Contributions of FGFR-mediated tumor-stromal interactions to breast cancer growth and progression

FGFR 介导的肿瘤间质相互作用对乳腺癌生长和进展的贡献

• 批准号: 9894751
• 负责人: Kathryn L Schwertfeger
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894751
• 关键词: Anti-Inflammatory Agents; Breast; Breast Cancer Cell; Breast Cancer Patient; CD44 Antigens; CD44 gene; CRISPR/Cas technology; ChIP-seq; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Development; Disease-Free Survival; Environment; Extracellular Matrix; FGFR1 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Genes; Goals; Growth; Health; Human; Hyaluronan; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Mediator of activation protein; Migration Inhibitory Factor; Neoplasm Metastasis; Pathway interactions; Patient-Focused Outcomes; Patients; Publishing; Receptor Activation; Receptor Signaling; Recurrence; Relapse; Research; Resistance; STAT protein; Signal Pathway; Signal Transduction; Stromal Neoplasm; Techniques; Therapeutic; Treatment Efficacy; base; breast cancer progression; breast cancer survival; cancer cell; cell stroma; clinically relevant; cytokine; efficacy testing; improved; in vivo; inflammatory milieu; inhibitor/antagonist; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient population; prevent; promoter; receptor; recruit; response; targeted treatment; therapeutic target; transcription factor; transcriptome; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenic

PROJECT SUMMARY Breast cancer growth and progression require complex interactions between tumor cells and their surrounding environment. Understanding the key tumor-stromal interactions that drive breast cancer growth and metastasis is critical for the development of strategies to inhibit tumor progression and recurrence. Breast cancers are often associated with an inflammatory environment, which has been linked to enhanced breast cancer progression. The availability of anti-inflammatory agents for clinical use enhances the feasibility of targeting the inflammatory microenvironment. However, understanding the mechanisms that drive the formation of an inflammatory environment and identifying key mediators that contribute to breast cancer growth and progression are critical for developing successful anti-inflammatory therapeutic strategies. Fibroblast growth factors (FGFs) are well-established promoters of cancer growth and progression. Collectively, FGFs and their receptors (FGFRs) are overexpressed and/or amplified in up to 75% of human breast cancers and increased FGFR activity is correlated with poor patient outcome. We have recently found that FGFR activation leads to pro-tumorigenic alterations within the extracellular matrix (ECM) including enhanced synthesis and fragmentation of the ECM component hyaluronan. Furthermore, we have identified a novel pathway activated by hyaluronan in breast cancer cells along with pro-inflammatory mediators that contribute to hyaluronan function. These studies have led to the hypothesis that activation of FGFR in breast cancer cells leads to the formation of an HA-rich inflammatory microenvironment, which promotes tumor growth and progression by activating pro-inflammatory signaling pathways and promoting expression of inflammatory mediators. The following specific aims are proposed: 1) Determine the functional contributions of FGFR-mediated HA synthesis and fragmentation to mammary tumor progression. 2) Delineate the specific signaling pathway through which HA regulates inflammatory gene expression in breast cancer cells. 3) Develop combination therapies that target FGFR and downstream HA effectors. The significance of these studies is that they will define novel interactions between tumor cells and the ECM. A major goal of these studies is to determine the ability of combination therapies that target both tumor cells and HA: receptor interactions in the microenvironment to limit tumor initiation and growth.

项目摘要 乳腺癌的生长和进展需要肿瘤细胞及其周围的复杂相互作用 环境。了解促进乳腺癌生长和转移的关键肿瘤相互作用 对于制定抑制肿瘤进展和复发的策略至关重要。乳腺癌是 通常与炎症环境有关，该环境与增强的乳腺癌有关 进展。抗炎剂用于临床使用的可用性增强了针对的可行性 炎症微环境。但是，了解驱动形成的机制 炎症环境和确定有助于乳腺癌生长和的关键介体 进展对于制定成功的抗炎治疗策略至关重要。成纤维细胞生长 因素（FGF）是癌症生长和进展的启动子。共同，FGF及其 受体（FGFR）过表达和/或在多达75％的人类乳腺癌中扩增并增加 FGFR活性与差的患者结局相关。我们最近发现FGFR激活导致 细胞外基质（ECM）内的促肿瘤性改变，包括增强的合成和 ECM组分透明质酸的破碎。此外，我们已经确定了激活的新途径 透明质酸在乳腺癌细胞中以及促炎性介质有助于透明质酸 功能。这些研究导致了以下假设：乳腺癌细胞中FGFR的激活导致 富含HA的炎症微环境的形成，可促进肿瘤的生长和进展 激活促炎信号通路并促进炎症介质的表达。这 提出了以下特定目标：1）确定FGFR介导的HA的功能贡献 乳腺肿瘤进展的合成和碎片化。 2）描述特定的信号通路 HA通过其中调节乳腺癌细胞中的炎症基因表达。 3）发展组合 靶向FGFR和下游HA效应子的疗法。这些研究的意义在于他们将 定义肿瘤细胞与ECM之间的新型相互作用。这些研究的主要目的是确定 靶向肿瘤细胞和HA：受体相互作用的组合疗法的能力 微环境限制肿瘤的启动和生长。