NF-kB Signaling in Osteoclastogenesis and Osteolytic Bone Metastasis

描述(申请人提供)：本申请的长期目标是了解控制乳腺癌骨转移的分子机制。在患有晚期疾病的患者中，乳腺癌经常转移到骨骼。与前列腺癌形成成骨细胞病变不同，乳腺癌的骨转移通常会导致骨溶解，通常伴随着剧烈的疼痛、病理性骨折和高钙血症。尽管骨转移的分子机制尚不清楚，但目前认为参与骨溶解的是乳腺癌细胞激活的破骨细胞，而不是乳腺癌细胞本身。破骨细胞在刺激骨髓腔内骨转移瘤生长中起着起始和关键的作用。虽然骨骼微环境允许循环中的乳腺癌细胞优先存活和生长，但寻骨型乳腺癌细胞可能具有促进破骨细胞形成和激活的内在特性。这一应用的中心假设是，乳腺癌细胞中的结构性核因子-kappaB(NF-？B)活性在溶骨性骨转移和破骨细胞形成中起着不可或缺的作用。核因子-β是一种炎性转录因子，可调节多种基因的表达，包括促炎细胞因子、趋化因子和细胞黏附分子。利用体外和体内模型系统，我们发现乳腺癌细胞中的结构性核因子-β活性通过刺激破骨细胞的生成来促进溶骨性肿瘤的生长。在这项应用中，我们将基于我们令人兴奋的初步研究，探索如何利用生物化学和遗传学相结合的方法，将核因子-βB失控并招募到染色质中，以刺激乳腺癌细胞中的靶基因转录。我们将确定核因子-B诱导的基因，如乳腺癌细胞分泌的趋化因子是否刺激破骨细胞的形成，从而促进溶骨性骨转移。有趣的是，NF-βB对破骨细胞的发生也是必不可少的，促炎性细胞因子和趋化因子通过激活NF-βB促进破骨细胞分化。然而，与细胞因子不同的是，人们对趋化因子如何激活NF-βB知之甚少。因此，我们还将探讨趋化因子如何触发细胞内信号转导来激活核因子-βB从而促进破骨细胞分化。综上所述，这一应用的结果将为研究核因子-β的溶骨性骨转移和破骨细胞激活提供新的见解，并有助于开发治疗骨转移的新策略。与公共健康相关：这项应用的长期目标是了解为什么乳腺癌经常扩散到骨骼并导致骨质破坏。伴有骨转移的晚期乳腺癌患者通常是无法治愈的，并且有严重的内科并发症。在这一应用中，我们将从机制和治疗两个方面来解决这一具有挑战性的问题。根据我们最近关于转录因子核因子-kappaB促进骨转移的研究结果，我们将探讨核因子-kappaB诱导的乳腺癌细胞中的趋化因子是否通过诱导破骨细胞(骨吸收细胞)的形成来促进骨转移。我们将探索如何在乳腺癌细胞中调节核因子？B的活性。我们研究的新发现将帮助我们开发通过抑制核因子-β来治疗骨转移的新策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The long-objectives of this application are to understand why breast cancer frequently spreads to bone and cause bone destruction. Advanced breast cancer patients with bone metastasis are often incurable and possess severe medical complications. In this application, we will attack this challenging issue from both mechanistic and therapeutic aspects. Based on our recent findings on the promotion of bone metastasis by the transcription factor nuclear factor-kappa B (NF-?B), we will examine whether NF-?B- induced chemokines in breast cancer cells promotes bone metastasis by inducing osteoclast (bone resorbing cells) formation. We will explore how NF-?B activities are regulated in breast cancer cells. New findings from our studies will help us to develop novel strategies for treating bone metastasis by inhibiting NF-?B.