Abstract
Simple SummaryWe 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. Stromal IL-6 and cancer-cell-associated autophagy proteins were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. We found that patients bearing a CCA with low 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 experiments with 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. Our data support a therapeutic strategy that includes drugs limiting the stromal inflammation and enhancing autophagy to improve the survival of CCA patients.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.
Highlights
Cholangiocarcinoma (CCA), the cancer of bile duct epithelia, is the second most common primary malignancy of the hepato-biliary system, and its incidence rate has significantly increased over the last few decades worldwide [1,2]
Chemotherapy was administered to 6 patients before and to 24 patients after surgery, while 40 patients were not subjected to any chemotherapy
We further investigated the link between the cancer-associated fibroblasts (CAFs) secretions and the autophagy-dependent response to 5-FU
Summary
Cholangiocarcinoma (CCA), the cancer of bile duct epithelia, is the second most common primary malignancy of the hepato-biliary system, and its incidence rate has significantly increased over the last few decades worldwide [1,2]. CCA remains a major concern, especially in Southeast Asia, where the pathogenesis is essentially associated with chronic liver fluke infection [3,4]. Otherwise, it is a deadly disease with a 9% mortality ratio within three months [5], and surgical resection followed by radio- and/or chemotherapies offers survival rates of approximately 20–40% and 5–10% at 5 years and 10 years, respectively [6,7]. A late diagnosis often precludes the possibility of surgical intervention Even in this case recurrence and progression with emergence of polychemoresistance are very common, which explains the very poor prognosis of CCA [9,10,11]. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
