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Biological activity of Oncostatin M in Liver Cancer: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Alessandra Caligiuri.

Oncostatin M (OSM) is a 26 kDa molecular weight multifunctional cytokine belonging to the IL-6 (or gp130) cytokine family, which includes IL-6, leukemia inhibitory factor (LIF), IL-11, IL-27, IL-30, IL-31, ciliary neurotrophic factor (CNTF), neuropoietin-1 (NP-1), and cardiotrophin 1 (CT-1). OSM critically contributes to physiological and pathological processes, including extracellular matrix remodeling, hematopoiesis, differentiation, inflammatory response, proliferation, acquisition of cancer stem cell markers, drug resistance, and metastatic phenotype.

  • oncostatin M
  • tumor microenvironment
  • inflammation
  • hepatocellular carcinoma

1. Oncostatin M: ID Card

Pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, as well as their signaling pathways, involving nuclear factor kappa B (NF-κB), c-Jun NH2-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3), play a key role in innate- and adaptive-immunity-mediated liver carcinogenesis [26][1]. In particular, IL-6 and STAT3 overexpression has been related to both HCC and CCA promotion and development, pointing out these molecules as potential therapeutic targets [26,27,28][1][2][3].
Oncostatin M (OSM) is a 26 kDa molecular weight multifunctional cytokine belonging to the IL-6 (or gp130) cytokine family, which includes IL-6, leukemia inhibitory factor (LIF), IL-11, IL-27, IL-30, IL-31, ciliary neurotrophic factor (CNTF), neuropoietin-1 (NP-1), and cardiotrophin 1 (CT-1). OSM, which shares high structural, functional, and genetic homology with LIF [29[4][5],30], is a unique cytokine, which critically contributes to physiological and pathological processes, including extracellular matrix remodeling, hematopoiesis, differentiation, inflammatory response, proliferation, acquisition of cancer stem cell (CSC) markers, drug resistance, and achievement of metastatic phenotype [29,30,31][4][5][6]. OSM, although mainly produced by activated cells of innate and adaptive immunity (monocytes/macrophages, neutrophils, dendritic cells, T lymphocytes, hematopoietic, and mesenchymal cells) [29,31,32][4][6][7] can be secreted also by cancer cells [33][8]. OSM operates through two different heterodimeric receptors: the type I receptor, formed by gp130 and the LIF receptor β (LIFRβ), and the type II receptor, formed by gp130 and the OSM receptor β (OSMRβ) (Figure 1), which are differentially engaged in human and mouse. Human OSM can bind to either gp130/OSMRβ or gp130/LIFRβ, whereas murine OSM binds only the type II receptor [34,35][9][10]. Of interest, the OSMRβ/LIFRβ ratio and their different expression on various cell types represent the mechanism by which OSM and LIF can exert common biological functions in some tissues and distinct unique actions in others [35][10].
Figure 1. Different receptor binding for human and mouse OSM. OSM binds two different heterodimeric receptors: the type I receptor, formed by gp130 and LIFRβ, and the type II receptor, formed by gp130 and the OSM receptor β (OSMRβ). Human OSM can bind to both gp130/OSMRβ and gp130/LIFRβ, whereas murine OSM interacts only with the type II receptor. OSM: oncostatin M; LIFRβ: LIF receptor β.
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][4][6][10]. JAKs’ recruitment activates intracellular signaling pathways and stabilizes the OSM receptor complex: the binding of JAK1 to the OSMRβ is crucial for masking hydrophobic amino acids, which usually regulate the confinement of OSMRβ in the endoplasmic reticulum [29,32,36][4][7][11].
The C-terminal region of receptor types I and II contains tyrosine motifs, which, phosphorylated by JAK1/2, act as a docking site for STAT1 and STAT3. Moreover, STAT1 tyrosine phosphorylation can be independent of the OSMRβ receptor tyrosine motifs and due to a direct action of JAKs [29][4]. Moreover, OSM, unlike the IL-6 family of cytokines, but similar to IL-4 and IL-13, can activate STAT6 in a cell-type-specific way [29,37][4][12]. Furthermore, OSM can recruit, on a conserved OSMRβ-Tyr861 residue, the adapter sarcoma (Src) homology and collagen (Shc) protein, which, in turn, can activate other downstream proteins such as extracellular-regulated kinase 1/2 (ERK1/2), p38, or JNK [31,32,35,38,39][6][7][10][13][14]. OSM has also been reported to activate the PI3K/Akt pathway [39][14] and PKCδ [40][15] through mechanisms still poorly characterized. OSM 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][6][7][10]. An overview of the signaling pathways activated by OSM is reported in Figure 2.
Figure 2. 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, which, phosphorylated by JAK1/2, act as a docking site for STAT1 and STAT3. OSM can also activate other downstream proteins such as ERK1/2, p38, JNK, the PI3K/Akt pathway, and PKCδ. OSM: oncostatin M; JAKs: Janus kinases; Erk1/2: extracellular-regulated kinase ½; PI3K: phosphatidylinositol 3-kinase; STAT: signal transducer and activator of transcription; JNK: Jun N-terminal kinase; PKC: protein kinase C.

