Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

Abstract

The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras-and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-Kras G12D , Tgfbr2 flox/flox , and K19 CreERT mice (KT-K19 CreERT ). However, KT-K19 CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19 CreERT mice were crossed with CDH1 flox/flox mice (KTC-K19 CreERT ). Surprisingly, KTC-K19 CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti-IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.extrahepatic cholangiocarcinoma | IL-33 | organoid | ILC2 | amphiregulin

Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis

“…In PSC, BTSCs proliferate extensively, show few signs of cellular senescence, and have been proven to be able to escape immune response . A report based on lineage tracing in mice suggested that cells within PBGs could represent the origin of extrahepatic CCA, which supports our data in patients with PSC . In keeping with this, CCAs in patients with PSC diffusely expressed stem cell markers and primarily involved PBGs, which were largely substituted by neoplastic cells.…”

Interleukin‐33 overexpression reflects less aggressive tumour features in large‐duct type cholangiocarcinomas

“…In the present study, KRAS mutations were slightly less common in IL‐33 high cases than in IL‐33 low cases. In an experimental model study, the administration of IL‐33 enhanced tumorigenesis of cancers with gene mutations that were insufficient for malignant transformation by themselves . A whole‐genome expression profiling study involving 149 iCCAs identified two subtypes with distinct molecular alterations .…”

“…Interleukin (IL)‐6 is regarded as a cytokine that is relevant to bile duct cancer development, because this inflammatory mediator, which is secreted by CCA cell lines, induces cell proliferation . Recent studies using transgenic mice also highlighted the pro‐oncogenic effects of IL‐33 on cholangiocytes . Although the combination of a Kras mutation and transforming growth factor‐β receptor type 2 gene ( Tgfbr2 ) deletion did not generate bile duct cancers, the additional administration of IL‐33 facilitated cancer development in the bile duct.…”

Potential Involvement of the ILC2-Regulatory T Cell - Amphiregulin Axisin Liver Cancer Development: Novel Concepts for Immunotherapy of Hepatocellular Carcinoma

“…In general, ILC2s have been considered as a population with predominant pro-tumorigenic activity and the IL-33/ILC2/IL-13 circuit was shown to be critically involved in promoting cholangiocyte hyperplasia in murine cholangiocarcinoma [26] and in activating myeloid-derived suppressor cells, which inhibit anti-cancer immunity in breast cancer [27]. Interestingly, IL-33-activated ILC2s also express AREG early after tissue damage.…”

“…In murine models of colitis [28] and infection-induced lung injury [29,30], AREG-expressing ILC2s were associated with restoration of epithelial integrity and tissue function. However, although early induction of AREG is important for the resolution of acute inflammation, the situation is quite different in the context of chronic inflammation where ILC2-derived AREG amplified excessive wound healing in skin lesions of atopic dermatitis patients [31] and triggered injury-induced regenerative responses driving development of extrahepatic cholangiocarcinoma [26].…”