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Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death. High recurrence rates after curative resection and the lack of specific biomarkers for intrahepatic metastases are major clinical problems. Recently, exosomal microRNAs (miRNAs) have been reported to have a role in the formation of the pre‐metastatic niche and as promising biomarkers in patients with malignancy. Here we aimed to clarify the molecular mechanisms of intrahepatic metastasis and to identify a novel biomarker miRNA in patients with HCC. A highly intrahepatic metastatic cell line (HuH‐7M) was established by in vivo selection. HuH‐7M showed increased proliferative ability and suppression of apoptosis and anoikis. HuH‐7M and the parental cell (HuH‐7P) showed the similar expression of epithelial‐mesenchymal transition markers and cancer stem cell markers. In vivo, mice treated with exosomes derived from HuH‐7M showed increased tumorigenesis of liver metastases. Exosomes from HuH‐7M downregulated endothelial cell expression of vascular endothelial‐cadherin (VE‐cadherin) and zonula occludens‐1 (ZO‐1) in non‐cancerous regions of liver and increased the permeability of FITC‐dextran through the monolayer of endothelial cells. The miRNAs (miR‐638, miR‐663a, miR‐3648, and miR‐4258) could attenuate endothelial junction integrity by inhibiting VE‐cadherin and ZO‐1 expression. In patients with HCC, higher serum exosomal miR‐638 expression was associated with tumor recurrence. In conclusion, the miRNAs secreted from a highly metastatic cancer cell can promote vascular permeability via downregulation of endothelial expression of VE‐cadherin and ZO‐1. Serum exosomal miR‐638 expression holds potential for serving as a significant and independent prognostic marker in HCC. miR‐638, miR‐663a, miR‐3648, and miR‐4258 downregulate VE‐cadherin and ZO‐1 expression in HUVECs.

The cancer drug gemcitabine (GEM) is a key drug for treating pancreatic ductal adenocarcinoma (PDAC), but PDAC cells develop chemoresistance after long-term administration. Since the tolerance was immediately spread to every PDAC tissue in a patient, it is assumed that some certain efficient mechanisms underlay in the development of chemoresistance. Changes in the levels of particular microRNAs or alterations in intercellular communication play a dominant role in chemoresistance development, and recent data also suggest that exosomes play an important role in this process. In this study, we revealed that the loop conferred chemoresistance in PDAC cells. The loop was as follows; 1, The long-term exposure of GEM increased miR-155 expression in PDAC cells. 2, The increase of miR-155 induced two different functions; exosome secretion and chemoresistance ability via facilitating the anti-apoptotic activity. 3, Exosome deliver the miR-155 into the other PDAC cells and induce the following function. The target therapy to miR-155 or the exosome secretion effectively attenuated the chemoresistance, and these results were validated with both clinical samples and in vivo experiments. This mechanism represents a novel therapeutic target in GEM treatment to PDAC.

BackgroundCD36, a multi-ligand scavenger receptor, has been associated with several cancers. Many studies have revealed that CD36 contributed to cancer malignancy. This study aimed to reveal the function of CD36 expression in pancreatic ductal adenocarcinoma (PDAC).MethodsCD36 expression was characterized using immunohistochemistry in 95 clinical specimens resected from patients with PDAC. We divided patients into two groups, with different CD36 expression levels, and analyzed and compared their prognoses. CD36 expression was also assessed in PDAC cell lines. Gemcitabine-resistant (GR) PDAC cell lines were transfected with small interfering RNA (siRNA) that specifically targeted CD36 to evaluate chemoresistance and apoptosis.ResultsIn resected PDAC samples, CD36 expression was significantly correlated with microinvasion into the venous system (p = 0.0284). Patients with high CD36 expression had significantly lower overall survival (OS) and recurrence-free survival (RFS) rates than patients with low expression; thus, CD36 was an independent prognostic factor for OS and RFS. In subgroup analyses, CD36 was an independent risk factor for OS and RFS in 59 patients treated with gemcitabine adjuvant chemotherapy. CD36 expression was upregulated in PDAC–GR cell lines compared with the PDAC parent cell line. Transduction with siRNA downregulated CD36, which reduced PDAC cell resistance to gemcitabine and inhibited anti-apoptosis proteins.ConclusionCD36 expression influenced gemcitabine resistance by regulating anti-apoptosis proteins. High CD36 expression was a significant, unfavorable prognostic factor in PDAC. Anti-CD36 treatment might serve as an optional treatment for lowering resistance to gemcitabine.

