Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation.
Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation.
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DOI：
10.1158/0008-5472.can-13-2469
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发表时间：
2014-01-01
期刊：
影响因子：
11.2
通讯作者：
Schwertfeger KL
中科院分区：
文献类型：
--
作者：
Bohrer LR;Chuntova P;Bade LK;Beadnell TC;Leon RP;Brady NJ;Ryu Y;Goldberg JE;Schmechel SC;Koopmeiners JS;McCarthy JB;Schwertfeger KL
成纤维细胞生长因子受体 (FGFR) 的异常激活会导致乳腺癌的生长、进展和治疗耐药。由于 FGF/FGFR 轴的复杂性，以及 FGFR 激活对肿瘤细胞和周围微环境的众多影响，异常 FGFR 活性导致乳腺癌的具体机制尚不完全清楚。我们在此表明，FGFR 激活会诱导细胞外基质 (ECM) 内透明质酸 (HA) 的积累，并且阻断 HA 合成会降低增殖、迁移和治疗耐药性。此外，FGFR 介导的 HA 积累需要激活信号转导器和转录激活剂 3 (STAT3) 途径，该途径调节乙酰透明质酸合酶 2 (HAS2) 的表达和随后的 HA 合成。使用 FGFR 依赖性肿瘤生长的新型体内模型，我们证明 STAT3 抑制可降低 FGFR 驱动的肿瘤生长和肿瘤内的 HA 水平。最后，我们的结果表明，抑制 FGFR 活性和 HA 合成的组合疗法比单独针对任一途径更有效，并且可能是与高水平 FGFR 活性相关的乳腺癌的相关治疗方法。总之，这些研究表明了一种新的靶向机制，乳腺癌细胞中的 FGFR 激活可诱导促肿瘤微环境。
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to breast cancer growth, progression and therapeutic resistance. Due to the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan (HA) within the extracellular matrix (ECM) and that blocking HA synthesis decreases proliferation, migration and therapeutic resistance. Furthermore, FGFR-mediated HA accumulation requires activation of the signal transducer and activator of transcription 3 (STAT3) pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent HA synthesis. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and HA levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and HA synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a pro-tumorigenic microenvironment.