Targeting interleukin 6 signaling by monoclonal antibody siltuximab on cholangiocarcinoma

Abstract

Background and Aim Cholangiocarcinoma has an unimproved prognosis. Interleukin 6 (IL‐6) has an oncogenic potential in some cancer diseases. However, the role of IL‐6 in cholangiocarcinoma carcinogenesis is not well understood. The current study investigated the role of IL‐6 signaling in cholangiocarcinoma carcinogenesis and efficacy of siltuximab treatment on cholangiocarcinoma in vitro and in vivo. Methods The expression of IL‐6 was analyzed on human cholangiocarcinoma cell lines and murine and human cholangiocarcinoma tissues, using reverse transcription real‐time polymerase chain reaction and immunohistochemistry. In addition, the effect of anti‐IL‐6 chimeric monoclonal antibody, siltuximab, was investigated in vitro by proliferation, migration, and two‐dimensional and three‐dimensional invasion assays and in vivo by xenograft mouse model. Western blot was applied to study the molecular alteration. Results Our result shows high expression of IL‐6 in human cholangiocarcinoma cells, and IL‐6 stimulants enhance cholangiocarcinoma cell proliferation. In addition, murine and human cholangiocarcinoma tissues express significantly higher levels of IL‐6, compared with adjacent non‐tumor tissues. On the cholangiocarcinoma engineered mouse model, IL‐6 level is associated with tumor volume. Taken together, our data indicate an oncogenic potential of IL‐6 in cholangiocarcinoma carcinogenesis. Siltuximab sufficiently abrogates IL‐6 signaling and inhibits cholangiocarcinoma progression in vitro and in vivo. The results additionally indicate a relative alteration of IL‐6 signaling and its molecular targets, such as STAT3, Wnt/β‐catenin, and mesenchymal markers. Conclusions Interleukin 6 plays an essential role in cholangiocarcinoma carcinogenesis, and siltuximab has the potential to be considered as a new treatment option for cholangiocarcinoma patients.

STAT3 pathway in cancers: Past, present, and future

“…IL‐6 is upregulated in cholangiocarcinoma and non‐small cell lung cancer, and treatment with siltuximab alters the IL‐6/STAT3 pathway and suppresses the growth and invasion of tumor. 281 , 282 The results of Phase I/II and II clinical trials conducted by Angevin et al. and Coward et al., respectively, indicated that siltuximab was safe in ovarian and Kirsten rat sarcoma‐2‐mutant cancers treatment.…”

Interleukins in cancer: from biology to therapy

“…While the antiIL6 antibody siltuximab reduced tumour growth in a xenografted cholangiocarci noma model 153 , it achieved only small effects in multiple myeloma as monotherapy 154 , in combination with the proteasome inhibitor bortezomib 155 and with bortezomib, the cytostatic agent melphalan and the antiinflammatory glucocorticoid prednisone 156 . Siltuximab was also not effective in solid tumours as monotherapy.…”

MiR-206 suppresses the deterioration of intrahepatic cholangiocarcinoma and promotes sensitivity to chemotherapy by inhibiting interactions with stromal CAFs

“…Current researches indicate that targeting crosstalk between cells populating local environment and CCA cells is a novel promising approach for the management of CCA. A recent study showed that IL-6 was highly expressed in murine and human CCA tissue, and targeting IL-6 signalling inhibited CCA progression in vitro and in vivo [55]. TGF-beta signaling is also an effective target to suppress CCA cell's proliferation and survival [56].…”