NF-kB Signaling in Osteoclastogenesis and Osteolytic Bone Metastasis

破骨细胞生成和溶骨性骨转移中的 NF-kB 信号传导

• 批准号: 8433529
• 负责人: CUN-YU WANG
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-10 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433529
• 关键词: Affect; Angiogenic Factor; Binding; Biochemical Genetics; Biological; Biological Assay; Biological Models; Breast Cancer Cell; Cancer Patient; Cell Adhesion Molecules; Cells; Chromatin; Frequencies; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Granulocyte-Macrophage Colony-Stimulating Factor; Hypercalcemia; IL8 gene; IL8RB gene; In Vitro; Inflammatory; Interleukin-8; Lesion; Lung; Malignant neoplasm of prostate; Marrow; Mediating; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Liver; Molecular; NF-kappa B; Neoplasm Metastasis; Osteoclasts; Osteolysis; Osteolytic; Pain; Pathological fracture; Patients; Phosphotransferases; Play; Property; Proteins; Public Health; Recruitment Activity; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal bone; Small Interfering RNA; Therapeutic; Transforming Growth Factors; abstracting; advanced disease; base; bone; cancer cell; chemical genetics; chemokine; chromatin immunoprecipitation; cytokine; functional genomics; in vivo; in vivo Model; insight; knock-down; malignant breast neoplasm; medical complication; neutralizing antibody; novel; novel strategies; osteoclastogenesis; p65; parathyroid hormone-related protein; promoter; receptor; transcription factor; tumor growth

Abstract The long-term objectives of this application are to understand the molecular mechanisms which control breast cancer bone metastasis. Breast cancer frequently metastasizes to bone in patients with advanced diseases. In contrast to prostate cancer which forms osteoblastic lesion, bone metastasis of breast cancer typically leads to osteolysis which is often accompanied with severe pain, pathological fracture, and hypercalcaemia. Although the molecular mechanism underlying the preferential bone metastasis is yet to be elucidated, it is believed that osteoclasts activated by breast cancer cells, but not breast cancer cells themselves, mediate osteolysis. Osteoclasts play an initiating and pivotal role in stimulating bone-metastatic tumor growth in the marrow cavity. While bone microenvironments allow circulating breast cancer cells to preferentially survive and grow, bone-seeking breast cancer cells may have intrinsic properties to promote osteoclast formation and activation. The central hypothesis of this application is that constitutive nuclear factor-kappa B (NF-¿B) activities in breast cancer cells play an integral role in osteolytic bone metastasis and osteoclastogenesis. NF-¿B is an inflammatory transcription factor which regulates a broad range of gene expression, including pro-inflammatory cytokines, chemokines and cell adhesion molecules. Using in vitro and in vivo model systems, we have found that constitutive NF-¿B activities in breast cancer cells promote osteolytic tumor growth by stimulating osteoclastogenesis. In this application, based on our exciting preliminary studies, we will explore how NF-¿B is disregulated and recruited to chromatin to stimulate target gene transcription in breast cancer cells using a combination of biochemical and genetic approaches. We will determine whether NF-¿B-induced genes such as chemokines secreted by breast cancer cells stimulate osteoclast formation, thereby promoting osteolytic bone metastasis. Intriguingly, NF-¿B is also essential for osteoclastogenesis, and pro-inflammatory cytokines and chemokines have been found to promote osteoclast differentiation by activating NF-¿B. However, unlike cytokines, little is known about how chemokines activate NF-¿B. Therefore, we will also explore how chemokines trigger an intracellular signaling cascade to activate NF-¿B to promote osteoclast differentiation. Taken together, the results from this application will provide novel insights into osteolytic bone metastasis and osteoclast activation by NF-¿B, and help to develop new strategies for treating skeletal bone metastasis.

抽象的 该应用的长期目标是了解分子机制 控制乳腺癌骨转移。乳腺癌经常转移到骨头 患有晚期疾病的患者。与形成成骨细胞的前列腺癌相反 病变，乳腺癌的骨转移通常会导致骨溶解，这通常是 伴随着严重的疼痛，病理骨折和高钙血症。虽然 首选骨转移基础的分子机制尚未阐明，它是 认为由乳腺癌细胞激活的破骨细胞，而不是乳腺癌细胞 本身，介导溶解性。破骨细胞在刺激中起启动和关键作用 骨髓腔中的骨骼肿瘤生长。而骨微环境允许 循环乳腺癌细胞优先生存和生长，寻求骨癌的乳腺癌 细胞可能具有内在特性以促进破骨细胞的形成和激活。中央 该应用的假设是构成性核因子-kappa B（NF-€）活性 乳腺癌细胞在骨化骨转移和骨质质发生中起着不可或缺的作用。 NF-€是一种调节广泛基因的炎症转录因子 表达，包括促炎性细胞因子，趋化因子和细胞粘附分子。 使用体外和体内模型系统，我们发现本构中的nf-¿b活动 乳腺癌细胞通过刺激破骨细胞生成来促进骨化肿瘤的生长。在这个 根据我们令人兴奋的初步研究的应用，我们将探讨NF-¿b是如何 被毫无调控并招募到染色质以刺激乳腺癌中的靶基因转录 结合生化方法和遗传方法的组合。我们将确定是否 NF- - B诱导的基因，例如由乳腺癌细胞分泌的趋化因子刺激 破骨细胞形成，从而促进骨化骨转移。有趣的是，nf-¿b也是 破骨细胞生成至关重要，促炎细胞因子和趋化因子和趋化因子一直是 发现通过激活NF-€B促进破骨细胞分化。但是，与细胞因子不同，很少 知道趋化因子如何激活NF-€B。因此，我们还将探讨如何 趋化因子触发细胞内信号传导级联反应激活NF- - b以促进破骨细胞 分化。综上所述，该应用程序的结果将为您提供新的见解 NF-€B激活溶性骨转移和破骨细胞，并有助于开发新的 治疗骨骼骨转移的策略。