ROLE OF BETA 3 INTEGRIN IN SKELETAL METASTASIS

描述（由申请人提供）：仅在美国，每年就有350，000人患有骨转移。 我们发现整合素3全球敲除小鼠受到保护，免受肿瘤相关的骨丢失和骨转移，这一发现与肿瘤细胞劫持血小板和破骨细胞中整合素3途径的模型一致，血小板和破骨细胞分别表达aIIb 3和av 3。 血小板和破骨细胞都是对肿瘤细胞在骨环境中的生长和存活至关重要的宿主细胞。 目标定位的问题？3对于骨转移的作用是，所有组织中3整合素亚基的缺失可以增强肿瘤相关的血管生成，这很可能是由于肿瘤环境中内皮细胞和活化巨噬细胞上存在3整合素的结果。 因此，av <$3的药理学抑制可能具有不利的促癌作用，而aIIb <$3的抑制导致出血。 为了解决生殖系3基因敲除的这些问题，我们产生了侧接loxP位点的3整合素基因的小鼠，并使用组织靶向Cre转基因小鼠在血小板和骨髓（巨噬细胞和破骨细胞）谱系中删除了该基因。 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P2 Y12和<$3整合素刺激蛋白CD 47对血小板和破骨细胞功能以及骨转移过程中的作用。 为了避免整体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3整合素刺激途径，可能会赋予细胞类型特异性和减少副作用。 我们的中心假设是，阻断血小板和骨髓细胞中的整合素刺激途径将破坏骨中的肿瘤生长和肿瘤驱动的骨质溶解。 因此，我们的具体目标是：1。确定骨转移和骨微环境中肿瘤生长过程中血小板和骨髓细胞上的3整合素的作用。 2.评估骨转移和肿瘤骨质溶解过程中，3整合素P2 Y12上游激活物对血小板和骨髓细胞的作用。 3.评估CD 47（一种整合素刺激蛋白）作为治疗靶点在消除骨转移和肿瘤骨质溶解中的作用。 在相对健康的癌症患者中使用的干预策略必须具有临床上最小的副作用。 因此，该项目的首要目标是设计新的新辅助治疗策略，通过靶向血小板和破骨细胞上的3种整合素途径来预防骨转移。 这些研究将导致在β 3整联蛋白途径中鉴定最佳药物靶标，其具有最小的副作用，克服了广义β 3整联蛋白抑制的问题，同时预防或减少骨转移。 公共卫生相关性：¿ 3种整合素（av 3和所有b 3）通过介导骨吸收、血小板聚集和新血管生成在肿瘤侵袭和转移中起关键作用。 该项目的主要目标是设计新的治疗策略，通过靶向血小板和破骨细胞上的3种整合素途径来预防骨转移。 携带整合素3的组织特异性缺失以及整合素调节分子CD 47和P2 Y12的抑制剂的小鼠将用于评估整合素3在肿瘤细胞归巢和骨生长中的个体作用，并可能发现新的分子靶点以更有效地治疗骨转移。 这些研究将导致在β 3整联蛋白途径中鉴定最佳药物靶标，其具有最小的副作用，克服了广义β 3整联蛋白抑制的问题，同时预防或减少骨转移的建立。

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.