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

项目总结 乳腺癌的生长和发展需要肿瘤细胞与其周围环境之间复杂的相互作用 环境。了解推动乳腺癌生长和转移的关键肿瘤-间质相互作用 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，而炎症环境与强化的乳腺癌有关 进步。临床使用的抗炎药增加了靶向治疗的可行性。 炎性微环境。然而，要了解推动形成一种 炎性环境和确定促进乳腺癌生长和 进展是开发成功的抗炎治疗策略的关键。成纤维细胞生长 因子(FGFs)是公认的癌症生长和进展的促进剂。总的来说，FGFs和他们的 受体(FGFR)在高达75%的人类乳腺癌中过度表达和/或放大，并增加 FGFR活性与患者预后不良相关。我们最近发现，FGFR激活会导致 细胞外基质(ECM)内的促肿瘤变化，包括增强的合成和 细胞外基质成分透明质酸的碎裂。此外，我们还发现了一种新的激活途径 通过乳腺癌细胞中的透明质酸以及促进透明质酸的促炎介质 功能。这些研究导致了一种假设，即乳腺癌细胞中FGFR的激活导致 形成富含HA的炎性微环境，通过以下途径促进肿瘤的生长和进展 激活促炎信号通路，促进炎症介质的表达。这个 提出了以下具体目标：1)确定FGFR介导的HA的功能贡献 合成和碎片化对乳腺肿瘤进展的影响。2)勾画出特定的信号通路 HA通过其调节乳腺癌细胞中炎性基因的表达。3)发展结合体 针对FGFR和下游HA效应器的治疗。这些研究的意义在于，它们将 定义肿瘤细胞和细胞外基质之间的新的相互作用。这些研究的一个主要目标是确定 同时针对肿瘤细胞和HA的联合治疗的能力：肿瘤细胞和HA的受体相互作用 限制肿瘤启动和生长的微环境。

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.