs. The nontransformed plasma cells that accumulate in interleukin 6 transgenic mice undergo accelerated apoptosis upon treatment with TGF-beta, but the 15 PCTs studied, including primary and transplanted tumors as well as established cell lines, were refractory to TGF-beta-mediated growth inhibition and apoptosis, Although PCTs lack functional TGF-beta receptors as demonstrated by chemical crosslinking to radiolabeled TGF-beta 1, they nonetheless contain mRNA and protein for both type I and II TGF-beta receptors, suggesting a potential defect in receptor trafficking or processing. The results clearly show the consistent inactivation of TGF-beta receptors in plasmacytoma cells, demonstrating for the first time that interruption of a tumor suppressor pathway contributes to plasmacytomagenesis.