Context-specific roles for paracrine IL-6 in lymphomagenesis
Context-specific roles for paracrine IL-6 in lymphomagenesis
复制标题
DOI：
10.1101/gad.197590.112
复制
发表时间：
2012-08-01
影响因子：
10.5
通讯作者：
Hemann, Michael T.
中科院分区：
文献类型：
--
作者：
Gilbert, Luke A.;Hemann, Michael T.
复杂器官系统发育的一个基本要求是，细胞对相同环境信号的反应在不同的细胞类型和发育阶段之间可能会有显著差异。虽然已经确定旁分泌信号传导可以类似地在不同的肿瘤类型中引起不同的反应，但是发育阶段特异性信号传导反应与肿瘤发展的相关性仍然不清楚。在这里，我们表明，相同的微环境因子，IL-6，可以通过作用于造血发育的不同阶段的细胞来促进和预防淋巴瘤的发展。具体地，旁分泌IL-6信号传导促进移植的造血干细胞在致死辐射后的存活，允许携带促癌改变的祖细胞的持续存在和扩增。相反，IL-6信号传导还启动骨髓中的旁分泌程序，其促进B细胞分化并抑制B细胞恶性肿瘤的发展。因此，对细胞因子的阶段特异性反应可能会促进祖细胞扩增，同时也抑制单个发育谱系内的肿瘤发育。一旦转化，产生的B细胞淋巴瘤再次使用旁分泌IL-6信号作为生存信号，突出了肿瘤细胞选择用于干细胞保护的途径的能力。这些数据不仅表明肿瘤前微环境对肿瘤发展的复杂调控，而且这种调控可以决定性地影响成熟的肿瘤建模方法的结果。
A basic requirement for the development of complex organ systems is that the cellular response to identical environmental cues can vary significantly between distinct cell types and developmental stages. While it is well established that paracrine signaling can similarly elicit diverse responses in distinct tumor types, the relevance of developmental stage-specific signaling responses to tumor development remains unclear. Here, we show that the same microenvironmental factor, IL-6, can both promote and prevent lymphoma development by acting on cells at distinct stages of hematopoietic development. Specifically, paracrine IL-6 signaling promotes the survival of transplanted hematopoietic stem cells following lethal irradiation, allowing for the persistence and expansion of progenitor cells bearing a cancer-promoting alteration. Conversely, IL-6 signaling also initiates a paracrine secretory program in the bone marrow that promotes B-cell differentiation and inhibits the development of B-cell malignancies. Thus, stage-specific responses to cytokines may promote progenitor cell expansion while also inhibiting neoplastic development within a single developmental lineage. Once transformed, the resulting B-cell lymphomas again use paracrine IL-6 signaling as a survival signal, highlighting the ability of tumor cells to co-opt pathways used for stem cell protection. These data not only suggest a complex regulation of tumor development by the preneoplastic microenvironment, but also that this regulation can decisively impact the outcome of wellestablished tumor modeling approaches.