肿瘤抑制因子
癌症研究
旁分泌信号
自分泌信号
癌症
乳腺癌
血管生成
间质细胞
脂肪组织
车站3
肿瘤进展
医学
生物
病理
信号转导
白细胞介素6
免疫学
内科学
细胞因子
细胞生物学
受体
作者
Lore Lapeire,An Hendrix,Kathleen Lambein,Mieke Van Bockstal,Geert Braems,Rudy Van den Broecke,Ridha Limame,Pieter Mestdagh,Jo Vandesompele,Christian Vanhove,Dawn Maynard,Camille Lehuédé,Cathérine Müller,Philippe Valet,Christian Gespach,Marc Bracke,Véronique Cocquyt,Hannelore Denys,Olivier De Wever
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2014-11-30
卷期号:74 (23): 6806-6819
被引量:104
标识
DOI:10.1158/0008-5472.can-14-0160
摘要
Abstract Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer–associated adipose tissue from freshly isolated tumors promotes F-actin remodeling, cellular scattering, invasiveness, and spheroid reorganization of cultured breast cancer cells. A combination of techniques, including transcriptomics, proteomics, and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45+ leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-) Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8, and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM-induced cellular scattering and peritumoral neovascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis, and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in patients with breast cancer harboring nuclear pSTAT3-Y705. Cancer Res; 74(23); 6806–19. ©2014 AACR.
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