BIOLOGY OF PLASMA CELL TUMOR DEVELOPMENT

浆细胞肿瘤发生的生物学

• 批准号: 6100822
• 负责人: S RUDIKOFF
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6100822
• 关键词: JAK kinase; Retroviridae; biological signal transduction; cell growth regulation; cytokine receptors; disease /disorder model; gene therapy; interleukin 2; interleukin 6; laboratory mouse; lymphocyte; molecular oncology; multiple myeloma; neoplasm /cancer transplantation; neoplastic process; oncogenes; plasma cell neoplasm; transcription factor

I. Interleukin-6 (IL-6) has been demonstrated to be the major growth factor involved in development of murine plasma cell tumors and human myeloma. Mice in which the IL-6 gene has been inactivated are resistant to tumor induction as evidenced by the failure of tumors to develop following treatment with retroviruses containing raf and myc oncogenes. However, these mice develop tumors when raf is replaced by abl, suggesting that IL-6 independent tumors can be generated either by other oncogene combinations or mutations. We have previously demonstrated that the mechanism by which cytokine independent tumors arise is through constitutive activation of the IL-6 signal transduction pathway. Recent studies have indicated that abl binds directly to the IL-6 receptor. However the receptor is not phosphorylated by abl and the immediate downstream signaling molecules, Jak1 and Jak2, are also unphosphorylated. Abl has been found to directly bind to STAT3, the major signal transducer and activator of transcription in the IL-6 pathway, and subsequent phosphorylation of this molecule leads to constitutive transcriptional activation of the pathway. This system has further been used to evaluate other interactions of abl with regard to possible dysregulation of cellular processes. Abl has been found to interact with molecules in the PI-3 kinase pathway and experiments are currently in progress to determine specific mechanisms by which abl may activate this pathway. II. Studies have continued on the development of a model for human myeloma using mouse plasma cell tumors to evaluate gene therapy approaches to disease treatment. One of the major differences between human myeloma and murine plasma cell tumors relates to tissue localization. In early stage disease, myeloma is largely restricted to bone marrow and bone disease is a frequent complication. BALB/c plasma cell tumors are induced in the peritoneal cavity and bone marrow disease and bone involvement have not been evaluated. Current studies have demonstrated that several murine tumors produce bone marrow disease. Detailed analysis of the S107 line demonstrates preferential bone marrow homing in that tumor cells are detected in the marrow at one week following injection, but are absent from other organs. Tumor cells subsequently disseminate to a variety of organs resembling the terminal phase of human disease. Bone destruction associated with osteoclast involvement is observed as tumor cells expand in the marrow. A sub-line has been isolated from the marrow localizing parental tumor which now seeds all organs without preference and thus provides a model to determine the molecular events effecting the ability of tumor cells to disseminate from bone marrow to other organs. The above described similarities between human and murine plasma cell disease suggest that the mouse model is likely to be valuable in developing therapeutic approaches to human disease.

I.白细胞介素-6（IL-6）已被证明是主要的增长， 参与小鼠浆细胞肿瘤和人类浆细胞肿瘤发展的因子 骨髓瘤其中IL-6基因已经失活的小鼠具有抗性 肿瘤诱导，如肿瘤不能发展所证明的， 在用含有raf和myc癌基因的逆转录病毒治疗后。 然而，当raf被abl取代时，这些小鼠会出现肿瘤， 这表明IL-6非依赖性肿瘤可以由其他肿瘤细胞产生， 致癌基因组合或突变。我们之前已经证明， 细胞因子非依赖性肿瘤产生的机制是通过 IL-6信号转导通路的组成性激活。最近 研究表明abl直接结合IL-6受体。 然而，受体不被abl磷酸化， 下游信号分子，Jak 1和Jak 2， 未磷酸化。已经发现Abl直接结合STAT 3， IL-6中的主要信号转导子和转录激活子 途径，随后该分子的磷酸化导致 该途径的组成性转录激活。该系统具有 进一步用于评估ABL在以下方面的其他相互作用： 细胞过程可能失调。ABL已被发现 与PI-3激酶途径中的分子相互作用， 目前正在确定ABL可据以 激活这条通道。 二.研究继续发展人类的模型， 使用小鼠浆细胞肿瘤评估骨髓瘤的基因治疗 疾病治疗的方法。之间的主要区别之一 人骨髓瘤和鼠浆细胞肿瘤涉及组织 本地化在早期疾病中，骨髓瘤主要限于 骨髓和骨骼疾病是常见的并发症。BALB/c血浆 在腹膜腔和骨髓疾病中诱发细胞肿瘤 和骨受累尚未评估。目前的研究 表明几种小鼠肿瘤产生骨髓疾病。 对S107细胞系的详细分析表明优先骨髓 一周后在骨髓中检测到肿瘤细胞归巢 注射后，但不存在于其他器官。肿瘤细胞 随后扩散到各种器官， 人类疾病的阶段。与破骨细胞相关的骨破坏 当肿瘤细胞在骨髓中扩展时，观察到参与。的副线 已经从骨髓定位的亲本肿瘤中分离出来， 种子所有器官没有偏好，从而提供了一个模型， 确定影响肿瘤细胞能力的分子事件， 从骨髓扩散到其他器官。上述 人类和鼠类浆细胞疾病之间的相似性表明， 小鼠模型可能在开发治疗性药物方面有价值。 接近人类疾病。