2. Biological Activity of Oncostatin M

OSM is a pleiotropic cytokine that can affect several biological processes depending on the cell type, including inflammatory response, proliferation, EMT, invasiveness, metastasis, and CSC behavior.

2.1. Role of OSM in Inflammation

OSM plays a major role in inflammation, being involved in the acute phase response and in chronic inflammatory conditions, leading eventually to tissue fibrosis and cancer, as well as being expressed by immune cells in response to a variety of soluble mediators [41][16]. OSM can act either directly recruiting/activating innate immune cells or, indirectly, by regulating stromal cells located at the injured areas. Depending on the cellular context and the intracellular signaling elicited, OSM may display either anti- or pro-inflammatory activities [42,43][17][18]. Murine and human recombinant OSM have been used in murine models to reveal OSM’s contribution to inflammation. Since human recombinant OSM can bind only the murine type I receptor and activate the related signaling pathway [44][19], the anti-inflammatory action of OSM operates through this receptor complex. Accordingly, OSM released by neutrophils in inflamed tissues can inhibit IL-1-induced expression of IL-8, then inhibiting local neutrophil infiltration and stimulating proliferation and collagen release by dermal fibroblasts, speeding up the wound healing process in a diabetic murine model [42,43][17][18]. Intramuscular OSM injection in mice, via adenoviral-OSM (AdOSM) delivery, resulted in IL-33’s increased secretion by liver endothelial cells and consequent expansion/activation of liver CD4+ ST2+ lymphocytes exhibiting hepato-protective role [45][20]. Similarly, intravenous injection of AdOSM in diethyl-nitrosamine (DEN)-treated rats protected them from liver damage, likely due to the pro-regenerative action exerted by OSM on hepatocytes [46][21]. In contrast, repetitive intravenous vector-delivered OSM administration in healthy mice resulted in hepatic fibrosis, whereas OSM-deficient mice were protected from thioacetamide-induced liver fibrosis [47][22].
OSM has been associated with pro-inflammatory activities, inducing target cells to release cytokines and chemokines such as CXCL3, CCL2, CCL5, and CCL20 [48][23], which further recruit neutrophils and monocytes/macrophages, thus creating positive feedback, which amplifies OSM’s effects. Accordingly, in chronic inflammatory conditions, OSM/OSMβR are often overexpressed and OSM sustains inflammation and promotes fibrosis. Notably, OSM is the only IL6-family member able to bind extracellular matrix (ECM) molecules (collagens, fibronectin, laminin), upregulating their expression and remaining localized in high concentrations at the site of injury [49,50][24][25].
In tumors, OSM and other members of the IL-6 cytokine family can exhibit indirect pro-tumorigenic effects affecting the tumor microenvironment and stromal cells and modulating inflammatory and immune responses [51][26]. In a murine model carrying a specific deletion of von Hippel-Lindau (VHL)-deficient renal tubular cells, OSM led to endothelial cells’ activation, favoring the recruitment and polarization of macrophages, then generating an inflammatory and tumorigenic microenvironment and promoting the development of clear-cell renal carcinoma [52][27]. At present, a role for the OSM/OSMR axis in reconstituting a milieu suitable to cancer progression has been reported in pancreatic ductal adenocarcinoma, with macrophage-derived OSM upregulating pro-inflammatory genes in CAFs, leading to tumor growth and metastasis [53][28]. In breast carcinoma, hypoxic epithelial tumor cells overexpress and release high levels of OSM, favoring the recruitment and M2 polarization of macrophages [54][29]. Moreover, myeloid-cell-derived OSM can drive CAFs to a pro-carcinogenic phenotype, showing increased contractility and secretion of soluble mediators, leading to immune cells’ accumulation and further supporting breast cancer development [55][30].
Regarding CCA, a recent study outlined the relevance of an inflammatory microenvironment in iCCA progression mediated in part by OSM [60][31]. Co-cultures of tumor-associated neutrophils (TANs)/TAMs with iCCA cells promoted tumor progression through OSM and IL-11 production by TANs and TAMs, respectively. Moreover, a positive correlation between immune cell infiltration and p-STAT3 expression was proposed to represent a predictive parameter for poor prognosis in CCA patients [60][31]. Indeed, the literature reported for CCA tissues a strong correlation between OSM expression and tumor infiltration of immune cells, including M2 macrophages, as well as a positive correlation with immune checkpoints such as PD-L1 and CTLA-4 [61][32].

