J BONE MINER RES ：锻炼身体能减少骨瘤生长

对比组和注射瘤体组胫骨（负载和无负载）的三围微型 CT 重建

　　通常要求做的负重运动可对抗骨质流失，可能起到抗癌效果。康奈尔生物医学研究人员报告，机械刺激癌骨增强骨头，削弱肿瘤。

　　在动物和离体模型上所做的研究表明，使骨头反复承受适中的重量与运动疗法类似，抑制由转移乳腺癌细胞组成的骨瘤的生长。研究人员认为，这样的机械刺激可能减少那些干扰正常健康骨头功能的基因的表达。

　　《骨与矿物质研究杂志》于五月三日在网上公布由第一作者兼博士后研究员 Maureen Lynch 和生物医学工程副教授兼资深作家 Claudia Fischbach-Teschl 领导的这项研究。

　　乳腺癌通常转移之骨头，然后恶化，因为肿瘤干扰了骨重建的正常过程。随之而来的是骨质流失，这通常是因为太多的裂骨（称之为骨质溶解）有助于供养肿瘤，因为这些骨头是提高肿瘤生长因子的仓库。退化的骨头释放这些存储的因子，从而导致肿瘤生长。

　　研究人员使用一种骨头“负载模型 (loading model)”，表明肿瘤对机械刺激有反应。负载模型由论文合著者 Marjolein van der Meulen 实验室和康奈尔生物医学工程 Swanson 教授发起， Swanson 教授尤其擅长研究骨生物力学。

　　实验表明，注射了恶性乳腺癌细胞的老鼠胫骨负载 — 重复转移条件 — 使肿瘤不生长并增加骨量。什么也不做会使肿瘤扩散且骨头退化。

胫骨相应的组织学横截面显示，无载荷肿瘤胫骨展示溶骨性退化和广泛的肿瘤形成，而负载的则抑制了这些变化。

　　“如果你想做典型的癌症治疗，如化疗，他们以癌细胞为靶向，”Lynch 说，“因此我们需要计算出负载除了影响骨细胞外是否还影响肿瘤细胞，或者这是否成为某种间接的效果。我们发现两者都有一点儿。”

　　为了控制微环境因素，研究人员在 Fischbach-Teschl 实验室设计使用三围肿瘤模型做了其他实验。他们将肿瘤细胞注射到看似一个阿司匹林药片的多孔支架中，然后使用活塞挤压支架负载细胞。他们检查在负载时肿瘤细胞特征如何表达不同的因子。

　　癌性基因并未受到太大影响，除了被称为 Runx2 的一个基因外，这是一个转录因子，调节基因表达和其他蛋白质生产。这反过来影响骨细胞功能。

　　在癌细胞中，研究人员提出 Runx2 支配细胞隐藏刺激骨质溶解的蛋白质，而这些蛋白质其中许多会导致骨质流失。机械负载抑制 Runx2 的表达，而且他们认为，这就是影响骨质溶解的蛋白质也减少的原因。需要更进一步的实验确定该理论。

　　Fischbach-Teschl 说，该论文的见解不仅会导致癌症患者的药物治疗，还会导致更多的针对性运动疗法。

　　“具体来说，对骨头物理介导可能导致癌症患者骨质流失，”她说，“因此，更好地安装那些东西会真正帮助患者。”

与癌症相关的拓展阅读：

• Onco & Cancer Res：袁增强等Hippo信号通路和癌症及细胞衰老研究获进展
• EBM：以崭新之生物医学造影技术研究癌症发展模式
• Am J Epidemiol：用体质指数判定癌症风险或需重新思考
• Nat Chem Biol：探究O-葡萄糖转移酶在癌症糖尿病等疾病中的作用 更多信息请点击：有关癌症更多资讯

原文阅读：Exercise could reduce bone tumor growth

Weight-bearing exercise, often prescribed to combat bone loss, might have anti-cancer effects. Cornell biomedical researchers report that mechanical stimulation of cancerous bone, in making bone stronger, seems to make tumors weaker.

