Differential TGF-Beta Signaling in Bone Microenviroment: Impact on Tumor Growth

TGF-β 1在骨中起着核心作用，在骨形成过程中，TGF-β metastases.lt以高浓度从骨中释放， 在所有骨转移瘤中，碎屑性骨吸收是一个活跃的过程。TGF-S增强肿瘤因子， 增加溶骨性骨破坏。TGF-B对成骨细胞和破骨细胞的作用及其后果 对骨中肿瘤生长的贡献的特征不太清楚。我们假设，除了它的 在对肿瘤细胞的作用中，TGF-β 1作用于成骨细胞以调节因子，如Wnt配体和BMP 拮抗剂，其对溶骨性与成骨性肿瘤类型的生长具有不同的作用。在 此外，TGF-β激活破骨细胞以增加所有类型的骨转移中的骨吸收。博士 Neil Bhowmick，范德比尔特大学肿瘤微环境网络（VUTMEN）和Theresa Guise博士， 印第安纳州大学，将研究TGF-β信号在骨中成骨细胞和破骨细胞中的作用 微环境和对骨转移的影响。Pi's将测试：假设1 TGF-B信号转导在 成骨细胞调节骨中的肿瘤生长，这种反应取决于肿瘤是否被 目的：1.确定成骨细胞对TGF-β的反应性在成骨细胞中的作用， 所有类型骨转移瘤的建立和进展：成骨细胞靶向缺失的小鼠 或激活TGF-β信号传导，即溶骨细胞、成骨细胞对骨转移的影响。 或乳腺、前列腺和黑色素瘤的混合瘤。假设2：TGF-B信号转导在 破骨细胞增加骨吸收，促进骨中肿瘤生长，与骨类型无关 目的2.确定骨细胞对TGF-β的反应性在骨转移中的作用， 破骨细胞靶向缺失或活化TGF-β的小鼠 将产生信号传导，并将如目的1所述研究对骨转移的影响。假设三： 成骨细胞以StatS依赖的方式通过分泌因子对TGF-β作出反应，以改变肿瘤行为 在骨头里。目标3. TGF-β介导的旁分泌调节转移性肿瘤生长的机制 骨：将在小鼠模型和人体组织中研究Stat 3对wntSa和脊索蛋白的调节作用。 相关性（参见说明）： 我们研究的目的是改善治疗和预防骨转移。我们将骨细胞 TGF-β信号传导（宿主）的特异性改变，伴随TGF-β的系统性抑制（宿主和肿瘤）。小说 TGF-β信号传导中骨细胞特异性改变的模型将为靶向TGF-β提供独特的见解， 治疗骨转移，并补充VUTMEN肿瘤微环境中TGF-B的作用。

TGF-li plays a central role in bone metastases.lt is released in high concerntrations from bone during osteo- clastic bone resorption, a process that is active in all bone metastases.TGF-S enhances tumor factors that increase osteolytic bone destruction.The actions of TGF-B on osteoblasts & osteoclasts & consequent contributions to tumor growth in bone are less well characterized. We hypothesize that, in addition to its effects on tumor cells, TGF-li acts on osteoblasts to regulate factors, such as Wnt ligands and BMP antagonists, which have differing effects on the growth of osteolytic vs osteoblastic tumor types. In addition,TGF-B activates osteoclasts to increase bone resorption in all types of skeletal mestastases. Dr. Neil Bhowmick, Vanderbilt University Tumor Microenvironment Network (VUTMEN), & Dr. Theresa Guise, Indiana University, will study the role of TGF-B signaling in osteoblasts & osteoclasts in the bone microenvironment and the effect on bone metastases. The Pi's will test:Hypothesis 1 TGF-B signaling in osteoblasts regulates tumor growth in bone, & the responses are dependent on whether the tumor is predominantly osteolytic or osteoblastic.Aim 1.Determine the role of osteoblastic responsiveness to TGF-B in the establishment and progression of bone metastases of all types: Mice with osteoblasts-targeted deletion or activation of TGF-B signaling will be generated & the effect on bone metastases by osteolytic, osteoblastic or mixed tumors of breast, prostate, & melanoma will be studied. Hypothesis 2:TGF-B signaling in osteoclasts increases bone resorption, favoring tumor growth in bone, independent ofthe type of bone metastasis.Aim 2.Determine the role of osteoclastic responsiveness to TGF-B in the establishment and progression of all types of bone metastases.Mice with osteoclast targeted deletion or activation of TGF-B signaling will be generated & the effect on bone metastases will be studied as in Aim 1. Hypothesis 3: Osteoblasts respond to TGF-B via secretion of factors, in a StatS-dependent manner, to alter tumor behavior in bone. Aim 3. Identify mechanisms of TGF-(3-mediated paracrine regulation of metastatic tumor growth in bone: the role of Stat3 regulation of wntSa and chordin will be studied in mouse models and human tissue. RELEVANCE (See instructions): The goal of our research is to improve treatment and prevent bone metastases. We will compare bone cell specific alterations in TGF-B signaling (host) with systemic inhibition of TGF-B (host & tumor). The novel models of bone cell-specific alterations in TGF-B signaling will give unique insight to target TGF-B to treatbone metastases and will complement sudles on TGF-B on the tumor microenvironment at VUTMEN.