Radiotherapy-Activated Cancer-Associated Fibroblasts Promote Tumor Progression through Paracrine IGF1R Activation
| Autor: | Karin Haustermans, Astrid De Boeck, Christian Vanhove, Benedicte Descamps, Tom Boterberg, Elodie Melsens, Joke Tommelein, Annelies Debucquoy, Pascal de Tullio, Marc Bracke, Pieter Demetter, Christian Gespach, Patrick Pauwels, Elly De Vlieghere, Anne Vral, Laurine Verset, Olivier De Wever, Justine Leenders, Wim Ceelen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Colorectal cancer Paracrine Communication Mice Nude Apoptosis Adenocarcinoma Metastasis Mice 03 medical and health sciences Paracrine signalling 0302 clinical medicine Cancer-Associated Fibroblasts Pancreatic cancer Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Cell Proliferation business.industry Cancer Receptors Somatomedin Prognosis medicine.disease Xenograft Model Antitumor Assays Cell Transformation Neoplastic 030104 developmental biology Oncology Gamma Rays Tumor progression 030220 oncology & carcinogenesis Cancer cell Metabolome Cancer research Female Human medicine Colorectal Neoplasms Transcriptome business Signal Transduction |
| Zdroj: | Cancer research |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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