PurposeIn this study, we aim to clarify whether exosomes secreted from hepatocellular carcinoma (HCC) cells under hypoxia affect angiogenesis in endothelial cells.MethodsExosomes derived from human liver cancer cell lines were cultured under hypoxic or normoxic conditions for 24 h, isolated using ExoQuick-TC®, and co-cultured with HUVECs to evaluate angiogenic activity. We also evaluated the expression of miR-155 in the exosomes from 40 patients with HCC.ResultsExosomes under hypoxia remarkably enhanced tube formation of HUVECs. Both cellular and exosomal miR-155 were significantly up-regulated under hypoxic conditions. Knockdown of miR-155 in HCC cells attenuated the promotion of tube formation by exosomes under hypoxia in HUVECs, and high expression of exosomal miR-155 in preoperative plasma was significantly correlated with early recurrence.ConclusionThese results suggest that exosomes derived from HCC cells under hypoxia induce tube formation of HUVECs and that exosomal miR-155 may affect angiogenic activity in HCC.

Tumor endothelial cells (TECs) promote tumor angiogenesis and regulate cytotoxic T cells in the tumor microenvironment. However, the roles of TECs for tumor‐infiltrating T‐cell in hepatocellular carcinoma (HCC) is still unknown. Here, we aimed to investigate how TECs influenced tumor growth and immune responses of HCC focusing on CD8+ T‐cell infiltration and exhaustion. First, TECs were isolated from subcutaneous HCC tumors with murine HCC cell lines (BNL‐T) with magnetic selection of CD31+ cells, and normal endothelial cells (NECs) were isolated from normal liver. Second, immunocompetent mice were injected with BNL‐T alone, BNL‐T + NECs, or BNL‐T + TECs for tumor formation, and the functions and exhaustion of tumor‐infiltrating CD8+ T cells were evaluated. The mice injected with BNL‐T + TEC showed rapid tumorigenesis and a decrease in the number of infiltrating CD8+ T cells. In addition, the percentage of CD8+ T‐cell exhaustion was significantly higher in tumors from the administration of BNL‐T + TEC. Third, the next‐generation sequencing on TECs was performed to identify mRNAs that might be a novel treatment target. The molecule of glycoprotein nonmetastatic melanoma protein B (GPNMB) was identified and the functions of GPNMB was analyzed by silencing of GPNMB expression using small interfering RNAs. The silencing of GPNMB expression in TECs induced the suppression of tumor growth and T‐cell exhaustion. In conclusion, TECs induced tumor‐infiltrating T‐cell exhaustion via GPNMB expression and GPNMB might be a novel therapeutic target in HCC. Tumor endothelial cells induced exhaustion in tumor‐infiltrating T cells by upregulating GPNMB; therefore, GPNMB might be a novel therapeutic target in hepatocellular carcinoma.

Background The reported incidence of postoperative delirium (POD) in elderly patients ranges from 6 to 53 %. Several preoperative and operative factors have been reported as risk factors of POD. Aim The aim of this study was to determine the incidence of and risk factors for POD in patients with colorectal cancer who had undergone laparoscopic colorectal resection. Methods A total of 311 consecutive patients aged 75 years and older who underwent laparoscopic surgery for colorectal cancer at our department from January 2008 to December 2013 were classified as delirious group ( n  = 44) and nondelirious group ( n  = 267). Short-term outcomes and risk factors for POD were analyzed. Results POD was diagnosed in 14.1 % of elderly patients with colorectal cancer. Univariate analysis showed that older age, high American Society of Anesthesiology (ASA) score, performance status >2, low prognostic nutrition index (PNI), past history of delirium or dementia, operative approach, Organ/Space SSI, and cardiac or pulmonary disease were significantly associated with POD. Multivariate logistic regression analysis identified older age, past history of delirium or dementia, operative approach, and Organ/Space SSI as four independent risk factors for POD. Conclusions Our results suggest that the risk of POD is associated with older age, past history of delirium or dementia, operative approach, Organ/Space SSI.

In pancreatic ductal adenocarcinoma (PDAC) patients, the importance of peritoneal lavage cytology, which indicates unresectability, remains controversial. This study sought to determine whether positive peritoneal lavage cytology (CY+) precludes pancreatectomy. Furthermore, we propose a novel liquid biopsy using peritoneal lavage fluid to detect viable peritoneal tumor cells (v-PTCs) with TelomeScan F35, a telomerase-specific replication-selective adenovirus engineered to express green fluorescent protein. Resectable cytologically or histologically proven PDAC patients (n = 53) were enrolled. CY was conducted immediately following laparotomy. The resulting fluid was examined by conventional cytology (conv-CY; Papanicolaou staining and MOC-31 immunostaining) and by the novel technique (Telo-CY; using TelomeScan F35). Of them, 5 and 12 were conv-CY+ and Telo-CY+, respectively. All underwent pancreatectomy. The two double-CY+ (conv-CY+ and Telo-CY+) patients showed early peritoneal recurrence (P-rec) postoperatively, despite adjuvant chemotherapy. None of the three conv-CY+ Telo-CY− patients exhibited P-rec. Six of the 10 Telo-CY+ conv-CY− patients (60%) relapsed with P-rec. Of the remaining 38 double-CY− [conv-CY−, Telo-CY−, conv-CY± (Class III)] patients, 3 (8.3%) exhibited P-rec. Although conv-CY+ status predicted poor prognosis and a higher risk of P-rec, Telo-CY was more sensitive for detecting v-PTC. Staging laparoscopy and performing conv-CY and Telo-CY are needed to confirm the indication for pancreatectomy.

