Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction

Background: The M2 phenotype of tumor-associated macrophages (TAM) inhibits the anti-tumor inflammation, increases angiogenesis and promotes tumor progression. The transcription factor Nuclear Factor (erythroid-derived 2)-Like 2 (Nrf2) not only modulates the angiogenesis but also plays the anti-inflammatory role through inhibiting pro-inflammatory cytokines expression; however, the role of Nrf2 in the cancer cell and macrophages interaction is not clear. Methods: Hepatocellular carcinoma cells (Hep G2 and Huh 7) and pancreatic cancer cells (SUIT2 and Panc-1) were co-cultured with monocytes cells (THP-1) or peripheral blood monocytes derived macrophages, then the phenotype changes of macrophages and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of Nrf2 in cancer cells and macrophages interaction were investigated. Results: In this study, we found that cancer cells could induce an M2-like macrophage characterized by up-regulation of CD163 and Arg1, and down-regulation of IL-1b and IL-6 through Nrf2 activation. Also, Nrf2 activation of macrophages promoted VEGF expression. The Nrf2 activation of macrophages correlated with the reactive oxygen species induced by cancer cells derived lactate. Cancer cells educated macrophages could activate Nrf2 of the cancer cells, in turn, to increase cancer cells epithelial-mesenchymal transition (EMT) through paracrine VEGF. These findings suggested that Nrf2 played the important role in the cancer cells and macrophages interaction. Conclusions: Macrophage Nrf2 activation by cancer cell-derived lactate skews macrophages polarization towards an M2-like phenotype and educated macrophages activate Nrf2 of the cancer cells to promote EMT of cancer cells. This study provides a new understanding of the role of Nrf2 in the cancer cell and TAM interaction and suggests a potential therapeutic target

Intraoperative 3D hologram in liver surgery

An intra-operative 3D hologram with mixed reality techniques contributed to “last-minute simulation”, not for “navigation” in liver surgery. This intra-operative hologram might be a new next-generation operation-supportive tool in terms of spatial awareness, sharing, and simplicity.Objective The aim of this study was to investigate the potential of an intra-operative 3D hologram, which was a computer graphics (CG) model liver, with mixed reality (MR) techniques in liver surgery. Summary Background Data The merits for the application of a hologram for surgical support are: 1) no sterilized display monitor; 2) better spatial awareness; and 3) 3D images shared by all the surgeons. Methods 3D polygon data using pre-operative computed tomography (CT) data was installed into head mount displays, HoloLens (Microsoft Corporation, Redmond, WA). Results In a Wi-Fi-enabled operative room, several surgeons wearing HoloLens succeeded in sharing the same hologram and moving that hologram from respective operators’ angles by means of easy gesture-handling without any monitors. The intra-operative hologram contributed to better imagination of tumor locations, and for determining the parenchymal dissection line in the hepatectomy for the patients with more than twenty (20) multiple colo-rectal liver metastases (CRLMs). In another case, the hologram enabled a safe Gliisonean pedicle approach for hepato-cellular carcinoma (HCC) with a hilar anatomical anomaly. Surgeons could easily compare the real patient’s anatomy and that of the hologram just before the hepatic hilar procedure. Conclusions This initial experience suggested that an intra-operative hologram with MR techniques contributed to “last-minute simulation”, not for “navigation”. The intra-operative hologram might be a new next-generation operation-supportive tool in terms of spatial awareness, sharing, and simplicity

Epigenetic modulation on sphere

Background : Cancer stem cell properties are highly relevant to the biology of treatment-resistant cancers. Epigenetic modification regulates gene expressions by chromatin remodeling during malignant transformation. The aim of this study was to elucidate the possible strategy for cancer stem cells focusing on epigenetic modification. Methods : We made cancer sphere from HepG2 cells, and we added Histone deacetylase (HDAC) inhibitor, valproic acid to cancer sphere. And we compared methylation status and the gene expression between normal HepG2 and cancer sphere groups, and between cancer sphere and sphere with HDAC inhibitor treatment groups. Results : Valproic acid (VPA) cancelled this spheroid formation. In comparison between normal HepG2 and cancer sphere, the number of methylation status changes more than 0.1 of beta level was 826 probes, and we could isolate some epithelial-mesenchymal transition (EMT) related genes. And VPA reduced the expressions of EMT related genes in sphere with RT-PCR. On the other hand, in comparison between cancer sphere and sphere with VPA treatment, we detected 29 probe of methylation status change, and VPA reduced the expressions of Bcl-6 in sphere. Conclusions : HDAC inhibitor affected the methylation status of cancer stem cells. Histone-acetylation might overcome treatmet-resistant cancer through the regulation of cancer stem cell

protective effect of EGCG on mouse islets

Purpose: Epigallocatechin 3-gallate (EGCG), a green tea polyphenol, has been shown to have anti-oxidant and anti-inflammatory effects in vitro and in vivo. The aim of this study was to investigate the effects and mechanism of EGCG on isolated pancreatic islets as pre-conditioning for pancreatic islet transplantation. Methods: The pancreatic islets were divided into two groups: an islet culture medium group (control) and an islet culture medium with EGCG (100 μM) group. We investigated the islet viability, Nrf2 expression, reactive oxygen species (ROS) production, and heme oxygenase-1 (HO-1) mRNA. Five hundred islet equivalents after 12 h of culture for the EGCG 100 μM and control group were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic ICR mice. Results: The cell viability and insulin secretion ability in the EGCG group were preserved, and the nuclear translocation of Nrf2 was increased in the EGCG group (p<0.01). While the HO-1 mRNA levels were also higher in the EGCG group than in the control group (p<0.05), the ROS production was lower (p<0.01). An in vivo functional assessment showed that the blood glucose level had decreased in the EGCG group after transplantation (p<0.01). Conclusion: EGCG protects the viability and function of islets by suppressing ROS production via the Nrf2 pathway

