Erythropoietin receptor-driven tumor initiation and progression

描述(申请人提供)：了解环境致癌物和促癌剂如何增加癌症风险的大多数努力都集中在它们对直接暴露的细胞的影响上，并确定了暴露组织内源性的局部作用机制。在拟议的研究中，我们将验证促红细胞生成素(EPO)和EPO受体(EPOR)通过内分泌样机制介导对致癌物和肿瘤促进剂的生理反应，并促进肿瘤的发生和发展的假说。我们研究的目的是了解致癌和促癌环境因素如何诱导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的形成和转移中发挥重要作用，以及在肿瘤发生过程中，哪些分子信号控制非红系EPO靶细胞中EPOR的表达。为了实现这一目标，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)；确定黑色素瘤表达的EPOR在肿瘤生长和转移中的作用(目标2)；确定EPOR在肿瘤前体和已建立的肿瘤中诱导的机制(目标3)。从我们的研究中获得的信息不仅将促进我们对皮肤癌的病因如何增加肿瘤形成和恶变率的理解，还将为内源性产生的EPO和非红系EPOR在癌症发展中的作用提供新的线索。我们预计，我们的发现最终将有助于设计新的癌症预防和管理策略。

DESCRIPTION (provided by applicant): 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.