No abstract

Our results show that NLR is an independent predictor of survival after hepatectomy in patients with HCC. Accumulation of tumor-associated macrophages in the tumor is associated with a high NLR.

Recent studies have shown that the tumor microenvironment plays an important role in cancer progression. Tumor-associated macrophages (TAMs), in particular, have been found to be associated with tumor progression. Macrophages have multiple biological roles, including antigen presentation, target cell cytotoxicity, removal of foreign bodies, tissue remodeling, regulation of inflammation, induction of immunity, thrombosis, and endocytosis. Recent immunological studies have identified two distinct states of polarized macrophage activation: the classically activated (M1) and the alternatively activated (M2) macrophage phenotypes. Bacterial moieties such as lipopolysaccharides and the Th1 cytokine interferon-γ polarize macrophages toward the M1 phenotype. The M2 polarization was discovered as a response to the Th2 cytokine interleukin-4. In general, M2 macrophages exert immunoregulatory activity, participate in polarized Th2 responses, and aid tumor progression. TAMs have recently been found to play an important role in hepatocellular carcinoma (HCC) progression. Based on the properties of TAMs, obtained from pathological examination of resected specimens, we have identified new therapeutic approaches, involving the targeting of TAMs with adjuvant therapy after hepatic resection for HCC. This review discusses the roles of TAM in HCC progression and the possibility of new therapies targeting TAMs.

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. YKL-40, chitinase-like protein expressed in multiple tissues including liver, is involved in cell proliferation, inflammation and remodeling of the extracellular matrix. The aim of this study was to assess whether serum YKL-40 levels are associated with liver fibrosis in NAFLD patients. Serum YKL-40 levels were quantified in 111 NAFLD patients and 23 HCC patients with NAFLD. To identify the source of YKL-40, immunofluorescence staining of liver specimens from NAFLD patients was performed. Serum YKL-40 levels in NAFLD patients increased in accordance with the progression of liver fibrosis. Multivariate analysis revealed that YKL-40 was one of the independent factors significantly associated with severe fibrosis (F3-4). We established a new predictive model for fibrosis of NAFLD, using logistic regression analysis: YKL-40 based fibrosis score = −0.0545 + type IV collagen 7s * 0.3456 + YKL-40 * 0.0024. Serum YKL-40 levels of HCC patients with non-cirrhotic NAFLD were significantly higher than those without HCC. Immunofluorescence staining showed that YKL-40 was expressed by macrophages in liver tissue of NAFLD patients. In conclusion, macrophage-derived YKL-40 is a feasible biomarker of liver fibrosis in NAFLD patients.

Objective: Signal transducer and activator of transcription 3 (STAT3) is activated in hepatocellular carcinoma (HCC), and tumor-associated macrophage plays an important role in tumor progression. Therefore, we examined STAT3 activation, cytokine expression and infiltration of tumor-associated macrophages in resected HCCs as well as the alteration of cell growth and migration by cytokine stimulation in HCC cell lines. Methods: Immunohistochemical staining of phosphorylated STAT3 (pSTAT3), CD163, interleukin (IL)-6, Ki-67 and Bcl-XL was performed for 101 cases of resected HCC, and correlations between pSTAT3 staining and clinicopathological findings were analyzed. In HCC cell lines (PLC/PRF/5 and Huh7), cell proliferation and migration by IL-6 stimulation and S3I-201 (STAT3 inhibitor) treatment were analyzed. Results: In HCC specimens, the pSTAT3-positive group showed high levels of α-fetoprotein (p = 0.0276), large tumor size (p = 0.0092), frequent intrahepatic metastasis (p = 0.0214), high Ki-67 (p = 0.0002) and Bcl-XL (p = 0.0001), poor prognosis (p = 0.0234), and high recurrence rate (p = 0.0003). CD163-positive cells were frequently observed in the pSTAT3-positive group (p = 0.0013). In two HCC cell lines, IL-6 stimulation promoted cell proliferation and migration via the STAT3 phosphorylation, and S3I-201 inhibited this activation. Conclusions: STAT3 activation was correlated with aggressive behavior of HCC and may be mediated via tumor-associated macrophage. We expect that STAT3 signaling and tumor-associated macrophages can be attractive therapeutic targets in HCC patients.