Chemokine Receptor Modulation of the Tumor Microenvironment

描述(由申请人提供)：趋化因子/细胞因子/生长因子的特定亚组上调通常与浸润性乳腺癌妇女较差的预后有关。趋化因子/细胞因子/生长因子在白细胞向肿瘤微环境的募集和为促进侵袭和转移的“转移前生态位”的准备中起着重要的作用。这项研究的基本原理是确定哪些受体参与将肿瘤微环境(TME)从非侵袭性环境转变为侵袭性微环境，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，以防止或逆转这一过程。通过对抗癌细胞(CACs)、癌相关成纤维细胞(CAF)或癌相关白细胞(CAL)在侵袭关键点产生的趋化因子/细胞因子，我们将确定参与推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亚群的激活，TME可以从促肿瘤/亲侵袭转变为抗肿瘤/抗侵袭。有两个特定的目的：1)确定CAF和CAL亚群在乳腺肿瘤向侵袭性表型转变过程中对早期进展的贡献，并确定参与这一过程的特异性细胞因子/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而不是仅靶向白细胞中的趋化因子受体对乳腺癌细胞体内侵袭的影响。 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，以介导导管原位癌(DCIS)向浸润性导管癌(IDC)的进展。这项提议的结果将揭示趋化因子/细胞因子/生长因子受体参与浸润性癌的进展，以及最有效地靶向这些受体以减缓向IDC进展的时间点。

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.