Role of Beta 3 Integrin in Skeletal Metastasis

Beta 3 整合素在骨骼转移中的作用

• 批准号: 6908156
• 负责人: Katherine Nelson Weilbaecher
• 金额: $ 34.04万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908156
• 关键词: X ray; biological signal transduction; bone marrow transplantation; bone neoplasms; deoxyglucose; genetically modified animals; integrins; laboratory mouse; metastasis; osteoblasts; osteoclasts; osteosarcoma; platelets; polymerase chain reaction; positron emission tomography; protein structure function

DESCRIPTION (provided by applicant): Skeletal metastases from breast and prostate cancer are the cause of significant morbidity and mortality. Mechanisms by which skeletal metastases are established are unclear. Drugs that inhibit osteoclast (OC) function (namely bisphosphonates) ameliorate both osteolytic and osteoblastic metastatic bone disease, suggesting that OCs are involved in the pathogenesis of both forms of bone metastases. One approach to examine the role of OCs in skeletal metastases is the use of a mouse lacking the integrin subunit beta3. We have preliminary data that osteolytic bone metastases are significantly decreased in beta3-/- mice. The beta3-/- mouse has two fundamental defects: diminished osteoclast resorption mediated by alpha-v beta3 and diminished platelet aggregation mediated by alphaIIbeta3, both of which may play a role in the establishment of bone metastases. Blockade of platelet/tumor interactions via the beta3 integrin decreases lung metastases in mice, suggesting a role for platelet beta3 integrin in metastases. Given the above facts, we hypothesize that 1) decreased osteolytic metastases in the beta3-/- mouse arise from diminished OC and/or platelet function; 2) osteoblastic bone metastases will be decreased in the beta3-/- mice as a result of osteoclast and platelet dysfunction. Thus our specific aims are: 1) Determine the roles of defective osteoclasts and defective platelets in inhibiting osteolytic bone metastases. 2) Determine the roles of defective osteoclasts and defective platelets upon the development of osteoblastic bone metastases. Bone metastases will be established in beta3-/- mice and the osteoclast defective src-/- mice and the platelet defective DiYF mice by left cardiac ventricle (LV) and intra-tibial (IT) injection of osteolytic and osteoblastic cells lines. Bone metastases will be monitored by x-ray, 18-fluorodeexyglucose (18-FDG) PET scanning of in vivo tumor activity, and histomorphometry. Inhibitors of osteoclast alpha v beta3 and alphaIIbeta3 platelet specific inhibitors will be used in the osteolytic and osteoblastic LV and IT, bone metastasis assays. These studies will define whether beta3 function on host osteoclasts and platelets facilitate osteolytic and osteoblastic metastases and whether therapeutic inhibition of OC and/or beta3 function has a role in preventing or ameliorating skeletal metastases. These findings will direct future studies to define the molecular role of beta3 integrin subunit in the development of skeletal metastases.

描述（由申请人提供）：乳腺癌和前列腺癌的骨骼转移是导致显着发病率和死亡率的原因。骨骼转移发生的机制尚不清楚。抑制破骨细胞 (OC) 功能的药物（即双膦酸盐）可改善溶骨性和成骨性转移性骨疾病，表明 OC 参与两种形式骨转移的发病机制。检查 OC 在骨骼转移中的作用的一种方法是使用缺乏整合素亚基 beta3 的小鼠。我们的初步数据表明，β3-/- 小鼠的溶骨性骨转移显着减少。 beta3-/-小鼠有两个基本缺陷：α-v beta3介导的破骨细胞吸收减少和αIIbeta3介导的血小板聚集减少，这两者都可能在骨转移的建立中发挥作用。通过β3整合素阻断血小板/肿瘤相互作用可减少小鼠的肺转移，这表明血小板β3整合素在转移中发挥作用。鉴于上述事实，我们假设 1) β3-/- 小鼠中溶骨性转移的减少是由于 OC 和/或血小板功能减弱所致； 2)由于破骨细胞和血小板功能障碍，β3-/-小鼠中成骨细胞骨转移将减少。因此，我们的具体目标是：1）确定有缺陷的破骨细胞和有缺陷的血小板在抑制溶骨性骨转移中的作用。 2)确定有缺陷的破骨细胞和有缺陷的血小板在成骨细胞骨转移发展中的作用。通过向左心室（LV）和胫骨内（IT）注射溶骨细胞和成骨细胞系，在β3-/-小鼠、破骨细胞缺陷型src-/-小鼠和血小板缺陷型DiYF小鼠中建立骨转移。将通过 X 射线、体内肿瘤活性的 18-氟脱氧葡萄糖 (18-FDG) PET 扫描和组织形态计量学来监测骨转移。破骨细胞αvβ3抑制剂和αIIβ3血小板特异性抑制剂将用于溶骨性和成骨性LV和IT、骨转移测定。这些研究将确定宿主破骨细胞和血小板上的β3功能是否促进溶骨性和成骨细胞转移，以及OC和/或β3功能的治疗性抑制是否在预防或改善骨骼转移中发挥作用。这些发现将指导未来的研究，以确定β3整合素亚基在骨骼转移发展中的分子作用。