The study, which involved both animal and in vitro models, showed that causing bone to bear moderate, repeated weight – akin to an exercise regimen – led to inhibited growth of bone tumors composed of metastasized breast cancer cells. The researchers think that such mechanical stimulation might reduce the expression of genes that interfere with normal, healthy bone functioning.

Published online May 3 by the Journal of Bone and Mineral Research, the study was led by first author and postdoctoral researcher Maureen Lynch and senior author Claudia Fischbach-Teschl, associate professor of biomedical engineering.

Breast cancer often metastasizes to bone, which then deteriorates because a tumor disturbs the normal process of bone remodeling. The subsequent bone loss, which is caused by too much bone breakdown known as osteolysis, helps feed the tumor, because the bone is a depot of factors that promote tumor growth. Degraded bone releases these stored factors, and the tumor grows.

The researchers used a bone “loading model” to show that tumors respond to mechanical stimulation. The loading model originated in the lab of paper co-author Marjolein van der Meulen, the Swanson Professor of Biomedical Engineering at Cornell, who studies biological mechanics particularly in bone.

The experiments showed that loading of a mouse tibia injected with malignant breast cancer cells – recreating the metastatic condition – kept the tumor from growing and increased bone mass. Doing nothing allowed the tumor to proliferate and the bone to degrade.

“If you think about typical cancer treatment, like chemotherapies, they are targeting the cancer cells,” Lynch said. “So we needed to figure out if loading is affecting the tumor cells in addition to the bone cells, or if this is some kind of indirect effect. We found a little bit of both.”

To control microenvironmental factors, the researchers did other experiments with a 3-D tumor model designed in Fischbach-Teschl’s lab. They injected tumor cells into a porous scaffold that looks like an aspirin pill, then loaded the cells by using a piston to squeeze the scaffold. They examined how different genes characteristic of tumor cells were expressed as the loading occurred.

Genes involved in cancer were largely unaffected, except one, called Runx2, a transcription factor that regulates gene expression and production of other proteins. This, in turn, affects what bone cells are doing.

In a cancer cell, the researchers have theorized, Runx2 directs the cells to secrete proteins that stimulate osteolysis, too much of which leads to bone loss. Mechanical loading inhibits expression of Runx2, and they think that’s why proteins that affect osteolysis are also reduced. Further experimentation to confirm this theory is needed.

The insights from this paper could lead not only to drug therapies but also to more targeted exercise regimens for cancer patients, Fischbach-Teschl said.

“Specifically, physically mediated mechanisms in bone might be contributing to bone loss in cancer patients,” she said. “So harnessing those things better is what could really help patients.”

The paper is titled “In Vivo Tibial Compression Decreases Osteolysis and Tumor Formation in Human Metastatic Breast Cancer Model.” The work was supported by the National Institutes of Health and The Hartwell Foundation.

In Vivo tibial compression decreases osteolysis and tumor formation in a human metastatic breast cancer model.
Abstract
Bone metastasis, the leading cause of breast cancer-related deaths, is characterized by bone degradation due to increased osteoclastic activity. In contrast, mechanical stimulation in healthy individuals upregulates osteoblastic activity, leading to new bone formation. However, the effect of mechanical loading on the development and progression of metastatic breast cancer in bone remains unclear. Here, we developed a new in vivo model to investigate the role of skeletal mechanical stimuli on the development and osteolytic capability of secondary breast tumors. Specifically, we applied compressive loading to the tibia following intratibial injection of metastatic breast cancer cells (MDA-MB231) into the proximal compartment of female immuno-compromised (SCID) mice. In the absence of loading, tibiae developed histologically-detectable tumors with associated osteolysis and excessive degradation of the proximal bone tissue. In contrast, mechanical loading dramatically reduced osteolysis and tumor formation and increased tibial cancellous mass due to trabecular thickening. These loading effects were similar to the baseline response we observed in non-injected SCID mice. In vitro mechanical loading of MDA-MB231 in a pathologically relevant 3-D culture model suggested that the observed effects were not due to loading-induced tumor cell death, but rather mediated via decreased expression of genes interfering with bone homeostasis. Collectively, our results suggest that mechanical loading inhibits the growth and osteolytic capability of secondary breast tumors following their homing to the bone, which may inform future treatment of breast cancer patients with advanced disease.