Integrated EGFR function in cytokine-driven inflammation and cancer

EGFR 在细胞因子驱动的炎症和癌症中的整合功能

• 批准号: 9072831
• 负责人: GEORGE ROBERT STARK
• 金额: $ 180.55万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072831
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Award; Cell Differentiation process; Cell Proliferation; Cells; Chronic; Complex; Couples; Cytokine Receptors; Development; EGF gene; Epidermal Growth Factor Receptor; Epithelial Cells; Erlotinib; Health; IL17 gene; IL6 gene; IL6ST gene; Individual; Inflammation; Inflammatory; Injury; Interleukin 6 Receptor; Interleukin-17; Interleukin-6; Ligands; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Myelogenous; Myeloid Cells; Outcome; Pathway interactions; Pattern recognition receptor; Performance; Population; Receptor Signaling; Role; Route; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Protein; Staging; Stromal Cells; System; TLR3 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Trastuzumab; base; carcinogenesis; cell behavior; cell type; cytokine; design; mouse model; neoplastic cell; novel; programs; receptor; receptor coupling; receptor function; regenerative; response; targeted treatment; therapy outcome; tumor; tumor microenvironment; tumor progression; tumorigenesis; Address; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Award; Cell Differentiation process; Cell Proliferation; Cells; Chronic; Complex; Couples; Cytokine Receptors; Development; EGF gene; Epidermal Growth Factor Receptor; Epithelial Cells; Erlotinib; Health; IL17 gene; IL6 gene; IL6ST gene; Individual; Inflammation; Inflammatory; Injury; Interleukin 6 Receptor; Interleukin-17; Interleukin-6; Ligands; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Myelogenous; Myeloid Cells; Outcome; Pathway interactions; Pattern recognition receptor; Performance; Population; Receptor Signaling; Role; Route; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Protein; Staging; Stromal Cells; System; TLR3 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Trastuzumab; base; carcinogenesis; cell behavior; cell type; cytokine; design; mouse model; neoplastic cell; novel; programs; receptor; receptor coupling; receptor function; regenerative; response; targeted treatment; therapy outcome; tumor; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The mechanisms through which chronic injury and inflammation contribute to cancer are diverse and include effects on proliferation and differentiation of tumor cells themselves and on the stromal cell activities upon which tumor survival and spread depend. The proposed Program emphasizes two major themes that are common to all 3 projects and the scientific core. The first will address the molecular controls of cytokine and pattern recognition (PR) receptor mediated inflammatory function in the context of a newly discovered requirement for Epidermal Growth Factor Receptor (EGFR). This concept will have significant impact in mechanistic studies of cytokine and PR receptor signaling as well as in development and implementation of therapeutic strategy. EGFR function is required for signaling through multiple PR receptors (e.g., TLRs 3 and 9 and STING), gp130 linked receptors (IL6, OSM), and IL17 receptors, but that this linkage occurs in each case via novel, EGF ligand-independent mechanisms. The role of EGFR in multiple cancers is well established and it is the target for many therapeutics (e.g., trastuzumab, erlotinib, geftinib etc). Hence the consideration of how EGFR participates in inflammatory signaling in tumor cells, in myeloid and in other tumor stromal cell populations is likely to have substantial impact on the design and outcomes of therapies that target EGFR. The second theme will consider the distinct ways in which cytokine and PR receptors operate in different cell populations to link inflammatory activity with promotion of tumorigenesis. In the proposed Program, Project 1 (Sen) will focus on cytokine expression associated with EGFR-coupled signaling through TLR3, TLR9 and STING in myeloid cells while Project 2 will consider how EGFR signaling couples with cytokines utilizing GP130 (e.g., IL6, OSM) to modulate tumor cell behaviors that are STAT3 dependent. In Project 3 Dr. Li will consider how IL17 may use both EGFR-dependent and EGFR-independent signaling pathways in different cell populations (epidermal and stromal) to impact on different aspects of inflammation-associated tumor development and progression. Collectively these projects will test the following overarching hypothesis: that EGFR is a common mechanistic feature of signaling through a specific subset of cytokine and PR receptors that serves to regulate the magnitude and duration of diverse responses within the selection of cell populations that contribute in temporally and functionally distinct fashion to the multiple stages of carcinogenesis and tumor progression. The three projects outline experimental strategies to test this hypothesis through performance of the following common specific aims: 1. Define the molecular mechanisms involved in EGFR-dependent signaling from PRRs (TLR3/9 AND STING), GP130-linked cytokine receptors (IL6, OSM), and IL17R to control the magnitude and character of downstream responses that link with different mechanistic aspects of tumor progression. Emphasis will be on the basis for EGFR/cytokine/TLR interactions and the consequences of such interaction on distinct signals emanating from both EGFR and the cytokine/PR receptor. 2. Assess the distinct cell type specific contributions of EGFR/cytokine-PR receptor pathways using multiple models of inflammation-linked cancer development and progression.

