REGULATION OF NORMAL AND NEOPLASTIC HEMATOPOIETIC CELL GROWTH--ROLE OF BRMS

正常和肿瘤造血细胞生长的调节——BRMS 的作用

• 批准号: 3874512
• 负责人: F W RUSCETTI
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 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/3874512
• 关键词: B lymphocyte; biological response modifiers; biological signal transduction; cell differentiation; cell growth regulation; colony stimulating factor; growth factor receptors; growth inhibitors; hematopoiesis; hematopoietic stem cells; human tissue; immunomodulators; interleukin 3; laboratory mouse; leukocyte activation disorder; lymphokines; myelogenous leukemia; neoplasm /cancer immunology; neoplastic cell; neoplastic growth; phorbols; receptor expression; tissue /cell culture; transforming growth factors

In studying humoral regulation of hematopoietic cell growth, we have found that transforming growth factor beta has potent bifunctional effects. TGF beta1 and TGF beta2 are equipotent selective inhibitors of hematopoiesis that halt the growth of early human and murine progenitors but not more differentiated progenitors. Using purified murine hematopoietic stem cells in single cell assays with IL 3, it was shown that TGF beta acted directly on the cells to block growth. Primitive hematopoietic cells such as high proliferative potential colony forming cell (HPP-CFU) and CFU-GEMM and BFU-E were inhibited by TGF beta in vitro. Thus, the ability of TGF beta to block hematopoietic cell growth depends on the state of differentiation of the cell. In contrast, addition of TGF beta to GM-CSF stimulated bone marrow cells greatly augmented growth, leading predominantly to an increase in granulocytes. In vivo experiments with TGF beta show that the hematopoietic stem cells are reversibly prevented from entering the cell cycle. This growth inhibitory action functions on at least two levels: 1) trans-down modulation of the cell surface receptors for positive regulatory signals and/or interfering with post-receptor signalling of these molecules. Leukemic cell lines could be either sensitive or insensitive to TGF beta mediated growth inhibition. Growth of neoplastic B lymphocytes can occur by escaping from a TGF beta mediated autocrine inhibitory loop. Activation signals (e.g. phorbol esters) can inhibit tumor cell growth by stimulation of active TGF beta production and induction of cell surface expression of functional TGF beta receptors. These results suggest that TGFbeta may have utility as a bone marrow protective and as an anti-tumor agent.

在研究造血细胞生长的体液调节时，我们发现 转化生长因子β具有有效的双功能作用。转化生长因子 beta1 和 TGF beta2 是等价的选择性造血抑制剂 阻止早期人类和小鼠祖细胞的生长，但不会更多 分化的祖细胞。使用纯化的小鼠造血干细胞 在使用 IL 3 的单细胞测定中，表明 TGF beta 直接作用 作用于细胞以阻止生长。原始造血细胞如高 增殖潜力集落形成细胞 (HPP-CFU) 和 CFU-GEMM 和 BFU-E 在体外被 TGF beta 抑制。因此，TGFβ 的能力 阻止造血细胞生长取决于造血细胞的分化状态 细胞。相反，在 GM-CSF 中添加 TGF β 可刺激骨 骨髓细胞大大增强了生长，主要导致增加 在粒细胞中。 TGF beta 的体内实验表明 造血干细胞被可逆地阻止进入细胞 循环。这种生长抑制作用至少在两个层面上发挥作用：1) 细胞表面受体的反式下调调节以进行正调节 信号和/或干扰这些受体后信号传导 分子。白血病细胞系可能对以下物质敏感或不敏感 TGFβ介导的生长抑制。肿瘤性 B 淋巴细胞的生长可以 通过逃离 TGFβ 介导的自分泌抑制环而发生。 激活信号（例如佛波酯）可以通过以下方式抑制肿瘤细胞生长： 刺激活性 TGF β 的产生并诱导细胞表面 功能性 TGF β 受体的表达。这些结果表明 TGFbeta 可能具有骨髓保护作用和抗肿瘤作用 代理人。