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Background: Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver.Methods: We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses.Results: The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC.Conclusion: Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC. [ABSTRACT FROM AUTHOR]

Aim: Liver ischemia–reperfusion (I/R) injury is a severe complication of liver surgery. However, the responsible molecular mechanism remains unclear. High‐mobility group box 1 (HMGB1) is released from the nuclei of cells and behaves as a damage‐associated molecular pattern. The aim of this study is to reveal the roles of HMGB1 and the effects of recombinant thrombomodulin (rTM) in I/R liver injury. Methods: Rats underwent partial hepatic ischemia followed by reperfusion, and changes in HMGB1 were assessed. Recombinant thrombomodulin was used as an inhibitor of HMGB1. Results: In rats with I/R injury, the HMGB1 level significantly decreased in the liver tissue and significantly increased in the serum after surgery (P < 0.001 for both). No difference in the HMGB1 level in the hepatocytes was observed between the rTM(−) group and rTM(+) group after surgery. Conversely, the serum HMGB1 level was significantly lower in the rTM(+) group than the rTM(−) group after surgery (P < 0.001). The levels of tumor necrosis factor‐α and interleukin‐6 in the liver tissue 24 h after surgery were significantly lower in the rTM(+) group than the rTM(−) group (P < 0.001). The plasma alanine aminotransferase level at 24 h after surgery of the rTM(+) group was significantly decreased after surgery compared with that of the rTM(−) group (P < 0.001). The necrotic area of the liver tissue 24 h after surgery was significantly smaller in the rTM(+) group than the rTM(−) group (P < 0.001). Conclusions: Recombinant thrombomodulin can serve as a treatment for I/R liver injury by inhibiting HMGB1. [ABSTRACT FROM AUTHOR]

Purpose: We analyzed the feasibility and safety of our preliminary surgical approach for total hepatic resection of the right hepatic vein drainage area (THR-RHV) with the aid of three-dimensional computed tomography (3D-CT) guidance. Methods: Clinical findings and 3D-CT volumetry results were investigated in five patients who underwent THR-RHV for a hepatic malignant tumor close to the right hepatic vein (RHV). Results: The mean estimated remnant liver volume after a conventional right lobectomy was 474 ml, whereas that after THR-RHV was 614 ml, indicating that 140 ml (13.8%) of additional liver volume had been preserved by performing THR-RHV. The median operative time, mean ischemic time, and mean blood loss during surgery were 406 min, 51 min, and 587 ml, respectively. Histological examinations confirmed a negative surgical margin in all five patients. The mean liver volume estimated by 3D-CT was 458 ml, whereas the mean actual resected liver volume was 468 g, resulting in a mean error ratio of 3.1%. Conclusions: THR-RHV allowed for a higher remnant liver volume than that after conventional right lobectomy of the liver, and proved feasible with acceptable perioperative results. This technique thus promotes both safety and curability for patients with a tumor close to the RHV. [ABSTRACT FROM AUTHOR]