Chemokine Receptor Modulation of the Tumor Microenvironment

肿瘤微环境的趋化因子受体调节

• 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
• 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

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/生长因子特定子集的上调通常与患有浸润性乳腺癌的女性的较差预后有关。趋化因子/细胞因子/生长因子对于将白细胞募集到肿瘤微环境以及准备促进侵袭和转移的“转移前生态位”非常重要。拟议研究的基本原理是确定哪些受体参与将肿瘤微环境（TME）从非侵入性转变为侵入性，并确定我们是否可以在肿瘤进展的特定时间点拮抗这些受体信号以阻止或逆转这一过程。通过在侵袭的关键点拮抗癌细胞（CaC）、癌症相关成纤维细胞（CAF）或癌症相关白细胞（CAL）产生的趋化因子/细胞因子，我们将确定参与驱动炎症和癌症侵袭的“细胞因子风暴”的趋化因子/趋化因子受体相互作用。我们假设，通过调节趋化因子受体子集的激活，TME 可以从促肿瘤发生/促侵袭转变为抗肿瘤发生/抗侵袭。有两个具体目标：1) 确定 CAF 和 CAL 亚群在转变为侵袭性表型期间对早期乳腺肿瘤进展的贡献，并确定参与此过程的特定细胞因子/趋化因子受体。 2) 确定靶向所有细胞中的特定趋化因子受体与单独靶向白细胞中的特定趋化因子受体如何影响体内乳腺癌细胞的侵袭。 公共健康相关性：我们将定义肿瘤微环境 (TME) 的细胞因子/趋化因子成分，它们与炎症细胞相互作用，介导导管原位癌 (DCIS) 进展为浸润性导管癌 (IDC)。该提案的结果将揭示参与侵袭性癌进展的趋化因子/细胞因子/生长因子受体，以及最有效地靶向这些受体以减缓 IDC 进展的时间点。