pexidartinib and Liver-Neoplasms

Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Macrophage Colony-Stimulating Factor; Receptor, Macrophage Colony-Stimulating Factor

MicroRNAs (miRNAs) are small non-coding molecules that exhibit important regulatory roles in various biological or cellular functions, including tumor metastasis. However, the detailed mechanisms of the expression and functions of miRNAs in hepatocellular carcinoma (HCC) have not yet been completely investigated.. In this study, the levels of miR-148b in HCC cells and patient specimens were determined using qPCR assays. MiR-148b-overexpressing HCC cells were used to investigate the effect of miR-148b in vitro and in vivo. The relationship between the expression of miR-148b and colony stimulating factor-1 (CSF1) in HCC patients and the infiltration of macrophages into the tumor microenvironment were assessed by immunohistochemical staining.. MiR-148b expression was decreased in metastatic HCC cells. A positive association between downregulated miR-148b expression and several clinical parameters, including recurrence, metastasis, and poor prognosis, was observed in patients with HCC. The results of bio-functional experiments indicated that the biological characteristics of HCC cells were not affected by miR-148b deficiency in vitro. However, miR-148b deficiency significantly enhanced the progression and metastasis of HCC in nude mice. By analyzing the gene expression profiles, we demonstrated that CSF1 was regulated by miR-148b and that miR-148b deficiency promoted HCC growth and metastasis through CSF1/CSF1 receptor (CSF1R)-mediated tumor-associated macrophage (TAM) infiltration. These results were supported by the negative relationship between miR-148b and CSF1 expression and TAM infiltration in HCC patients. Moreover, HCC patients with low miR-148b levels and high TAM infiltration were associated with poorer prognosis.. MiR-148b-CSF1 signaling-induced TAM infiltration promotes HCC metastasis. Therefore, miR-148b plays a suppressor role in HCC and might be a potential prognostic factor and therapeutic candidate for HCC.

Topics: Aminopyridines; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice; Mice, Nude; MicroRNAs; Neoplasm Metastasis; Neoplasms, Experimental; Pyrroles; Signal Transduction

In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models.. OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Biomarkers, Tumor; Carcinoma, Hepatocellular; Chemotaxis; Cytokines; Gene Deletion; Humans; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice, Knockout; Molecular Targeted Therapy; Osteopontin; Prognosis; Pyrroles; Tumor Cells, Cultured; Tumor Escape; Tumor Microenvironment

Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1R, regulate the differentiation and function of macrophages and play an important role in macrophage infiltration in the context of hepatocellular carcinoma. The therapeutic effects of CSF-1R blockade in hepatocellular carcinoma remain unclear. In this study, we found that CSF-1R blockade by PLX3397, a competitive inhibitor with high specificity for CSF-1R tyrosine kinase, significantly delayed tumor growth in mouse models. PLX3397 inhibited the proliferation of macrophages

Topics: Aminopyridines; Animals; Biomarkers, Tumor; Bone Marrow Cells; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Polarity; Cell Proliferation; Humans; Liver Neoplasms; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Monocytes; Phenotype; Pyrroles; Receptor, Macrophage Colony-Stimulating Factor; Tumor Microenvironment