RESUMO
BACKGROUND & AIMS: Notch1 activation promotes ICC progression and is associated with chemoresistance; however, therapies directly targeting Notch1 showed severe adverse effects. Notch1 activation is mediated by ADAM10, a molecular scissor that separates the target protein from its substrates in the cell membrane. Tspan15 regulates ADAM10 function, but the role of Tspan15 in ICC progression is unclear. METHODS: Tspan15, ADAM10, and Notch1 expression and activation in fresh surgical specimens from 80 ICC patients and ICC cells were evaluated by immunohistochemistry, RT-PCR, western blotting, and flow cytometry. RESULTS: Tspan15 expression was increased in ICC compared with adjacent liver tissue, and high Tspan15 expression was an independent factor for poor prognosis. In ICC with high Tspan15 expression, vascular invasion, lymph node metastasis, and haematogenous recurrence were increased. Tspan15 was co-expressed with ADAM10 in ICC, and associated with the expression of stemness and EMT markers. In ICC cells, Tspan15 induced ADAM10 activation by mediating the translocation of activated m-ADAM10 from the cytoplasm to the surface of the cell membrane, which further activated Notch1 by separating the intracellular domain of Notch1 from its extracellular domain, leading to enhancement of CSC-like properties and EMT. This signalling was associated with enhanced chemoresistance against gemcitabine and cisplatin. Inhibition of Tspan15 or ADAM10 is a promising therapeutic strategy in ICC, as Tspan15 or ADAM10 knockdown or treatment with ADAM10 inhibitor reduced chemoresistance and invasiveness by suppressing Notch1-mediated CSC-like properties and EMT. CONCLUSIONS: Tspan15-ADAM10-Notch1 signalling is associated with aggressive tumour progression and poor prognosis in ICC.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Transdução de Sinais , Células-Tronco Neoplásicas/patologia , Receptor Notch1/genética , Receptor Notch1/metabolismo , Linhagem Celular Tumoral , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismoRESUMO
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a subtype of biliary tract cancer (BTC). Recently, downsizing chemotherapy has been applied to initially unresectable BTCs, including ICC. CASE PRESENTATION: We report a case of liver resection in a 23-year-old woman who was diagnosed with initially unresectable ICC attached to the inferior vena cava, with portal vein (PV) cavernous transformation. Positron emission tomography (PET) showed fluorodeoxyglucose (FDG) uptake in the para-aortic lymph nodes. Upon using downsizing chemotherapy (the combination of gemcitabine [GEM] and cisplatin [CDDP]), the size of tumor reduced by 55% and FDG uptake in the para-aortic lymph node metastases disappeared. A right hemihepatectomy was performed, along with dissection of lymph nodes, including the para-aortic lymph nodes. The PV cavernous transformation was preserved to maintain collateral flow as much as possible, as it was considered to originate from a congenital anomaly. Pathological examination revealed that R0 resection was performed and that there were no viable neoplastic cells remaining in the para-aortic lymph nodes. The patient is alive at 31 months after initial treatment, with a local recurrence. CONCLUSION: Downsizing chemotherapy with GEM plus CDDP followed by radical surgical resection is an attractive treatment for initially unresectable BTC.