We aimed to clarify usefulness of the modified Frailty Index 11 (mFI-11) for assessing risk of postoperative complications (POCs) and effectiveness of perioperative management team (POMT) intervention for improving postoperative status of frail aged patients requiring colorectal cancer (CRC) surgery. We compared, retrospectively, surgical outcomes among 151 consecutive CRC surgery patients aged ≥80 years. Patients were grouped by mFI-11 scores and by POMT intervention (vs. no POMT intervention). POCs were more prevalent, postoperative stays were longer, and discharge status was poorer among high-risk (mFI-11 ≥ 3/11) patients without POMT intervention than among low-risk (mFI-11 ≤ 2/11) patients (p = 0.04, p = 0.02, p < 0.01). Multiple POCs occurred less frequently and performance of activities of daily living was better for high-risk patients with (vs. those without) POMT intervention (p = 0.04, p = 0.03). POMT intervention appears beneficial for frail aged patients scheduled for CRC surgery. •mFI-11 is useful to identify high-risk frail aged patients requiring CRC surgery.•POMT intervention improves postoperative status of frail aged patients.•POMT intervention appears beneficial for frail aged patients for CRC surgery.

Background/AimWe previously demonstrated that inflammatory cytokine interleukin-6 (IL-6) was produced during cancer progression, worked together with transforming growth factor-beta 1 (TGF-β1), and induced the epithelial–mesenchymal transition (EMT) with chemo-resistance against gemcitabine (GR) at the invasion front of biliary tract cancers (BTCs). However, the significance of cytokine-induced T cell accumulation at the tumor microenvironment in biliary tract cancer (BTC) is not well understood. Because these cytokines (IL-6 and TGF-β1) are able to differentiate naïve T cells into Foxp3-expressing T cells (Tregs) and/or IL-17–producing T helper 17 (Th17) cells, we investigated the relationship between heterogeneous, cancer-producing cytokines and T cell differentiation.MethodsIn total, 127 curative resected specimens from patients with BTCs at Osaka University Hospital between 2000 and 2012 were evaluated for IL-6, TGF-β1, Tregs, and Th17 cells by immunohistochemistry. The ability of BTC–GR cells to undergo T cell differentiation was investigated in vitro.ResultsTregs accumulated at the tumor center and Th17 cells accumulated at the invasion front during cancer progression and/or metastasis; each signaled poor prognosis. Treg accumulation was related to TGF-β1 expression by cancer cells, and Th17 cell accumulation was related to IL-6 expression by cancer cells, in resected specimens; this was confirmed in vitro. Compared with parent cells, GR cells produced IL-6 but not TGF-β1 in a time-dependent manner, had EMT features, and induced T cell differentiation to Th17 cells but not Tregs.ConclusionCytokines produced by cancer cells (IL-6 and TGF-β1) induced heterogeneity of Tregs and Th17 cells in the tumor microenvironment, supporting progression of BTC.

Current therapies for pancreatic ductal cancer (PDAC) do not sufficiently control distant metastasis. Thus, new therapeutic targets are urgently needed. Numerous studies have suggested that the epithelial‐mesenchymal transition (EMT) is pivotal for metastasis of carcinomas. The fact that the EMT is reversible suggests the possibility that it is induced by an epigenetic mechanism. In this study, we aimed to investigate the role of histone deacetylase 1 (HDAC1), which is an epigenetic mechanism on distant metastasis of PDAC. We investigated the HDAC1 expression in 103 resected PDAC specimens obtained from patients who were treated with/without preoperative therapy using immunohistochemistry. To validate the findings in the clinical samples, we evaluated the HDAC1 activity, the EMT‐associated genes and the migration/invasion ability in vitro, and performed an HDAC1 inhibitor assay. The high expression of HDAC1 in clinical samples was significantly associated with poor progression‐free survival, especially distant metastasis‐free survival. In vitro, HDAC1 inhibitors decreased the invasion ability and reversed the EMT change; the only factor to show a concomitant decrease was the expression of SNAIL. We confirmed that the HDAC1 expression was associated with the SNAIL expression in clinical samples. Moreover, the resistant cells and parental cells did not show any significant differences in the expression of HDAC1; this was consistent with the finding that preoperative therapy did not alter the HDAC1 expression in clinical samples. The targeting of HDAC1, which could suppress metastasis by inhibiting the EMT, is a promising treatment option for PDAC. The expression of histone deacetylase 1 (HDAC1) in pancreatic ductal carcinoma (PDAC) indicates a higher migration ability, and a lack of response to chemotherapy/radiotherapy. Therapy targeting HDAC1, which might suppress metastasis, would be a promising treatment option for PDAC.