IL‐33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction

Abstract

Histopathology 75, 365-375. https://doi.org/10.1111/his.13863 IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunctionAims: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). Methods and results: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. Conclusions: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.

Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

“…Out of 92 articles, 30 were excluded due to: no data for adenocarcinoma of the gallbladder available (N = 12), overlapping cohorts (N = 8), the wrong type of article (N = 5), no genetic alteration frequency data available (N = 3), wrong study population (N = 1), and not written in English (N = 1). A total of 62 articles were included for final data extraction, describing a total of 3893 GBC samples from individual patients [ 18 , 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ,…”

“… China Li 2019 [ 18 ] 6/54 11% NGS AC Greece Papadopoulou 2018 [ 40 ] 8/21 38% PCR-RFLP AC India Singh 2004 [ 63 ] 8/34 24% Seq AC India Sharma 2017 [ 65 ] 9/81 11% PCR N.A. Japan Tomioka 2019 [ 45 ] 10/17 59% …”

Precursor Lesions of Gallbladder Carcinoma: Disease Concept, Pathology, and Genetics

“…In addition, some previous studies reported that KRAS mutations are more frequent in PBM-associated events than de novo gallbladder carcinomas [ 61 , 62 ]. In contrast, recent studies showed that the frequency of KRAS mutations is <20% in PBM-associated gallbladder cancer, which is comparable to that in non-PBM-associated gallbladder cancer [ 64 ]. According to our study data, KRAS mutations are not frequent events in gallbladder carcinogenesis in PBM [ 55 ].…”

IL33 and Mast Cells—The Key Regulators of Immune Responses in Gastrointestinal Cancers?

“…IL33 administration promoted the growth of Kras and TGFbR2 mutant biliary tract cancers ( 105 ) and in mouse models with constitutively active AKT/YAP pathway ( 106 , 107 ). Moreover, IL33 is overexpressed in human gallbladder cancer patients ( 108 ). However, in pancreatic cancer patients high IL33 expression and high number of tumor-infiltrating ILC2s correlated with better survival ( 41 ).…”