MECHANISMS BY WHICH METASTASIZING OSTEOLYTIC BREAST CANCER INTERACTS WITH BONE

转移性溶骨性乳腺癌与骨相互作用的机制

• 批准号: 6236747
• 负责人: TOSHIYUKI YONEDA
• 金额: $ 20.27万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6236747
• 关键词: X ray; athymic mouse; breast neoplasms; clone cells; disease /disorder model; histopathology; interleukin 1; laboratory rat; metastasis; organ culture; parathyroid hormones; phosphonate; physiologic bone resorption

Breast cancer has a special predilection to cause osteolytic metastases. This is a much more common problem than that of hypercalcemia, and is responsible for considerable morbidity and mortality in patients with many common solid tumors. We have recently modified an in vivo model of bone metastasis to allow us to study the mechanisms involved in osteolysis mediated by human breast cancer cells, and human breast cancer cell metastasis to bone. We plan to use this model to characterize the interactions which occur between metastasizing human breast cancer cells and the bone microenvironment. Our hypothesis is that normal bone remodeling releases factors into the bone microenvironment which stimulate aggressive growth and behavior of human breast cancer cells in this site, and that by altering rates of remodeling by pharmacologic inhibitors of bone resorption, we can limit tumor growth in bone. Our approach is to use this in vivo model and alter rates of bone remodeling in tumor bearing nude mice. Nude mice will be inoculated with MDA-231 human breast cancer cells and subsequent osteolysis in the vertebrae and extremities will be assessed by x-ray and quantitative bone histomorphometry. In the first series of experiments, we will use inhibitors of bone resorption such as the bisphosphonates and assess the effects of inhibition of bone remodeling on tumor growth in bone and the development of osteolytic metastases. In the second series of experiments we will examine the development of metastases in tumor bearing mice which have been exposed to stimulators of bone resorption and bone remodeling such as IL-I and PTH-rP. In a third series of experiments, we will use in vitro techniques to examine specific factors in the bone microenvironment which may be responsible for enhancing breast cancer cell growth in bone. Our hope is that such studies will not only allow us to develop better understanding of the responsible mechanisms, but also more appropriate therapies to prevent the formation of osteolytic lesions and to treat established osteolytic lesions, and hopefully to eventually reverse the dismal picture this common complication of cancer currently exhibits.

乳腺癌有一个特殊的倾向，导致溶骨性转移。 这是一个比高钙血症更常见的问题， 导致了相当大的发病率和死亡率的患者 许多常见的实体瘤。我们最近修改了体内模型， 骨转移，使我们能够研究涉及的机制， 人乳腺癌细胞介导的骨质溶解和人乳腺癌 细胞转移到骨。我们计划用这个模型来描述 转移的人乳腺癌细胞之间的相互作用 和骨骼微环境。 我们的假设是正常的骨骼 重塑释放因子进入骨微环境， 刺激人乳腺癌细胞侵袭性生长和行为 这个网站，并通过改变重塑率的药理学 骨吸收抑制剂，我们可以限制肿瘤在骨中的生长。 我们的方法是使用这种体内模型， 在荷瘤裸鼠中的重构。裸鼠将接种 MDA-231人乳腺癌细胞和随后的骨溶解 将通过X射线和定量骨评估椎骨和四肢 组织形态计量学在第一系列实验中，我们将使用 骨吸收抑制剂，如双膦酸盐，并评估 抑制骨重建对骨肿瘤生长的影响 发生溶骨性转移。在第二组实验中 我们将检查荷瘤小鼠中转移的发展， 暴露于骨吸收和骨重建的刺激物 如IL-1和PTH-rP。在第三个系列的实验中，我们将使用 体外技术检查骨中的特定因子 微环境可能是导致乳腺癌的原因 骨骼中的细胞生长。我们希望这样的研究不仅能 让我们更好地了解责任机制，但 也更适当的治疗，以防止溶骨性形成 病变和治疗已建立的溶骨性病变，并希望 最终扭转这种癌症常见并发症的惨淡局面 目前展出。