NF-kB Signaling in Osteoclastogenesis and Osteolytic Bone Metastasis

摘要 本申请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， 晚期疾病患者。与前列腺癌形成成骨细胞相反， 乳腺癌的骨转移通常会导致骨质溶解， 伴有剧烈疼痛、病理性骨折和高钙血症。虽然 优先骨转移的分子机制尚未阐明， 认为破骨细胞被乳腺癌细胞激活，而不是乳腺癌细胞， 自身介导骨质溶解。破骨细胞在刺激骨形成中起着起始和关键的作用。 骨髓腔中的骨转移性肿瘤生长。虽然骨骼微环境允许 循环乳腺癌细胞优先生存和生长，骨寻求性乳腺癌 细胞可能具有促进破骨细胞形成和活化的内在特性。中央 本申请假设是，细胞中的组成型核因子-κ B（NF-B）活性 乳腺癌细胞在溶骨性骨转移和破骨细胞生成中起着不可或缺的作用。 NF-B是一种炎性转录因子，调节多种基因， 表达，包括促炎细胞因子、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，组成型NF-B活性， 乳腺癌细胞通过刺激破骨细胞生成促进溶骨性肿瘤生长。在这 应用，基于我们令人兴奋的初步研究，我们将探讨NF-B是如何 在乳腺癌中失调并募集到染色质以刺激靶基因转录 使用生物化学和遗传学方法相结合的细胞。我们将决定 NF-κ B诱导的基因，如乳腺癌细胞分泌的趋化因子，刺激 破骨细胞形成，从而促进溶骨性骨转移。有趣的是，NF-B也是 破骨细胞生成所必需的，促炎细胞因子和趋化因子已经被 发现通过激活NF-B促进破骨细胞分化。然而，与细胞因子不同， 关于趋化因子是如何激活NF-B的。因此，我们也将探讨如何 趋化因子触发细胞内信号级联以激活NF-B，从而促进破骨细胞 分化总之，该应用程序的结果将为以下方面提供新的见解： 溶骨性骨转移和破骨细胞激活NF-B，并有助于开发新的 治疗骨骼骨转移的策略。

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.