High expression of cancer stem cell markers in cholangiolocellular carcinoma

Purpose Cholangiolocellular carcinoma (CLC) is an extremely rare malignant liver tumor. It is thought to originate from the ductules and/or canals of Hering, where hepatic stem cells (HpSC) are located, but there are few reports on cancer stem cell markers in CLC. Thus, we evaluated the significance of cancer stem cell markers, including CD133, CD44, and EpCAM, in CLC. Methods The subjects of this study were three patients with CLC and one patient with an intermediate type of combined hepatocellular cholangiocarcinoma (CHC). The cancer cell markers, CK7, CK19, and EMA, were evaluated immunohistochemically. Results Histological examination of the CLC revealed morphologically cholangiolar features and immunohistochemical examination revealed positivity for CD133, CD44, and EpCAM. On the other hand, in the intermediate type of CHC, only CD44 was positive, whereas CD133 and EpCAM were negative. Conclusion CLC may have stronger features derived from HpSCs than an intermediate type of CHC

Complication of portal vein thrombosis after right hemihepatectomy in a patient lacking the portal vein bifurcation

Absence of portal vein bifurcation is a rare anomaly. We report a patient with this anomaly who underwent right hemihepatectomy for treatment of hepatocellular carcinoma. Although the procedure was carefully performed with a preoperative three-dimensional simulation and intraoperative cholangiography, postoperative portal vein thrombosis occurred

Effect of histone deacetylase inhibitor in combination with 5-fluorouracil on pancreas cancer and cholangiocarcinoma cell lines

Background : Histone deacetylase (HDAC) is well known to be associated with tumorigenesis through epigenetic regulation, and its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. We examined the therapeutic effects of valproic acid (VPA, a HDACI) with a combination of 5-fluorouracil (5-FU) in vitro. Methods : A human pancreas cancer cell line (SUIT-2) and a cholangiocarcinoma cell line (HuCCT1) were used. Cell viabilities were evaluated by a cell proliferation assay. We determined the anticancer effects of VPA combined with 5-FU in these cell lines. Results : Pancreas cancer (SUIT-2) : No effect of 5-FU (1.0 μM) was observed, but 17% and 30% of proliferationinhibitory effects were recognized in a dose of 2.5 or 5.0 μM, respectively. Cell viability was only weakly reduced by VPA (0.5 mM). However, in combination of 5-FU (1.0 μM) with VPA (0.5 mM), 19% of inhibitory effect was observed. Cholangiocarcinoma (HuCCT1) : 5-FU (1.0 μM) did not suppress the cell viability, but 5-FU (2.5 μM) suppressed by 23%. VPA (0.5 mM) did not suppress the cell viability, while VPA (1.0 mM) weakly decreased it by 11%. Combination of 5-FU (1.0 μM) and VPA (0.5 mM) markedly reduced the cell viability by 30%. Conclusion : VPA augmented the anti-tumor effects of 5-FU in cancer cell lines. Therefore, a combination therapy of 5-FU plus VPA may be a promising therapeutic option for patients with pancreas cancer and cholangiocarcinoma

Fbxw7発現低下は大腸癌肝転移切除症例の再発予測因子である

Background/Purpose Fbxw7 is a tumor suppressor through ubiquitination and degradation of multiple oncoproteins. Loss of Fbxw7 is frequently observed in various human cancers. In this study, we examined the role of Fbxw7 expression in colorectal liver metastasis (CRLM) and its mechanism. Methods Fifty-six patients with CRLM who undergo curative resection were enrolled. Fbxw7 in tumor tissue was determined by immunohistochemistry. Patients were divided into two groups, the Fbxw7 high and low group. Clinicopathological factors including miR-223 expression were compared between the high (n=32) and low Fbxw7 group (n=24). Results Fbxw7 expression in tumor tissues was significantly lower than that in normal tissues. The disease-free survival in the low Fbxw7 group was significantly worse than that in the high Fbxw7 group, and 3years disease-free survival of the low and the high Fbxw7 group were 12.5% and 47.0%, respectively (p=0.023). On multivariate analysis, loss of Fbxw7 was detected as one of the independent risk factor for recurrence of CRLM (Hazard ratio: 2.390, p=0.017). Likewise, Fbxw7 expression inversely correlated to miR-223 expression (p=0.017). Conclusion Loss of Fbxw7 in tumor tissues could be a reliable predictor of recurrence after hepatectomy in patients with CRLM, and miR223 might be a possible regulator of Fbxw7

Hepatic screlosed hemangioma which was misdiagnosed as metastasis of gastric cancer : report of a case

A screlosed hemangioma of the liver is rare among hepatic tumors. A 75 years old male was referred to our hospital for gastric cancer and a hepatic tumor. The histological finding of gastric cancer was revealed to be well differentiated adenocarcinoma. The liver tumor was 1.1×1.0 cm in size and located in segment 8 of the liver. Computed tomography (CT) showed it to be a tumor with ring enhancement. Magnetic resonance imaging (MRI) showed the tumor to have a low signal on T1-weighted and slightly high signal on T2-weighted images. Level of hemoglobin was 7.8 g/dl. It was thought to be persistent bleeding from gastric cancer. With diagnosis of liver metastasis from gastric cancer, chemotherapy is recommended. However, to control the bleeding from gastric cancer, we performed distal gastrectomy and wedge resection of liver (S8). The histological examination of the liver tumor revealed to be a hepatic sclerosed hemangioma with hyalinized tissue and collagen fibers. We report herein a case of the rare tumor which was misdiagnosed as a liver metastasis of gastric cancer