Role of Adenosine in TGF-beta Effects in Cancers

TGFβ和腺苷是肿瘤微环境中普遍存在的分子，它们参与了肿瘤微环境的调节。 调节肿瘤进展和转移的各个阶段。我们最近的研究表明 TGFβ信号传导在CD39+CD73+终末分化的 单核骨髓细胞（TDMMC）在肿瘤进展过程中。我们发现肿瘤中的TDMCC 组织通过由TGFβ调节CD39和CD73的独特共表达产生高水平的腺苷。 腺苷是炎症、血管生成和免疫细胞功能的关键调节剂。我们的新数据显示 TDMMC以旁分泌方式产生的腺苷降低成纤维细胞对TGFβ的反应。损失 肿瘤组织中成纤维细胞上的TGFβ信号转导与肿瘤转移的增加和 癌症患者。我们推测，CD39+CD73+髓系细胞负调节TGFβ的作用， 肿瘤相关的成纤维细胞通过激活A2腺苷受体，促进它们成为具有促转移活性的细胞， 和促肿瘤发生特性。我们建议在具体目标1中检验这一假设， 检测TDMMC上CD39和CD73表达在调节成纤维细胞中的功能意义 在体外发挥作用。在具体目标2中，我们将确定 腺苷信号传导和TGFβ信号传导对癌症相关成纤维细胞的影响。在第三个目标中，我们将 确定成纤维细胞上腺苷受体在肿瘤进展、微环境 变化和转移。我们预计，拟议研究的结果将为以下方面提供新的见解： 腺苷对TGFβ信号传导的影响的机制的深度和复杂性， 肿瘤进展。我们的研究结果将有助于开发新的治疗策略，以减少肿瘤 进展和转移。

TGFβ and adenosine are ubiquitous molecules in the tumor microenvironment that participate in the regulation of various stages of tumor progression and metastasis. Our recent studies have demonstrated an essential role for TGFβ signaling in the differentiation of CD39+CD73+ terminally-differentiated mononuclear myeloid cells (TDMMC) during tumor progression. We discovered that TDMCCs in tumor tissue generate high levels of adenosine via unique co-expression of CD39 and CD73 regulated by TGFβ. Adenosine is a key regulator of inflammation, angiogenesis and immune cell function. Our novel data show that adenosine generated by TDMMC in a paracrine manner decreases fibroblast responses to TGFβ. Loss of TGFβ signaling on fibroblasts in tumor tissue correlates with increase metastasis and poor survival of cancer patients. We hypothesize that that CD39+CD73+ myeloid cells negatively regulate TGFβ effects on tumor-associated fibroblasts promoting them, via activation of A2 adenosine receptors, to cells with pro-metastatic and pro-tumorigenic properties. We propose to test this hypothesis in Specific Aim 1 by examining the functional significance of CD39 and CD73 expression on TDMMC in regulation fibroblasts functions in vitro. In Specific Aim 2, we will determine the molecular mechanisms of interactions between adenosine signaling and TGFβ signaling on cancer-associated fibroblasts. Finally, in Specific Aim 3, we will determine the role of adenosine receptors on fibroblasts in tumor progression, microenvironmental changes and metastasis. We anticipate that findings from the proposed studies will provide new insight into the depth and complexity of mechanisms that mediate the effects of adenosine on TGFβ signaling during tumor progression. Our findings will aid in developing novel therapeutic strategies to decrease tumor progression and metastases.