Fibrinogen‑like protein 2 promotes the accumulation of myeloid‑derived suppressor cells in the hepatocellular carcinoma tumor microenvironment

Abstract

The tumor microenvironment in hepatocellular carcinoma can be classified into cellular and non-cellular components. Myeloid-derived suppressor cells (MDSCs) are cellular components of this microenvironment that serve an important role in the progression of hepatocellular carcinoma. Fibrinogen-like protein 2 (FGL2) has been demonstrated to promote tumor progression by regulating cellular components of the tumor microenvironment in various types of malignant tumor. The present study aimed to determine the expression of FGL2 in hepatocellular carcinoma and its effect on the tumor microenvironment in order to determine novel targets for liver cancer treatment. Immunohistochemistry and reverse transcription quantitative PCR were performed to determine the expression level of FGL2 and the correlation with surface markers of human MDSCs in hepatocellular carcinoma. Furthermore, a mouse hepatocellular carcinoma cell line overexpressing FGL2 was established by stable transfection of a lentivirus expressing FGL2. In addition, fresh bone marrow cells extracted from mouse femurs were in vitro cultured using conditioned medium derived from the cell line overexpressing FGL2. An orthotopic hepatocellular carcinoma mouse model was also established. The results demonstrated that FGL2 expression level in hepatocellular carcinoma tissues was closely associated with tumor size. FGL2 level was positively correlated with the expression level of the MDSC surface markers CD11b and CD33 in hepatocellular carcinoma. The in vitro results demonstrated that FGL2 could maintain the undifferentiated state of bone marrow cells, therefore promoting MDSC accumulation. Furthermore, in the orthotopic hepatocellular carcinoma mouse model, we observed that overexpression of FGL2 could promote tumor growth and significantly increase the number of MDSCs in the tumors and spleen. Taken together, these findings suggested that FGL2 may promote hepatocellular carcinoma tumor growth by promoting the accumulation of MDSCs in the tumor microenvironment.

The role of Fibrinogen-like proteins in Cancer

“…In GBM, targeting expression of FGL2 in vivo can strengthen the immune function and improve the therapeutic outcome of glioma patients 77 . In vitro studies have shown that knockdown of FGL2 expression can inhibit the proliferation of HCC cells by arresting G0/G1 cell cycle and affecting angiogenesis in HCC 78 , or by promoting the accumulation of myeloid-derived suppressor cells (MDSCs), which promote cancer progression, in liver tumor microenvironment 79 . Studies have shown that Ad-hFGL2-miRNA (an adenoviral vector expressing anti-hFGL2 artificial miRNA) proscribes tumor growth and is involved in its repression of hFGL2 and attenuation of angiogenesis.…”

CFTR interactome mapping using the mammalian membrane two‐hybrid high‐throughput screening system

“…It exists as both a type II transmembrane protein found on the surface of macrophages and endothelial cells, and a secreted protein by T cells (Marazzi et al , 1998) and it has been associated with liver, interstitium and renal fibrosis by facilitating macrophage polarization (Foerster et al , 2010; de Ridder et al , 2016; Wu et al , 2020). The membrane bound FGL2 has been shown to possess a serine protease activity, cleaving prothrombin to thrombin leading to fibrin deposition and thrombosis and was originally found to be implicated in the pathogenesis of fulminant hepatitis in humans (Levy et al , 2000) and has been used as a biomarker of severe liver diseases, including cancer (Foerster et al , 2010; Manns et al , 2017; Liu et al , 2021). Though little is known about the immunoregulatory properties of FGL2, its expression also seems to play a critical role in the pathogenesis of allograft rejection (Ning et al , 2005; Bézie et al , 2015) and thus in innate immunity.…”

Predictive Value of Biomarkers Fibrinogen Like Protein-2 and A-Fetoprotein for Hepatocellular Carcinoma Among Patients with Liver Cirrhosis

“…Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells are antitumor immune cells that play an integral role in cancer immune surveillance and eradication of tumor cells whereas accumulation of regulatory T cells (Tregs) that frequently occurs in HCCs, is associated with CTLs and NK cells dysfunction, tumor invasiveness as well as progression, and poor patient outcomes [12,13]. Fibrinogen-like protein 2 (FGL-2), that is mainly secreted by regulatory T cells, has been demonstrated to promote tumor progression by regulating cellular components of the tumor microenvironment [9,13]. In our study we evaluate soluble FGL-2 levels in Caucasian cirrhotic patients with or without HCC as well as their predictive value for HCC emergence during the surveillance program.…”

“…Soluble fibrinogen-like protein 2 (sFGL-2) is the soluble form of fibrinogen-like protein 2, that is mainly secreted by regulatory T cell (Treg) populations and creates a potently immunosuppressive microenvironment, so sFGL-2 might play a role in inhibiting endogenous antitumor immune responses [8]. A recent study suggests that FGL-2 may promote the growth of hepatocellular carcinoma by promoting the accumulation of myeloid-derived suppressor cells in the tumor microenvironment [9]. Data concerning soluble FGL-2 levels in patients with chronic hepatitis B [10], chronic hepatitis C [8], liver cirrhosis and HCC [11] suggest that there is a significant correlation between them and the progression and severity of underlying liver disease as well as with the clinical outcome.…”