Suyanee Thongchot 1 2 3 , Chiara Vidoni 2 , Alessandra Ferraresi 2 , Watcharin Loilome 1 4 , Narong Khuntikeo 4 5 , Sakkarn Sangkhamanon 4 6 , Attapol Titapun 4 5 , Ciro Isidoro 2 , Nisana Namwat 1 4
Affiliations
1 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand.
2 Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy.
3 Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
4 Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand.
5 Department of Surgery, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand.
6 Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand.
PMID: 33925189
PMCID: PMC8124468
Cancers (Basel). 2021 Apr 28;13(9):2134. doi: 10.3390/cancers13092134.
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.
Keywords: autophagy; cancer therapy; cancer-associated fibroblasts; cholangiocarcinoma; cytokines; desmoplastic stroma; interleukin-6.
