Erythropoietin receptor-driven tumor initiation and progression

项目摘要/摘要 最大的努力是了解环境致癌物和促癌剂如何增加癌症风险 专注于它们对直接暴露的细胞的影响，并确定了局部操作机制 外露组织的内源性。在拟议的研究中，我们将验证促红细胞生成素的假设 促红细胞生成素(EPO)和EPO受体(EPOR)介导对致癌物和促癌剂的生理反应 内分泌样机制，并有助于肿瘤的发生和发展。我们研究的目标是 了解致癌和促癌环境因子如何诱导EPO和EPOR的表达， EPOR在癌前细胞和已建立的肿瘤中的表达是否在肿瘤中起重要作用 非红系EPOR的形成和转移进展及其分子信号调控 促红细胞生成素在肿瘤发生过程中的靶细胞。为了达到这一目标，我们将追求以下具体目标： 确定表皮EPOR在皮肤癌发生中的作用(目标1)；确定黑色素瘤的作用- EPOR在肿瘤生长和转移中的表达(目的2)；探讨EPOR诱导肿瘤生长和转移的机制。 肿瘤前体和已建立的肿瘤(目标3)。从我们的研究中获得的信息不仅将推动 我们对皮肤癌病因如何增加成瘤率和恶化率的认识 但也揭示了内源性产生的EPO和非红系EPOR在 癌症的发展。我们希望我们的发现最终将有助于设计出治疗癌症的新策略。 预防和管理。

PROJECT SUMMARY/ABSTRACT Most efforts to understand how environmental carcinogens and tumor-promoting agents increase cancer risk have focused on their effects on directly exposed cells and have identified locally operating mechanisms endogenous to the exposed tissue. In the proposed study, we will verify the hypothesis that erythropoietin (EPO) and EPO receptor (EPOR) mediate physiological responses to carcinogens and tumor promoters via endocrine-like mechanisms and contribute to tumor initiation and progression. The goal of our study is to understand how carcinogenic and tumor-promoting environmental agents induce EPO and EPOR expression, whether EPOR expressed in preneoplastic cells and established tumors plays an important role in tumor formation and metastatic progression, and what molecular signals govern EPOR expression in non-erythroid EPO target cells during tumorigenesis. To achieve this goal, we will pursue the following specific aims: To determine the role of epidermal EPOR in skin carcinogenesis (Aim #1); To determine the role of melanoma- expressed EPOR in tumor growth and metastasis (Aim #2); To identify the mechanisms of EPOR induction in tumor precursors and established tumors (Aim #3). Information obtained from our study will not only advance our understanding of how etiologic agents of skin cancer increase the rate of tumor formation and malignant conversion but also shed new light on the role of endogenously produced EPO and non-erythroid EPOR in cancer development. We expect that our findings will ultimately help devise new strategies for cancer prevention and management.