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

转化生长因子-1在骨转移中起核心作用，在骨转移过程中从骨组织中释放出高浓度的转化生长因子-1。 碎裂性骨吸收，在所有骨转移中都是活跃的过程。转化生长因子-S增强肿瘤因子，使其 增加溶骨性骨破坏。转化生长因子-β对成骨细胞和破骨细胞的作用及后续研究 对骨中肿瘤生长的贡献还没有得到很好的描述。我们假设，除了它的 对肿瘤细胞的影响，转化生长因子-1作用于成骨细胞，调节Wnt配体和BMP等因子 拮抗剂，对溶骨型和成骨细胞型肿瘤的生长有不同的影响。在……里面 此外，转化生长因子-β可激活破骨细胞，以增加所有类型的骨骼间质瘤的骨吸收。Dr。 Neil Bhowmick，范德比尔特大学肿瘤微环境网络(VUTMEN)，和Theresa Guise博士， 印第安纳大学将研究转化生长因子-β信号在成骨细胞和破骨细胞中的作用 微环境及其对骨转移的影响。PI‘s Will检验：假设1转化生长因子-B信号传导 成骨细胞调节骨中肿瘤的生长，其反应取决于肿瘤是否 主要是溶骨性或成骨性。目的1.确定成骨细胞对转化生长因子-β的反应在 所有类型骨转移瘤的建立和进展：成骨细胞靶向缺失小鼠 或激活转化生长因子-β信号转导&溶骨、成骨对骨转移的影响 或乳腺癌、前列腺癌和黑色素瘤的混合瘤将被研究。假设2：转化生长因子-β信号转导 破骨细胞增加骨吸收，有利于肿瘤在骨中生长，与骨类型无关 目的2.确定破骨细胞对转化生长因子-β的反应性在建立和 所有类型骨转移的进展。结合破骨细胞靶向缺失或激活转化生长因子-β 将产生信号，并将研究其对骨转移的影响，如目标1所示。假设3： 成骨细胞对转化生长因子-β的反应是通过分泌因子来改变肿瘤行为，这种反应依赖于统计数据。 骨瘦如柴。目的3.确定转化生长因子-(3)介导的旁分泌调节转移瘤生长的机制。 骨骼：将在小鼠模型和人类组织中研究STAT3对wntSa和Chordin的调节作用。 相关性(请参阅说明)： 我们研究的目标是改进治疗和预防骨转移。我们将会比较骨细胞 转化生长因子-B信号的特异性改变(宿主)与全身抑制转化生长因子-β(宿主和肿瘤)。这部小说 转化生长因子-β信号转导中骨细胞特异性改变的模型将为靶向转化生长因子-β提供独特的见解 治疗骨转移，补充转化生长因子-β对VUTMEN肿瘤微环境的影响。

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.