2.2. Role of OSM in Cell Proliferation and Tumor Growth

OSM was originally described as a cytokine able to inhibit the proliferation of cancer cell lines related to melanoma (A375 cells and SK-MEL-28), lung carcinoma (A549), neuroblastoma (HTB10), and embryonic lung (WI-26 and WI-38) [34[9][33],62], with a growth decrease frequently linked to stimulation of cellular differentiation. Moreover, OSM displayed its growth-inhibitory effects in breast cancer cell lines (MCF-7 and MDA-MB231) through activation of STAT1 and STAT3 transcription factors, as well as by modulating the mitogen-activated protein kinase kinase (MEK)/ERK pathways [63][34]. Accordingly, no tumor formation has been observed in mice transfected with OSM-secreting glioblastoma cells, suggesting an anti-tumorigenic effect of OSM [64][35]. An anti-proliferative role of OSM was reported in immune-deficient mice injected with human melanoma cells [65][36] and in a chondrosarcoma model, where local intra-tumor overexpression of OSM reduced tumor development and enhanced tumor cell apoptosis through the JAK3/STAT1 axis [66][37]. Regarding HCC, OSM increased apoptosis and decreased the clonogenicity and growth of SMMC-7721 [67][38] and HepG2 cells [59][39], by reducing the percentage of cells in the S phase due to an arrest at G0/G1. Moreover, xenografted mice injected with OSM-overexpressing HepG2 cells showed smaller tumors, but increased vascularization and spontaneous lung metastasis [59][39]. Similarly, in CD133+ HepG2 cells, OSM treatment resulted in an increased apoptosis, as identified through increased annexin V and cleaved caspase 3 levels [59][39].
On the other hand, data from the last decade also indicate OSM as a pro-carcinogenic cytokine. OSM has been associated with increased proliferation and tumor growth in endometrial [68][40], ovarian [31][6], prostate [69][41], and lung cancer [70][42]. In addition, elevated OSM levels were found in the serum and/or tumor mass and correlated with tumor progression, in brain [71][43] and colon cancers [72][44], myeloma [73][45], pancreatic cancer [74][46], and hepatoblastoma and HCC [58,59][39][47]. Accordingly, treatment with OSM of EpCAM+ HCC cells, but not CD133+ HepG2 cells, induced colony formation and cell proliferation [75,76][48][49]. OSM-supplemented media also led to an expansion rate of 3D organoids populated by adult-donor-derived hepatocytes or by HepG2 cells [77][50].
Regarding CCA, an interesting study showed an increased proliferation and colony-forming ability of iCCA cells following exposure to conditioned medium (CM) collected from TANs and TAMs isolated from iCCA specimens, as well as after exposure of iCCA cells to CM derived from TAN-TAM co-cultures [60][31]. Remarkably, OSM and IL-11 were the most abundant cytokines produced by TANs and TAMs, respectively, and their levels were enhanced in TAN-TAM co-cultures. Accordingly, co-injection of iCCA cells with either TANs, TAMs, or TAN-TAM co-cultures in xenograft experiments resulted in larger tumors than xenografts consisting of only iCCA cells. The protumorigenic action of TANs and TAMs was dependent on the activation of STAT3 in iCCA cells [60][31]. It is then conceivable that OSM, produced by cells of the TME, could contribute to iCCA growth and progression, with TANs, TAMs, and p-STAT3 levels being independent predictors of patient prognosis.

