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: 8212212
• 负责人: Katherine Nelson Weilbaecher
• 金额: $ 36.04万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212212
• 关键词: Adverse effects; Affect; Blood Platelets; Bone Growth; Bone Resorption; Bone neoplasms; CD47 gene; Cells; Drug Delivery Systems; Endothelium; Environment; Genes; Goals; Growth; Hemorrhage; Homing; Individual; Integrin Inhibition; Integrin beta3; Integrins; Intervention; Knock-out; Knockout Mice; Lead; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Modeling; Molecular Target; Mus; Myelogenous; Myeloid Cells; Neoadjuvant Therapy; Neoplasm Metastasis; Osteoclasts; Osteolysis; Pathway interactions; Patients; Platelet aggregation; Play; Proteins; Role; Site; Specificity; Tissues; Transgenic Mice; Tumor Cell Invasion; United States; angiogenesis; bone; bone loss; cell type; design; inhibitor/antagonist; macrophage; neoplastic cell; new therapeutic target; novel; prevent; public health relevance; receptor; therapeutic target; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): Bone metastases affect 350,000 people per year in the United States alone. We found that the integrin ¿3 global knockout mouse was protected from tumor-associated bone loss and bone metastasis, a finding consistent with the model that tumor cells highjack the ¿3 integrin pathways in platelets and osteoclasts, which express express aIIb¿3 and av¿3, respectively. Both platelets and osteoclasts are host cells that are critical for the growth and survival of tumor cells in the bone environment. A problem with targeting ¿3 for bone metastasis is that deletion of the ¿3 integrin subunit in all tissues can enhance tumor-associated angiogenesis, most likely as a result of ¿3 integrin present on the endothelium and on activated macrophages in the tumor environment. Therefore, pharmacologic inhibition of av¿3 may have adverse procancer effects and inhibition of aIIb¿3 causes bleeding. To obviate these issues of the germline ¿3 knockout we generated mice with a ¿3 integrin gene flanked by loxP sites and deleted the gene in platelets and myeloid (macrophage and osteoclast) lineages using tissue-targeted Cre transgenic mice. As alternative approaches to modulating ¿3 integrin function in platelets and osteoclasts, we will investigate the roles of the ¿3 integrin activating receptor, P2Y12, and a ¿3-integrin stimulating protein, CD47, on platelet and osteoclast function and during bone metastasis. In order to avoid the negative effects of global ¿3 integrin inhibition and to identify novel therapeutic targets, we will study these ¿3 integrin stimulatory pathways that may confer cell type specificity and reduce side effects. Our central hypothesis is that blockade of ¿3 integrin stimulatory pathways in platelets and myeloid cells will disrupt tumor growth in bone and tumor-driven osteolysis. Thus, our Specific Aims are to: 1. Define the role of ¿3 integrins on platelets and myeloid cells during metastasis to bone and tumor growth in the bone micro-environment. 2. Evaluate the role of the upstream activator of ¿3 integrin P2Y12 on platelets and myeloid cells during skeletal metastasis and tumor osteolysis. 3. Evaluate the role of CD47, a ¿3 integrin stimulatory protein, as a therapeutic target to abrogate bone metastasis and tumor osteolysis. Intervention strategies to be used in relatively healthy patients with cancer must have side effects that are clinically minimal. Thus the over-arching goal of this project is to design novel neoadjuvant treatment strategies to prevent bone metastasis through targeting ¿3 integrin pathways active on platelets and osteoclasts. These studies will lead to identification of optimal drug targets within the ¿3 integrin pathway with minimal side effects that overcome the problem of generalized ¿3 integrin inhibition, while preventing or decreasing bone metastasis. PUBLIC HEALTH RELEVANCE: ¿3 integrins (av¿3 and aIIb¿3) play critical roles in tumor invasion and metastasis by mediating bone resorption, platelet aggregation, and neo-angiogenesis. The over-arching goal of this project is to design novel treatment strategies to prevent bone metastasis through targeting ¿3 integrin pathways active on platelets and osteoclasts. Mice harboring tissue-specific deletions of integrin ¿3, and inhibitors of integrin modulating molecules, CD47 and P2Y12, will be used to assess the individual roles of ¿3 integrins in tumor cell homing to and growth in bone and may uncover novel molecular targets to more effectively treat skeletal metastasis. These studies will lead to identification of optimal drug targets within the ¿3 integrin pathway with minimal side effects that overcome the problem of generalized ¿3 integrin inhibition, while preventing or decreasing establishment of bone metastasis.

描述（由申请人提供）：仅在美国，骨转移每年就影响35万人。我们发现整合素¿3全球敲除小鼠免受肿瘤相关骨丢失和骨转移的影响，这一发现与肿瘤细胞劫持血小板和破骨细胞中表达aIIb¿3和av¿3的整合素通路的模型一致。血小板和破骨细胞都是宿主细胞，对肿瘤细胞在骨环境中的生长和存活至关重要。靶向- 3骨转移的一个问题是，在所有组织中缺失- 3整合素亚基可以增强肿瘤相关的血管生成，这很可能是由于- 3整合素存在于肿瘤环境中的内皮和活化的巨噬细胞上。因此，药物抑制av¿3可能有不良的促癌作用，抑制aIIb¿3会导致出血。为了消除这些生殖系¿3基因敲除的问题，我们用组织靶向的Cre转基因小鼠在血小板和髓系（巨噬细胞和破骨细胞）中删除了带有loxP位点的¿3整合素基因的小鼠。作为调节血小板和破骨细胞中- 3整合素功能的替代方法，我们将研究- 3整合素激活受体P2Y12和- 3整合素刺激蛋白CD47在血小板和破骨细胞功能以及骨转移过程中的作用。为了避免全球¿3整合素抑制的负面影响并确定新的治疗靶点，我们将研究这些可能赋予细胞类型特异性并减少副作用的¿3整合素刺激途径。我们的中心假设是，阻断血小板和髓细胞中的整合素刺激通路将破坏骨中的肿瘤生长和肿瘤驱动的骨溶解。因此，我们的具体目标是：1。明确整合素在骨转移和骨微环境中肿瘤生长过程中对血小板和骨髓细胞的作用。2. 评估在骨骼转移和肿瘤骨溶解过程中，上游激活物- 3整合素P2Y12对血小板和髓细胞的作用。3. 评价CD47（一种3整合素刺激蛋白）作为抑制骨转移和肿瘤骨溶解的治疗靶点的作用。用于相对健康的癌症患者的干预策略必须具有临床最小的副作用。因此，本项目的首要目标是设计新的辅助治疗策略，通过靶向血小板和破骨细胞上活性的整合素通路来预防骨转移。这些研究将导致在¿3整合素途径内确定最佳药物靶点，以最小的副作用克服普遍的¿3整合素抑制问题，同时防止或减少骨转移。