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Overview of the OSM signaling pathways. OSM-receptor hetero-dimerization drives JAKs' recruitment. The C-terminal region of receptor types I and II contains tyrosine residues,
Source publication
Primary liver cancers represent the third-most-common cause of cancer-related mortality worldwide, with an incidence of 80–90% for hepatocellular carcinoma (HCC) and 10–15% for cholangiocarcinoma (CCA), and an increasing morbidity and mortality rate. Although HCC and CCA originate from independent cell populations (hepatocytes and biliary epithelia...
Contexts in source publication
Context 1
... can also negatively modulate MAP kinase cascades by recruiting the tyrosine phosphatase SHP-2 on Tyr759 and Tyr974 of the type I receptor, as well as the suppressors of cytokine signaling (SOCS), in particular SOCS3, on Tyr759, or through the direct action of JAK1/2 [31,32,35]. An overview of the signaling pathways activated by OSM is reported in Figure 2. OSM receptor complexes lack intrinsic kinase activity, and OSM-receptor interaction and receptor hetero-dimerization lead to Janus kinases' (JAKs) recruitment and activation, by transphosphorylation on the receptor intracellular domain [29,31,35]. ...
Context 2
... can also negatively modulate MAP kinase cascades by recruiting the tyrosine phosphatase SHP-2 on Tyr759 and Tyr974 of the type I receptor, as well as the suppressors of cytokine signaling (SOCS), in particular SOCS3, on Tyr759, or through the direct action of JAK1/2 [31,32,35]. An overview of the signaling pathways activated by OSM is reported in Figure 2. which, phosphorylated by JAK1/2, act as a docking site for STAT1 and STAT3. ...
Citations
... OSM in the TME contributes to cancer progression by recruiting M2 macrophages into the tumor environment and by altering the phenotype of CAFs. In general, elevated OSM levels in serum as well as in the TME have been associated with disease progression in different cancer types [75]. While aerobic exercise increases OSM concentration in muscle tissue, it has been shown that OSM concentration also increases in serum after aerobic exercise in mice that were previously injected with breast cancer cells [73,76]. ...
In this narrative review, we summarize the direct and indirect effects that myokines have on the tumor microenvironment. We took studies of various cancer types and species into account. Systematic reviews and meta-analyses that matched the search terms were also considered. We searched databases for six months. As a narrative approach was chosen, no data was analyzed or reanalyzed. The goal of this narrative review is to create an overview on the topic to identify research gaps and answer the questions as to whether myokine expression may be relevant in cancer research in regard to the tumor microenvironment. Six commonly known myokines were chosen. We found strong links between the influence exercise has on interleukin-6, oncostatin M, secreted protein acidic and rich in cysteine, and irisin in the context of tumor progression and inhibition via interactions with the tumor microenvironment. It became clear that the effects of myokines on the tumor microenvironment can vary and contribute to disease progression or regression. Interactions among myokines and immune cells must also be considered and require further investigation. To date, no study has shown a clear connection, while multiple studies suggest further investigation of the topic, similar to the effects of exercise on myokine expression.
... 12 Similarly, OSM is recognized for its role in promoting EMT in HCC. 25 To assess the association between CD147 and OSM, we evaluated their expression pro les using immunohistochemistry. OSM was predominantly expressed in stromal cells adjacent to the periphery of the tumor cell cords ( Fig. 2A). Immunohistochemical analysis revealed a higher density of OSM-positive cells in CD147-high than CD147-low HCC (median, 61/mm 2 vs. 25/mm 2 ; P = 0.0017; Fig. 2B), suggesting possible interaction between CD147-expressing tumor cells and OSM-positive cells. ...
Purpose
In hepatocellular carcinoma (HCC), CD147 expression contributes to tumor malignancy; however, its relationship with the tumor-immune microenvironment (TIME) remains unclear. This study aimed to elucidate the clinicopathological characteristics associated with CD147 expression in HCC and investigate its association with the TIME, specifically its association with tumor-infiltrating lymphocytes (TILs) and oncostatin M (OSM).
Methods
Using 397 HCC specimens from patients undergoing curative-intent resection, we assessed CD147 expression in tumor cells and quantified OSM-positive cells and various TILs (CD8⁺, CD4⁺, FOXP3⁺, and CD20⁺ cells) in the TIME. Using tissue microarrays, these assessments were performed through immunohistochemical analysis. We investigated the associations between CD147 expression status, the density of OSM-positive cells, and the densities of various TILs.
