Background and Aims Cholangiocarcinoma (CCA) is a highly aggressive tumor characterized by high resistance to chemotherapy and poor prognosis. Increasing evidence highlights that oncostatin M (OSM) regulates the tumor microenvironment (TME) and orchestrates the crosstalk between cancer and stromal cells. This project aims at elucidating the involvement of this factor and its receptor in iCCA progression, as well as in tumor-stroma interaction. Method Expression of OSM and its receptor was analysed in patients with iCCA by immunohistochemistry or RT-PCR. Two human iCCA cell lines (HuCCT-1 and CCLP-1) and two type of cultured stromal cells have been used in this study. Cell migration and invasiveness of iCCA cells has been evaluated by performing chemotaxis and invasion assays. Knockdown of OSMR and gp130 was carried out with specific siRNA in iCCA cells. Results iCCA cells expressed both OSM receptors and OSM at protein levels. In human CCA specimens, OSM was expressed at higher levels in cancer cells and in the tumor microenvironment with respect to peritumoral tissue. In addition, OSMR mRNA levels were higher in CCA. Exposure of iCCA to OSM induced a dose-dependent increase in cell migration and invasion. These effects were mediated by cytoskeletal rearrangement (increased expression of p-FAK, p-paxillin and p-MLC2), and inducing EMT. OSM also upregulated cancer-associated pathways including c-Myc, G6PD, p-Rb, and p-Akt The ability of OSM to induce iCCA cell migration and invasion was reduced after knockdown of the OSMR or of gp130, or treatment with ruxolitinib. Incubation of primary hepatic stellate cells, HSCs or cancer-associated fibroblasts, CAFs with conditioned medium collected from iCCA cells treated with OSM resulted in increased cell migration, suggesting a role in the formation of a dense fibrotic tumor microenvironment. Conclusions This study identifies the OSM/OSMR axis as a novel system potentially implicated in cholangiocarcinogenesis with modulation of the tumor microenvironment.
Oncostatin M modulates the biology of cholangiocarcinoma cells and the tumor microenvironment / Porro, N.; Nurcis, J.; De Siervi, S.; Cadamuro, M.; Turato, C.; Mantovani, S.; Oliviero, B.; Fabris, L.; Mondelli, M.; Marra, F.; Parola, M.; Caligiuri, Al.; Pastore, M.; Cannito, S.; Gentilini, A.. - In: DIGESTIVE AND LIVER DISEASE. - ISSN 1590-8658. - ELETTRONICO. - 57:(2025), pp. 0-0. [10.1016/j.dld.2025.01.031]
Oncostatin M modulates the biology of cholangiocarcinoma cells and the tumor microenvironment
Porro, N.;Fabris, L.;Parola, M.;Caligiuri, Al.;Gentilini, A.
2025
Abstract
Background and Aims Cholangiocarcinoma (CCA) is a highly aggressive tumor characterized by high resistance to chemotherapy and poor prognosis. Increasing evidence highlights that oncostatin M (OSM) regulates the tumor microenvironment (TME) and orchestrates the crosstalk between cancer and stromal cells. This project aims at elucidating the involvement of this factor and its receptor in iCCA progression, as well as in tumor-stroma interaction. Method Expression of OSM and its receptor was analysed in patients with iCCA by immunohistochemistry or RT-PCR. Two human iCCA cell lines (HuCCT-1 and CCLP-1) and two type of cultured stromal cells have been used in this study. Cell migration and invasiveness of iCCA cells has been evaluated by performing chemotaxis and invasion assays. Knockdown of OSMR and gp130 was carried out with specific siRNA in iCCA cells. Results iCCA cells expressed both OSM receptors and OSM at protein levels. In human CCA specimens, OSM was expressed at higher levels in cancer cells and in the tumor microenvironment with respect to peritumoral tissue. In addition, OSMR mRNA levels were higher in CCA. Exposure of iCCA to OSM induced a dose-dependent increase in cell migration and invasion. These effects were mediated by cytoskeletal rearrangement (increased expression of p-FAK, p-paxillin and p-MLC2), and inducing EMT. OSM also upregulated cancer-associated pathways including c-Myc, G6PD, p-Rb, and p-Akt The ability of OSM to induce iCCA cell migration and invasion was reduced after knockdown of the OSMR or of gp130, or treatment with ruxolitinib. Incubation of primary hepatic stellate cells, HSCs or cancer-associated fibroblasts, CAFs with conditioned medium collected from iCCA cells treated with OSM resulted in increased cell migration, suggesting a role in the formation of a dense fibrotic tumor microenvironment. Conclusions This study identifies the OSM/OSMR axis as a novel system potentially implicated in cholangiocarcinogenesis with modulation of the tumor microenvironment.
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