Erythropoietin receptor-driven tumor initiation and progression

促红细胞生成素受体驱动的肿瘤发生和进展

基本信息

批准号：
8975178
负责人：
Jin Mo Park
金额：
$ 34.65万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8975178
关键词：
Acetates Anemia Blood Circulation Body Surface Cancer Etiology Carcinogens Cell Lineage Cell Proliferation Cell physiology Cells Chemicals Clinical Cutaneous Melanoma Development Distant Endocrine Environmental Carcinogens Environmental Risk Factor Epidermis Epithelial Cells Erythroid Erythropoiesis Erythropoietin Erythropoietin Receptor Event Evolution Exposure to Gene Expression Goals Growth Health Hematopoietic Human Immigration Immune Immune response Immunosuppression Inflammation Injury Kidney Knockout Mice Light Link Location Lymphoid Tissue Malignant - descriptor Malignant Conversion Malignant Neoplasms Mediating Mediator of activation protein Melanoma Cell Modeling Molecular Mus Neoplasm Metastasis Oncogenes Penetration Phenotype Physiological Play Prevention Prostaglandins Receptor Signaling Recombinant Erythropoietin Risk Role Signal Transduction Skin Skin Aging Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Spleen Stimulus Subfamily lentivirinae Sunlight Tissues Tumor Promoters Ultraviolet B Radiation Xenograft procedure cancer prevention cancer risk clinical effect environmental agent keratinocyte knock-down loss of function melanoma neutralizing antibody premature prevent progenitor radiation effect receptor receptor expression response tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

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.

描述（由申请人提供）：了解环境致癌物和肿瘤促进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，并已确定了暴露组织内源性的局部操作机制。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有助于肿瘤的发生和进展的假设。我们研究的目的是了解致癌和促肿瘤环境因素如何诱导 EPO 和 EPOR 表达，在肿瘤前细胞和已形成的肿瘤中表达的 EPOR 是否在肿瘤形成和转移进展中发挥重要作用，以及哪些分子信号控制肿瘤中的 EPOR 表达。肿瘤发生过程中的非红细胞 EPO 靶细胞。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）；确定肿瘤前体和已形成肿瘤中 EPOR 诱导的机制（目标#3）。从我们的研究中获得的信息不仅将增进我们对皮肤癌病因如何增加肿瘤形成和恶性转化率的理解，而且还为内源性产生的 EPO 和非红细胞 EPOR 在癌症发展中的作用提供了新的线索。我们期望我们的发现最终将有助于制定癌症预防和管理的新策略。