Connexin hemichannels in suppression of breast cancer bone metastasis

连接蛋白半通道抑制乳腺癌骨转移

基本信息

批准号：
9030104
负责人：
Jean X Jiang
金额：
$ 35.59万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030104
关键词：
ATP Receptors Adverse effects Anchorage-Independent Growth Attenuated Biochemical Biological Assay Biology Blocking Antibodies Bone Diseases Breast Cancer Cell Breast Cancer Treatment Cancer Etiology Cell physiology Cells Clinical Collaborations Complication Connexin 43 Connexins Data Defense Mechanisms Development Disseminated Malignant Neoplasm Down-Regulation Drug Targeting Genes Goals Growth Housing Human Imaging Techniques In Vitro Intervention Knockout Mice Laboratories Malignant Neoplasms Mechanical Stimulation Mechanics Mediator of activation protein Metastatic Neoplasm to the Bone Metastatic breast cancer Microtubule Stabilization Microtubules Modality Modeling Mus Neoplasm Metastasis Osteoblasts Osteoclasts Osteocytes Outcome Patients Pharmaceutical Preparations Physical Exercise Physical activity Play Purinoceptor Receptor Signaling Research Research Activity Role Sampling Site Specimen Structure Testing The Sun Time Tissues base bisphosphonate bone bone cell bone strength calmodulin-dependent protein kinase II cancer cell cell type experience in vivo knock-down malignant breast neoplasm migration mouse model new therapeutic target novel optical imaging paracrine public health relevance receptor receptor-mediated signaling release factor shear stress stathmin targeted biomarker tibia tumor

项目摘要

DESCRIPTION (provided by applicant): Bone is a major site for the preferential metastasis by advanced breast cancers. Bone metastases by breast cancers cause deadly complications and there is an unmet need for efficacious intervention with minimal side effect. The majority of previous studies have primarily focused on metastasized cancer cells or tumor supporting bone microenvironments. Here we propose to investigate the intrinsic anti-cancer metastatic potentials of the osteocytes, the most abundant bone cell type in the bone. Connexin (Cx) 43 hemichannels are richly present in osteocytes. Our preliminary study showed that the opening of Cx43 hemichannels by either bisphosphonate drugs or mechanical stimulation inhibited migration and anchorage-independent growth of breast cancer cells. Moreover, breast cancer bone metastasis appears to be augmented in osteocyte-specific Cx43 knockout mice when compared to wild-type controls. As such, we hypothesize that active Cx43 hemichannels in osteocytes release ATP and ATP acting in a paracrine manner activates purinergic receptor signaling in breast cancer cells, leading to the suppression of breast cancer bone metastasis. The goal is to establish the importance of osteocytic Cx43 hemichannels as a potential, novel drug target for the treatment. In this proposal, first, we will test the hypothesis that active osteocytic Cx43 hemichannels inhibit breast cancer cell metastasis. The effect of Cx43 hemichannel inhibition on breast cancer bone metastasis will be examined in vivo using in-house developed Cx43-deficient mouse models and hemichannel-specific blocking antibodies. The cell-based studies will be used to dissect the effect of osteocytic Cx43 hemichannels on various subtypes of breast cancer cells. Second, we will test the hypothesis that osteocytic Cx43 hemichannels activated by mechanical loading, associated with physical exercise, plays a critical role in the inhibition of breast cancer bone metastasis. We will apply mechanical loading through flow shear stress in vitro and tibial loading in vivo to assess the functional involvement of osteocytic Cx43-hemichannels in breast cancer migration and bone metastasis, and on bone cell function and bone strength, as the latter could serve as a complementary defense mechanism against bone metastasis. Third, we will test the hypothesis that P2X7 receptor in breast cancer cells activated by ATP released by osteocytic Cx43 hemichannels is responsible for the suppression of bone metastasis by first investigating the roles of ATP and P2X7 purinergic receptor, and followed by studying the underlying mechanism concerning how the activation of P2X7 receptor-mediated signaling inhibits breast cancer cell function and if down-regulation of this mechanism is more prevalent in clinical samples associated with bone metastases. Through a unique collaboration with the laboratories of the two PIs with their strong, complementary expertise, the proposed studies are expected to reveal a novel, inhibitory mechanism in the suppression of breast cancer bone metastasis, and should make significant contributions to the discovery of new therapeutic targets for the treatment of breast cancer-induced bone metastases.

描述（由申请人提供）：骨是晚期乳腺癌优先转移的主要部位，乳腺癌骨转移会导致致命的并发症，并且对副作用最小的有效干预的需求尚未得到满足。在此，我们建议研究骨细胞（骨骼中最丰富的骨细胞类型）的内在抗癌转移潜力。连接蛋白 (Cx) 43 半通道在骨细胞中大量存在，我们的初步研究表明，通过双膦酸盐药物或机械刺激打开 Cx43 半通道可抑制乳腺癌细胞的迁移和锚定非依赖性生长。与野生型对照相比，骨细胞特异性 Cx43 敲除小鼠的效果有所增强，因此，我们在骨细胞释放中采用了活性 Cx43 半通道。 ATP 和 ATP 以旁分泌方式激活乳腺癌细胞中的嘌呤能受体信号传导，从而抑制乳腺癌骨转移。目标是确定骨细胞 Cx43 半通道作为潜在的新型治疗药物靶点的重要性。这个提议，首先，我们将检验活性骨细胞Cx43半通道抑制乳腺癌细胞转移的假设。Cx43半通道抑制对乳腺癌骨转移的影响。使用内部开发的 Cx43 缺陷小鼠模型和半通道特异性阻断抗体进行体内检查。基于细胞的研究将用于剖析骨细胞 Cx43 半通道对各种乳腺癌细胞亚型的影响。假设与体育锻炼相关的机械负荷激活的骨细胞 Cx43 半通道在抑制乳腺癌骨转移中发挥着关键作用，我们将通过流动剪切应力施加机械负荷。体外和体内胫骨负载，以评估骨细胞 Cx43 半通道在乳腺癌迁移和骨转移中的功能参与，以及骨细胞功能和骨强度，因为后者可以作为对抗骨转移的补充防御机制。将通过首先研究 ATP 和P2X7 嘌呤能受体，然后通过与骨转移相关的临床样本中研究 P2X7 受体介导信号的激活如何抑制乳腺癌细胞功能的潜在机制，以及这种机制的下调是否更普遍。两位 PI 的实验室凭借其强大、互补的专业知识，拟议的研究有望揭示抑制乳腺癌骨转移的新颖的抑制机制，并应为发现乳腺癌骨转移的新治疗靶点做出重大贡献。治疗乳腺癌引起的骨转移。