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

项目摘要 乳腺癌的生长和进展需要肿瘤细胞及其周围环境之间的复杂相互作用 环境了解驱动乳腺癌生长和转移的关键肿瘤-基质相互作用 对于发展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，这与乳腺癌的增强有关 进展临床使用的抗炎剂的可用性增强了靶向治疗的可行性。 炎症微环境然而，了解驱动形成的机制， 炎症环境和识别有助于乳腺癌生长的关键介质， 进展对于开发成功的抗炎治疗策略至关重要。成纤维细胞生长 生长因子（FGF）是公认的癌症生长和进展的促进剂。总的来说，FGFs及其 在高达75%的人类乳腺癌中，FGFR过表达和/或扩增，并且在20%的人类乳腺癌中，FGFR表达增加。 FGFR活性与患者预后不良相关。我们最近发现FGFR激活导致 细胞外基质（ECM）内的促肿瘤发生改变，包括合成增强， ECM组分透明质酸的片段化。此外，我们还发现了一种新的激活途径， 由乳腺癌细胞中的透明质酸沿着促炎介质引起， 功能这些研究导致了这样的假设，即乳腺癌细胞中FGFR的激活导致了乳腺癌细胞的凋亡。 形成富含HA的炎症微环境，通过以下方式促进肿瘤生长和进展： 激活促炎信号通路并促进炎症介质的表达。的 提出了以下具体目标：1）确定FGFR介导的HA的功能贡献 合成和断裂与乳腺肿瘤进展的关系。2)描述特定的信号通路 HA通过其调节乳腺癌细胞中的炎性基因表达。3)发展组合 靶向FGFR和下游HA效应物的治疗。这些研究的意义在于， 定义肿瘤细胞和ECM之间的新的相互作用。这些研究的一个主要目标是确定 靶向肿瘤细胞和HA的联合治疗的能力： 微环境，以限制肿瘤的发生和生长。

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.