Illegitimate WNT signaling promotes proliferation of multiple myeloma cells
Illegitimate WNT signaling promotes proliferation of multiple myeloma cells
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DOI：
10.1073/pnas.0305855101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Pals, ST
中科院分区：
文献类型：
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作者：
Derksen, PWB;Tjin, E;Pals, ST
肿瘤细胞的无限制生长通常归因于必要的生长控制基因的突变，但肿瘤细胞也受到来自环境的信号的影响。在多发性骨髓瘤(MM)中，来自骨髓微环境的因素和信号可能对肿瘤细胞的生长是必不可少的。作为干预的目标，这些信号可能与突变的癌基因一样重要。鉴于它们的致癌潜力，WNT信号形成了一类旁分泌生长因子，可以影响MM细胞的生长。在本文中，我们报道了MM细胞具有活跃的WNT信号的特征，而这些细胞没有经历可检测到的WNT信号基因的突变，如腺瘤性息肉病结肠和β-连环蛋白(CTNNB1)。我们发现恶性MM浆细胞过度表达β-连环蛋白，包括其IN末端的非磷酸化形式，提示激活的β-连环蛋白/T细胞因子介导的转录。Wnt3a、LiCl或β-catenin的S33Y突变体对WNT信号的刺激可使β-catenin进一步积累和核定位，和/或促进细胞增殖。相反，通过显性负性T细胞因子阻断WNT信号，我们可以干扰MM细胞的生长。因此，我们认为多发性骨髓瘤细胞依赖于活跃的WNT信号，这可能对这种无法治愈的癌症的治疗具有重要意义。
The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also influenced by signals from the environment. In multiple myeloma (MM), the factors and signals coming from the bone marrow microenviromment are possibly even essential for the growth of the tumor cells. As targets for intervention, these signals may be equally important as mutated oncogenes. Given their oncogenic potential, WNT signals form a class of paracrine growth factors that could act to influence MM cell growth. In this paper, we report that MM cells have hallmarks of active WNT signaling, whereas the cells have not undergone detectable mutations in WNT signaling genes such as adenomatous polyposis coli and beta-catenin (CTNNB1). We show that the malignant MM plasma cells overexpress beta-catenin, including its IN-terminally unphosphorylated form, suggesting active beta-catenin/T cell factor-mediated transcription. Further accumulation and nuclear localization of beta-catenin, and/or increased cell proliferation, was achieved by stimulation of WNT signaling with either Wnt3a, LiCl, or the constitutively active S33Y mutant of beta-catenin. In contrast, by blocking WNT signaling by dominant-negative T cell factor, we can interfere with the growth of MM cells. We therefore suggest that MM cells are dependent on an active WNT signal, which may have important implications for the management of this incurable form of cancer.