Chemokine Receptor Modulation of the Tumor Microenvironment

肿瘤微环境的趋化因子受体调节

基本信息

批准号：
8398852
负责人：
Oriana E. Hawkins
金额：
$ 4.58万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-11-16 至 2014-10-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8398852
关键词：
Affect Age Antibodies Bone Marrow Transplantation Breast Carcinoma C57BL/6 Mouse Cancer Patient Carcinoma Cell Line Cells Coculture Techniques Cytokine Receptors Enzyme-Linked Immunosorbent Assay Fibroblasts Flow Cytometry Genes Growth Factor Growth Factor Receptors Human Implant Inbred BALB C Mice Inflammation Inflammatory Knock-out Lesion Leukocytes Link Malignant Epithelial Cell Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Marrow Matrigel Invasion Assay Mediating Molecular Profiling Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma PTPRC gene Partner in relationship Patients Pattern Phenotype Polyomavirus Population Preparation Process Production Property Receptor Signaling Role Staging Time Transplantation Up-Regulation Woman cancer cell chemokine chemokine receptor cytokine in vivo infiltrating duct carcinoma malignant breast neoplasm neoplastic cell outcome forecast peripheral blood prevent receptor receptor expression small hairpin RNA tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The up-regulation of specific subsets of chemokines/cytokine/ growth factors is often linked to poorer prognosis for women with invasive mammary carcinoma. Chemokines/cytokines/growth factors are important in the recruitment of leukocytes to the tumor microenvironment and for preparation of the "pre-metastatic niche" which facilitates invasion and metastasis. The rationale for the proposed studies is to determine which receptors are involved in shifting the tumor microenvironment (TME) from one that is non-invasive to one that is invasive, and to determine if we can antagonize those receptor signals at specific time points in tumor progression to prevent or reverse this process. By antagonizing production of chemokines/cytokines by cancer cells (CaCs), cancer associated fibroblasts (CAFs) or cancer associated leukocytes (CALs) at key points in invasion, we will determine the chemokine/chemokine receptor interactions that participate in the "cytokine storm" that drives inflammation and cancer invasion. We hypothesize that by modulating activation of subsets of chemokine receptors, the TME can be shifted from pro-tumorigenic/pro-invasion to one that is anti-tumorigenic/anti-invasion. There are two specific aims: 1) To determine the contribution made by CAFs and subpopulations of CALs on early mammary tumor progression during the switch to an invasive phenotype and to determine the specific cytokines/chemokine receptors involved in this process. 2) To determine how targeting specific chemokine receptors in all cells versus in leukocytes alone affects invasion of mammary cancer cells in vivo. PUBLIC HEALTH RELEVANCE: We will define the cytokine/chemokine components of the tumor microenvironment (TME) that interact with the inflammatory cells to mediate progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Results from this proposal will reveal chemokine/cytokine/growth factor receptors involved in progression to invasive carcinoma and time points to most effectively target those receptors to mitigate progression to IDC.

描述（由申请人提供）：趋化因子/细胞因子/生长因子的特定子集的上调通常与侵入性乳腺癌女性的预后较差有关。趋化因子/细胞因子/生长因子在募集白细胞至肿瘤微环境中很重要，并为促进侵袭和转移的“前转移生态位”制备。拟议的研究的基本原理是确定哪些受体参与将肿瘤微环境（TME）转移到无创的肿瘤微环境（TME）转变为具有侵入性的受体，并确定我们是否可以在肿瘤进展的特定时间点对这些受体信号进行拮抗以防止或反向此过程。通过癌细胞（CAC）对趋化因子/细胞因子的产生，癌症相关的成纤维细胞（CAF）或癌症相关的白细胞（CAL）在入侵中的关键点，我们将确定参与“细胞因子风暴”的趋化因子/趋化因子受体相互作用，从而吸引炎症和癌症。我们假设通过调节趋化因子受体亚群的激活，可以将TME从促肿瘤/促侵袭转移到抗肿瘤/抗侵袭性的趋化性/促侵袭。有两个具体的目的：1）确定CAF的贡献以及CAL在切换到浸润性表型期间对早期乳腺肿瘤进展的亚群，并确定此过程中涉及的特定细胞因子/趋化因子受体。 2）确定仅白细胞中所有细胞中特定趋化因子受体的靶向如何影响体内乳腺癌细胞的侵袭。公共卫生相关性：我们将定义与炎症细胞相互作用的肿瘤微环境（TME）的细胞因子/趋化因子成分，以介导导管癌的原位（DCIS）向入侵性导管性癌（IDC）的进展。该提案的结果将揭示趋化因子/细胞因子/生长因子受体涉及的侵入性癌和时间点最有效地靶向这些受体以减轻向IDC的进展。