Results
High CD147 expression, found in 332 specimens (83.6%), was associated with advanced clinical stage (P = 0.0029), fibrosis (P = 0.036), and higher densities of FOXP3⁺ cells (P = 0.0039), CD4⁺ cells (P = 0.0012), and OSM-positive cells (P = 0.0017). In CD147-high tumors, OSM-positive cell density was associated with all assessed TIL subsets (CD8⁺, CD4⁺, FOXP3⁺, and CD20⁺ cells; all Ps < 0.001), whereas in CD147-low tumors, OSM-positive cell density was associated only with FOXP3⁺ cells (P = 0.0004).
Conclusions
In HCC, CD147 expression is associated with an immunosuppressive TIME, characterized by increased FOXP3⁺ regulatory T cells and an association with OSM-positive cells. These results elucidate the potential mechanisms through which CD147 facilitates tumor immune evasion, suggesting the CD147-OSM axis as a promising target for therapeutic intervention in HCC.
... CCA is a fatal tumor, accounting for 2% of all cancer-related mortalities worldwide yearly due to its high aggressiveness and poor response to current therapies. Furthermore, over the past few decades, CCA mortality has increased globally [3,4]. ...
... Mostly asymptomatic in the early phases, it is diagnosed at an advanced state of disease when therapeutic treatments are inefficient, and only a few CCA patients qualify for potentially curative surgical procedures [3,4]. ...
... Although the pathogenesis of CCA is still largely unknown, this tumor arises in a background of chronic hepatobiliary inflammation. Numerous risk factors have been associated with its onset, especially for iCCA, including primary sclerosing cholangitis (PSC), alcohol abuse, chronic hepatitis B and C, cirrhosis, diabetes, and nonalcoholic fatty liver disease (NAFLD), even if most CCAs have no recognizable cause [4]. All these ...
Citation: Caligiuri, A.; Becatti, M.; Porro, N.; Borghi, S.; Marra, F.; Pastore, M.; Taddei, N.; Fiorillo, C.; Gentilini, A. Oxidative Stress and Redox-Dependent Pathways in Cholangiocarcinoma. Antioxidants 2024, 13, 28. https://doi. Abstract: Cholangiocarcinoma (CCA) is a primary liver tumor that accounts for 2% of all cancer-related deaths worldwide yearly. It can arise from cholangiocytes of biliary tracts, peribiliary glands, and possibly from progenitor cells or even hepatocytes. CCA is characterized by high chemoresistance, aggressiveness, and poor prognosis. Potentially curative surgical therapy is restricted to a small number of patients with early-stage disease (up to 35%). Accumulating evidence indicates that CCA is an oxidative stress-driven carcinoma resulting from chronic inflammation. Oxidative stress, due to enhanced reactive oxygen species (ROS) production and/or decreased antioxidants, has been recently suggested as a key factor in cholangiocyte oncogenesis through gene expression alterations and molecular damage. However, due to different experimental models and conditions, contradictory results regarding oxidative stress in cholangiocarcinoma have been reported. The role of ROS and antioxidants in cancer is controversial due to their context-dependent ability to stimulate tumorigenesis and support cancer cell proliferation or promote cell death. On these bases, the present narrative review is focused on illustrating the role of oxidative stress in cholangiocarcinoma and the main ROS-driven intracellular pathways. Heterogeneous data about antioxidant effects on cancer development are also discussed.
... Oncostatin M (OSM) is a family of Interleukin-6 (IL-6), a wide-purpose glycoprotein, known due to its ability to participate in the systemic inflammatory response, as well as a broad and often context-dependent action on various cellular processes, ranging from differentiation, hematopoiesis, proliferation, and survival [13]. Studies have reported OSM as a potential biomarker in various types of cancer [14][15][16] and inflammatory-related diseases [17][18][19]. Evidence from animal models confirmed the involvement of OSM in 1 1 1 1 1 1 ischemic stroke [20], cardiac disease [21], and lipolysis of adipose tissue [22]. ...
Background: The expression of oncostatin M (OSM) has been studied in various diseases related to inflammatory response, but its implementation in acute ischemic stroke (AIS) remains to be explored.
