Tumor-stromal interactions as targets of tumor metastasis suppressors

肿瘤-基质相互作用作为肿瘤转移抑制因子的靶点

• 批准号: 9223680
• 负责人: MARSHA R ROSNER
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-19 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223680
• 关键词: Binding; CCR5 gene; Cancer Patient; Cancer cell line; Cells; Cessation of life; Clinical; Data; ERBB2 gene; Employee Strikes; Epidermal Growth Factor Receptor; FDA approved; Gene Expression; Genetic; Genetically Engineered Mouse; Goals; Human; Infiltration; Knockout Mice; Lead; Ligands; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Metastasis Suppression; Methodology; Molecular; Molecular Mechanisms of Action; Nature; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Proteins; Proteomics; RANTES; Recruitment Activity; Relapse; Risk Factors; Role; Signal Pathway; Signal Transduction; Stromal Neoplasm; Testing; Therapeutic; Transgenic Mice; Woman; Xenograft Model; base; cancer cell; chemokine; combinatorial; effective therapy; genetic signature; humanized mouse; inhibitor/antagonist; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; overexpression; prognostic; prognostic of survival; public health relevance; raf Kinases; receptor; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Women with triple-negative breast cancer (TNBC) have the shortest survival and highest relapse rates; however, there are no known targeted therapies. Metastasis, the cause of most cancer-related deaths, is dependent upon specific molecular interactions between tumor cells and their microenvironment. We recently conducted a study to characterize these tumor-stromal interactions in a TNBC xenograft model. To identify drivers of metastasis, we compared gene expression in an invasive tumor, and a genetically matched noninvasive tumor that stably expressed the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP). Our studies revealed a striking loss of macrophage infiltration in noninvasive (RKIP+) tumors when compared to invasive tumors. Preliminary results suggest that RKIP inhibits expression of the macrophage chemokine, CCL5, in tumor cells and its receptor, CCR5, in the stroma. CCL5 overexpression in noninvasive (RKIP+) tumors partially rescued macrophage infiltration suggesting that CCL5 is sufficient to initiate metastasis. The CCL5-CCR5 axis has been implicated in BLBC metastasis, but its mechanisms of action and the role of macrophages are not known. We hypothesize that the chemokine CCL5 mediates interaction between TNBC cells and tumor-associated macrophages to drive invasion and metastasis AND that blocking CCL5 activity combined with targeted EGFR therapy in humanized mice will lead to reduced tumor and metastatic burden. We propose to elucidate the nature and role of these interactions. Specifically, we will: 1) Characterize CCL5-mediated crosstalk between TNBCs and TAMs; 2) Investigate the role of TAMs and Ccl5 in a TNBC mouse model; and 3) Investigate the mechanism by which RKIP regulates CCL5 expression and its potential therapeutic application. Our studies could both inform clinicians about risk factors leading to triple-negative breast cancer as well as lead to potential therapeutic targets.

描述（由申请人提供）：患有三阴性乳腺癌（TNBC）的女性具有最短的生存期和最高的复发率;然而，没有已知的靶向治疗。转移是大多数癌症相关死亡的原因，取决于肿瘤细胞与其微环境之间的特定分子相互作用。我们最近进行了一项研究，以表征TNBC异种移植模型中这些肿瘤-基质相互作用。为了确定转移的驱动因素，我们比较了侵袭性肿瘤和稳定表达转移抑制因子Raf激酶抑制蛋白（RKIP）的遗传匹配的非侵袭性肿瘤中的基因表达。 我们的研究显示，与侵袭性肿瘤相比，非侵袭性（RKIP+）肿瘤中巨噬细胞浸润显著减少。初步结果表明，RKIP抑制肿瘤细胞中巨噬细胞趋化因子CCL 5及其基质中受体CCR 5的表达。非侵袭性（RKIP+）肿瘤中的CCL 5过表达部分挽救了巨噬细胞浸润，表明CCL 5足以引发转移。CCL 5-CCR 5轴与BLBC转移有关，但其作用机制和巨噬细胞的作用尚不清楚。 我们假设趋化因子CCL 5介导TNBC细胞和肿瘤相关巨噬细胞之间的相互作用以驱动侵袭和转移，并且在人源化小鼠中阻断CCL 5活性与靶向EGFR治疗组合将导致肿瘤和转移负荷降低。我们建议阐明这些相互作用的性质和作用。具体而言，我们将：1）表征TNBC和TAM之间CCL 5介导的串扰; 2）研究TAM和CCL 5在TNBC小鼠模型中的作用;和3）研究RKIP调节CCL 5表达的机制及其潜在的治疗应用。我们的研究既可以告知临床医生导致三阴性乳腺癌的风险因素，也可以找到潜在的治疗靶点。