Publication: Cancer‐associated fibroblast‐derived il‐6 determines unfavorable prognosis in cholangiocarcinoma by affecting autophagy‐associated chemoresponse
Issued Date
2021-05-01
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ISSN
20726694
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2-s2.0-85115674716
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Mahidol University
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SCOPUS
Bibliographic Citation
Cancers. Vol.13, No.9 (2021)
Suggested Citation
Suyanee Thongchot, Chiara Vidoni, Alessandra Ferraresi, Watcharin Loilome, Narong Khuntikeo, Sakkarn Sangkhamanon, Attapol Titapun, Ciro Isidoro, Nisana Namwat Cancer‐associated fibroblast‐derived il‐6 determines unfavorable prognosis in cholangiocarcinoma by affecting autophagy‐associated chemoresponse. Cancers. Vol.13, No.9 (2021). doi:10.3390/cancers13092134 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/76182
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Title
Cancer‐associated fibroblast‐derived il‐6 determines unfavorable prognosis in cholangiocarcinoma by affecting autophagy‐associated chemoresponse
Abstract
Background: Interleukin‐6 (IL‐6) released by cancer‐associated fibroblasts (CAFs) has been shown to associate with the malignant behavior of cholangiocarcinoma (CCA). Here, we aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL‐6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells. Methods: Stromal IL‐6 and cancer‐cell‐associated autophagy proteins LC3 and p62 were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. The 5‐FU cytotoxicity and autophagy were determined in CCA cells cultured with CAF‐conditioned medium. Results: We show that patients bearing a CCA with low production of stromal IL‐6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post‐operative chemotherapy. A similar trend was observed in CCA patients from the TCGA database. In vitro genetic manipulation of IL‐6 production by primary CAFs isolated from human CCA showed that IL‐6 impairs the autophagy‐associated apoptotic response to 5‐FU in human CCA cells. Stromal IL‐6 inhibition of autophagy in cancer cells was confirmed in an animal model of CCA. Conclusion: Our data support a therapeutic strategy that includes autophagy‐enhancing drugs along with adjuvants limiting the stromal inflammation (i.e., the secretion of IL‐6) to improve the survival of CCA patients.