Objective: The objective of this study is to assess the correlation between serum OSM expression and various aspects of AIS in a clinical setting.
Materials and method: A single-centered case-control study was performed in the First Affiliate Hospital of Chongqing Medical University from October 2020 to March 2021. A total of 134 patients were enrolled in the AIS group and 34 healthy individuals were enrolled in the control group. Physical examinations were performed and venous blood samples were collected. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum OSM. Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, National Institutes of Health Stroke Scale (NIHSS) score, magnetic resonance imaging (MRI) scan, and modified Rankin scale (mRS) were used to assess the classification, etiology, severity, and prognosis of the AIS group. Assessments were done to analyze serum OSM expression based on sensitivity, etiology, severity, prognosis, and several risk factors of AIS. Regression models, correlation, and sensitivity tests were performed to explore the correlation of OSM expression with various aspects of AIS.
Results: There was a statistically significant elevation of serum OSM expression in the AIS group (P<0.001). All AIS subgroups showed elevation in OSM level and statistically significant results were reflected in three subgroups. The area under the curve to differentiate AIS patients and control by serum OSM level was 0.747 (P<0.001), with the optimal cut-off value showing sensitivity at 58.82% and specificity at 75.37%. The elevation of serum OSM expression was proportional with severity, not proportional to the volume of infarct, and less elevated in the favorable outcome group. Serum OSM correlation with several risk factors of AIS was statistically significant in age, low-density lipoprotein, non-high-density lipoprotein, prothrombin time, and systolic blood pressure.
Conclusion: Serum OSM was expressed differently in correlation with various aspects of AIS. Our findings supported the initial hypothesis that OSM is correlated with various aspects of AIS in humans.
... Interestingly, in a mouse model of spontaneous cervical cancer (K14-HPV/E(2) mice), MMP-9 + neutrophils represented an alternative source to TAM in providing MMP-9 (82) and, in murine models of colorectal cancer (MC26) and lung carcinoma (3LL), MDSC-derived MMP-9 was associated to enhanced tumor vascularization (83). In addition, when co-cultured with human breast cancer cells, neutrophils produced high levels of oncostatin M (OSM) (84), which was shown to act on the endothelium via STAT-3/VEGF signaling in vivo and to enable the remodeling of the TME by activating cancerassociated fibroblasts (CAF) (85,86). In several murine transplantable models of cancer, MDSC were found to be the predominant source of prokineticin-2 (Bv8), a secreted protein involved in tissue-specific angiogenesis, which promoted vessel formation and tumor growth (87). ...
Endothelial cells and immune cells are major regulators of cancer progression and prognosis. Endothelial cell proliferation and angiogenesis are required for providing nutrients and oxygen to the nascent tumor and infiltration of immune cells to the tumor is dependent on endothelial cell activation. Myeloid cells and innate lymphocytes have an important role in shaping the tumor microenvironment by crosstalking with cancer cells and structural cells, including endothelial cells. Innate immune cells can modulate the activation and functions of tumor endothelial cells, and, in turn, endothelial cell expression of adhesion molecules can affect immune cell extravasation. However, the mechanisms underlying this bidirectional crosstalk are not fully understood. In this review, we will provide an overview of the current knowledge on the pathways regulating the crosstalk between innate immune cells and endothelial cells during tumor progression and discuss their potential contribution to the development of novel anti-tumor therapeutic approaches.
... The effects reported in this study were enabled through type II OSM receptors, as they were the only OSM receptors identified in nasal polyps. Therefore, we can infer some of the signaling pathways involved with type II OSM receptors for which heterodimerization drives JAK recruitment even though no mechanistic studies have been performed [62]. The C-terminal region of receptor type II contains tyrosine residues, which, phosphorylated by JAK1/2, act as a docking site for STAT1 and STAT3. ...