描述（应用程序提供）：慢性损伤和感染导致癌症的机制是多种多样的，包括对肿瘤细胞本身的增殖和分化以及肿瘤存活和扩散取决于的基质细胞活性的影响。拟议的计划强调了所有3个项目和科学核心共有的两个主要主题。第一个将解决细胞因子和模式识别（PR）受体介导的炎症功能的分子控制，在新发现的表皮生长因子受体（EGFR）的要求下。该概念将在细胞因子和PR受体信号的机械研究以及热策略的开发和实施中产生重大影响。 EGFR功能是通过多种PR受体（例如TLRS 3和9和STING），GP130链接受体（IL6，OSM）和IL17接收器信号传导所必需的，但是这种链接在每种情况下都通过新颖的EGF GF GIF GINDINGID-INDEPDICTIPD机制出现。 EGFR在多种癌症中的作用已经建立得很好，它是许多疗法的靶标（例如曲妥珠单抗，erlotinib，geftinib等）。因此，考虑了EGFR如何参与肿瘤细胞，髓样和其他肿瘤基质细胞种群中的炎症信号传导可能对靶向EGFR的疗法的设计和结果产生重大影响。第二个主题将考虑细胞因子和PR受体在不同细胞群中起作用的不同方式，以将炎症活性与促进肿瘤发生联系起来。在拟议的计划中，项目1（SEN）将重点介绍与EGFR偶联信号通过TLR3，TLR9和髓样细胞中的eGFR耦合信号相关的，而项目2将考虑如何利用GP130的EGFR信号伴侣使用GP130（例如，IL6，OSM）的细胞因子来调节Tumor Cell Cell cell Behapi cell cant cant cant cant cant cant cant cant catt catt catt catt catt catt catt catt catt 3 rection3。在项目3中，LI博士将考虑IL17如何在不同细胞群体（表皮和基质）中使用EGFR依赖性和EGFR独立的信号通路来影响炎症相关肿瘤的发展和进展的不同方面。总的来说，这些项目将测试以下总体假设：EGFR是通过特定的细胞因子和PR受体子集发出信号的常见机械特征，这些特征是在选择细胞群体中的潜水员响应的大小和持续时间，这些细胞群体的大小和持续时间在临时和功能上与癌变和thumor进展的多个阶段相关的方式有效。三个项目概述通过以下共同特定目的的性能进行测试的三个项目策略：1。定义来自PRR（TLR3/9和STING）的EGFR依赖性信号传导所涉及的分子机制，GP130连接的细胞因子受体（IL6，OSM）以及IL17R控制着位式的机制和特征，该方面响应了下降的机制，以下方面响应了下降的范围。 EGFR/细胞因子/TLR相互作用以及这种相互作用对来自EGFR和细胞因子/PR受体发出的不同信号的后果的重点。 2。使用多种炎症连锁癌症的发育和进展的多种模型来评估EGFR/Cytokine-PR受体途径的不同细胞类型特异性贡献。