旁分泌信号
癌症研究
医学
结直肠癌
癌症
胰岛素样生长因子1受体
间质细胞
癌细胞
自分泌信号
肿瘤进展
PI3K/AKT/mTOR通路
生长因子
内科学
生物
信号转导
受体
细胞生物学
作者
Joke Tommelein,Elly De Vlieghere,Laurine Verset,Elodie Melsens,Justine Leenders,Benedicte Descamps,Annelies Debucquoy,Christian Vanhove,Patrick Pauwels,Christian Gespach,Anne Vral,Astrid De Boeck,Karin Haustermans,Pascal De Tullio,Wim Ceelen,Pieter Demetter,Tom Boterberg,Marc Bracke,Olivier De Wever
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2018-01-31
卷期号:78 (3): 659-670
被引量:98
标识
DOI:10.1158/0008-5472.can-17-0524
摘要
Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659-70. ©2017 AACR.
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