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a typical type-2 inflammation involving several cytokines and is associated with epithelial cell dysfunction. Oncostatin M (OSM) (belonging to the interleukin(IL)-6 family) could be a key driver of epithelial barrier dysfunction. Therefore, we investigated the presence of OSM and IL-6 and the expression pattern of tight junctions (TJs) in the nasal tissue of CRSwNP patients and controls using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Then, their potential role in the epithelial barrier was evaluated in vitro in 27 different primary cultures of human nasal epithelial cells (HNECs) by measuring TJ expression and transepithelial electric resistance (TEER) with or without OSM or IL-6 (1, 10, and 100 ng/mL). The effect on ciliary beating efficiency was evaluated by high-speed videomicroscopy and on repair mechanisms with a wound healing model with or without OSM. OSM and IL-6 were both overexpressed, and TJ (ZO-1 and occludin) expression was decreased in the nasal polyps compared to the control mucosa. OSM (100 ng/mL) but not IL-6 induced a significant decrease in TJ expression, TEER, and ciliary beating efficiency in HNECs. After 24 h, the wound repair rate was significantly higher in OSM-stimulated HNECs at 100 ng/mL. These results suggest that OSM could become a new target for monoclonal antibodies.
Aim
Vessels encapsulating tumor clusters (VETC) represents an adverse prognostic morphological feature of hepatocellular carcinoma (HCC), which is associated with an immunosuppressive tumor immune microenvironment (TIM). However, the underlying factors characterizing the TIM in HCC with a VETC pattern (VETC‐positive HCC) remain uncertain. Oncostatin M (OSM), a pleiotropic cytokine of the interleukin‐6 family, regulates various biological processes, including inflammation, proliferation, and invasiveness of tumor cells. We aimed to test a hypothesis that OSM is associated with the immunosuppressive TIM of VETC‐positive HCC.
Methods
A total of 397 consecutive HCC patients with curative‐intent hepatectomy were included. OSM‐positive cells and inflammatory cells including CD4‐, CD8‐, CD163‐, and FOXP3‐positive cells were immunohistochemically evaluated. We compared VETC‐positive and VETC‐negative HCCs in terms of the number of these cells.
Results
We found the VETC pattern in 62 patients (15.6%). Our analysis revealed a significant decrease in the expression of arginase‐1, a marker associated with mature hepatocyte differentiation, in VETC‐positive HCC ( p = 0.046). The number of tumor‐infiltrating OSM‐positive cells was significantly low in VETC‐positive HCC ( p = 0.0057). Notably, in VETC‐positive HCC, the number of OSM‐positive cells was not associated with vascular invasion, whereas in VETC‐negative HCC, an increase in the number of OSM‐positive cells was associated with vascular invasion ( p = 0.042).
Conclusions
We identified an association between a decrease in OSM‐positive cells and the VETC pattern. Additionally, our findings indicate that VETC‐positive HCC is characterized by low hepatocyte differentiation and OSM‐independent vascular invasion. These findings highlight the potential interaction between VETC‐positive HCC cells and their TIM through the reduction of OSM‐expressing cells.
Ochratoxin A (OTA) is a mycotoxin that causes renal carcinogenicity following induction of karyomegaly in proximal tubular cells after repeated administration to rats. Here, we performed gene profiling regarding altered DNA methylation and gene expression in the renal tubules focusing on the mechanism of OTA-induced carcinogenesis. For this purpose, OTA or 3-chloro-1,2-propanediol (3-MCPD), a renal carcinogen not inducing karyomegaly, was administered to rats for 13 weeks, and DNA methylation array and RNA-Seq analyses were performed on proximal tubular cells. Genes for which OTA altered the methylation status and gene expression level, after excluding genes showing similar expression changes by 3-MCPD, were subjected to confirmation analysis of the transcript level by real-time reverse-transcription PCR. Gene Ontology (GO)-based functional annotation analysis of validated genes revealed a cluster of hypermethylated and downregulated genes enriched under the GO term "mitochondrion," such as those associated with metabolic reprogramming in carcinogenic process (Clpx, Mrpl54, Mrps34, and Slc25a23). GO terms enriched for hypomethylated and upregulated genes included "response to arsenic-containing substance," represented by Cdkn1a involved in cell cycle arrest, and "positive regulation of IL-17 production," represented by Osm potentiating cell proliferation promotion. Other genes that did not cluster under any GO term included Lrrc14 involved in NF-κB-mediated inflammation, Gen1 linked to DNA repair, Has1 related to chromosomal aberration, and Anxa3 involved in tumor development and progression. In conclusion, a variety of genes engaged in carcinogenic processes were obtained by epigenetic gene profiling in rat renal tubular cells specific to OTA treatment for 13 weeks.