2.3. OSM and Cancer Progression: Cancer Stem Cell Features, Epithelial–Mesenchymal Transition, and Angiogenesis

OSM has been reported to induce EMT [81][51], a crucial process that drives tumor metastasis [82][52], and CSCs’ plasticity program, with CSCs showing self-renewal, tumor initiation, and long-term repopulation potential properties [83][53]. OSM-dependent EMT and stem-like features require STAT3 activation [29,81][4][51]. OSM-activated STAT3 cooperates with TGF-β to induce mesenchymal stem cells’ properties in breast cancer [84][54] and in pancreatic cancer [81][51]. Along these lines, several studies demonstrated a critical role for OSM in metastasis in breast, lung, and gastric cancer [85,86,87][55][56][57].
Concerning HCC, overexpression of OSM in HCC cells or treatment of HCC cells with human recombinant OSM resulted in a rapid activation of STAT3 and induction of typical EMT changes, sprinkling from cell clusters, loss of cell-to-cell contacts, and acquisition of mesenchymal-like features. OSM inhibits E-cadherin and results in increased matrix metalloproteinases 2 (MMP2) and transglutaminase 2 (TGM2) protein levels, thus enhancing HCC cell invasiveness [59][39], similar to a study in which overexpression of OSMR in squamous cell carcinoma triggered TGM2/integrin–α5β1 interaction, leading to an enhanced aggressiveness [88][58]. In addition, xenograft experiments in nude mice showed the formation of spontaneous lung metastasis following injection with HepG2 cells overexpressing OSM; moreover, EMT markers were increased in cancer nodules and correlated with OSM expression in a DEN/choline-deficient L-amino acid (CDAA) hepatocarcinogenic protocol [59][39].
Remarkably, higher levels of OSMR are expressed in epithelial-cell-adhesion-molecule (EpCAM)-positive tumor cells displaying CSC properties. In EpCAM+ HCC cells, OSM induced a decrease of stemness markers, (EpCAM, albumin, and cytokeratin-19) and an increase in albumin expression by the activation of STAT3, indicating that this cytokine plays a role in hepatocyte differentiation. Moreover, in nude mice injected with EpCAM+ HCC cells, a strong inhibition of tumor growth was achieved when 5-fluorouracil (5-FU) and OSM were administered together. Indeed, OSM increased the chemosensitivity of these cells, boosting the antitumor action of 5-FU in HCC and inducing the shift of EpCAM+ CSCs into EpCAM− non-CSCs, highly sensitive to 5-FU [76][49]. Similarly, OSM induced expression of CSCs’ differentiation-related markers in CD133+ HepG2 cells, also inhibiting cell invasion, effects enhanced by the combined treatment with salinomycin, a chemotherapeutic agent targeting CSCs [75][48].
Regarding the promotion of angiogenesis, OSM is able to activate STAT3, and vascular-endothelial growth factor (VEGF) represents the main STAT3-regulated gene product [89][59]. Overexpression of OSMR in cervical SCC cells induced a proangiogenic phenotype [90][60], and in both osteosarcoma and endometrial cancer cells, OSM boosted angiogenesis via JAK/STAT3 pathway activation and enhanced expression of VEGF [68,91][40][61]. In relation to HCC, OSM, by activating the STAT3, ERK1/2, and p38 pathways, was able to induce HIF1α in normoxic conditions, enhancing the expression and release of VEGF and promoting angiogenesis in vivo and in vitro [59,92][39][62]. Moreover, in vivo experiments showed that tumors of mice injected with HCC cells overexpressing OSM are characterized by a more widespread vascularization [59][39].
The biological effects of OSM are resumed in Table 1.
Table 1.
Biological effects of oncostatin M in liver cancer.

Tumor Type

Inflammation

Cancer Cell Proliferation/Tumor Growth

CSCs’ Features and EMT

Angiogenesis

HCC

Induces macrophage recruitment and TNFα secretion [93][63]

Decreases proliferation and increases apoptosis in SMMC-7721 and CD133+ HepG2 cells [67][38].

Induces Grp78 expression in HepG2 and Huh-7 cells [78][64].

Induces cell proliferation in EpCAM+ HCC cells [75][48].

Induces a decrease of stemness markers in EpCAM+ HuH1 and HuH7 cells.

Increases the chemosensitivity of EpCAM+ HCC cells in xenograft mice [76][49].

Induces the expression of CSCs’ differentiation-related markers in CD133+ HepG2 cells and inhibits cell invasion [75][48].

Induces HIF1 upregulation and VEGF gene overexpression.

Xenograft mice injected with OSM-overexpressing HepG2 cells show a more extensive tumor vascularization [59][39].

CCA

Secreted by co-cultured TANs and TAMs [60][31].

Promotes proliferation in iCCA cells via STAT3 [60][31].

Induces iCCA cell invasion via STAT3. Xenograft mice co-injected with TANs, TAMs, and iCCA cells show less metastasis when STAT3 is knocked down in iCCA cells [60][31].

  

CCA: cholangiocarcinoma; CSCs: cancer stem cells; EMT: epithelial–mesenchymal transition: EpCAM: epithelial cell adhesion molecule; HCC: hepatocellular carcinoma; iCCA: intrahepatic cholangiocarcinoma; OSM: oncostatin M; STAT3: signal transducer and activator of transcription 3; TAMs: tumor-associated macrophages; TANs: tumor-associated neutrophils; TNFα: tumor necrosis factor α; VEGF: vascular endothelial growth factor.

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