Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant ...behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis.
We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo.
CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups.
Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.
Background
Sarcopenia is closely associated with morbidity after pancreatic surgery. We investigated the impact of preoperative nutritional support and rehabilitation on patients undergoing ...pancreaticoduodenectomy.
Methods
This was a retrospective analysis of 101 patients who underwent pancreaticoduodenectomy. Skeletal muscle (SM) loss was defined using the SM index (cutoff level: 42 cm
2
/m
2
in men and 38 cm
2
/m
2
in women). A total of 33 and 30 patients received preoperative nutrition and prehabilitation, respectively. The neutrophil-to-lymphocyte ratio (NLR), Prognostic Nutritional Index (PNI), and modified Glasgow Prognostic Score (mGPS) values were calculated during the first visit and immediately before surgery.
Results
SM loss was present in 65 of 101 patients and was significantly correlated with female sex, older age, lower body mass index, and low PNI. Preoperative nutritional support and prehabilitation prevented the decrease in PNI values in patients with SM loss. The NLR significantly improved in patients with SM loss who received nutritional support and prehabilitation. In patients with SM loss, the lack of preoperative nutrition and prehabilitation was an independent risk factor for postoperative pancreatic fistula.
Conclusions
Preoperative nutritional support and prehabilitation may reduce the incidence of pancreatic fistula in patients with SM loss and improve the surgical outcomes of patients undergoing pancreaticoduodenectomy.
Wisteria floribunda agglutinin (WFA)
Mac-2-binding protein (M2BPGi) is a novel serum marker for liver fibrosis. Although an elevated serum level of M2BPGi can predict development of hepatocellular ...carcinoma (HCC), the effect of M2BPGi on HCC remains unclear. There are no reports about the association of M2BPGi with HCC aggressiveness. We aimed to clarify the significance of M2BPGi in HCC.
The protein expression of M2BPGi and galectin-3, a ligand of M2BP, and the mRNA expression of M2BP were evaluated in surgically resected human HCC samples. M2BPGi-regulating signals in HCC cells were investigated using transcriptome analysis. The effects of M2BPGi on HCC properties and galectin-3/mTOR signaling were evaluated.
M2BPGi and galectin-3 proteins co-localised in HCC cells, while M2BP mRNA was detected in cirrhotic liver stromal cells. mTOR signaling was upregulated in M2BPGi-treated HCC cells. Moreover, M2BPGi treatment induced tumour-promoting effects on HCC in vitro by activated mTOR signaling. In addition, M2BPGi bound to galectin-3 to induce membranous galectin-3 expression in HCC cells. In vivo, M2BPGi enhanced the growth of xenografted HCC.
M2BPGi is produced in stromal cells of the cirrhotic liver. Furthermore, M2BPGi enhances the progression of HCC through the galectin-3/mTOR pathway.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV establishes a life-long infection in ...its host and alternates between a latent and lytic infection state. During lytic infection, lytic-related genes are expressed in a temporal manner and categorized as immediate early, early, and late gene transcripts. ORF34 is an early-late gene that interacts with several viral transcription-associated factors, however its physiological importance remains poorly understood. Here, we investigated the role of ORF34 during KSHV infection by generating ORF34-deficient KSHV, using a bacterial artificial chromosome system. Our results reveal that ORF34-deficient KSHV exhibited significantly attenuated late gene expression and viral production but did not affect viral DNA replication. ORF34 interacted with transcription factors ORF18, ORF24, ORF31, and ORF66, and a novel ORF34-interaction partner, ORF23. The C-terminal region of ORF34 was important for interaction with ORF24 and viral production. Our data support a model, in which ORF34 serves as a hub for recruiting a viral transcription complex to ORF24 to promote late viral gene expression.
Background/Purpose
To overcome liver failure, we focused on liver regeneration mechanisms by the activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs). It is known that the HSC‐secreted ...Mac‐2‐binding protein glycan isomer (M2BPGi) activates KC in the fibrotic liver. However, its importance for liver regeneration of the HSCs/M2BPGi/KCs axis after hepatectomy is still unknown. The aim of this study was to clarify whether the HSC‐derived M2BPGi can activate KCs after hepatectomy, and elucidate the new molecular mechanism of liver regeneration.
Methods
We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi‐activated KCs using proteomics. Furthermore, the effect on liver regeneration of glucose‐regulated protein 78 (GRP78) as one of the M2BPGi‐related secreted proteins was examined in vitro and in murine hepatectomy models.
Results
Although M2BPGi had no hepatocyte‐promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KC‐driven GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration after 70% hepatectomy and increased the survival rate after 90% hepatectomy in mice.
Conclusions
The M2BPGi‐activated KCs secrete GRP78, which facilitates liver regeneration and improves the survival in a lethal mice model. Our data suggest that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure.
Hagiwara and colleagues report on the new hepatotrophic factor glucose‐regulated protein 78 (GRP78) produced by Kupffer cells (KCs). Mac‐2‐binding protein glycan isomer (M2BPGi) produced by hepatic stellate cells activates KCs. The M2BPGi‐activated KCs secrete GRP78, and GRP78 facilitates liver regeneration and improves the survival in a lethal mouse model.
Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. ...Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
Cancer‐associated fibroblasts (CAF) are responsible for pancreatic cancer desmoplasia and promote cancer progression. This study shows that a natural compound conophylline (CnP) suppressed CAF activity, production of cancer‐promoting cytokines, and desmoplastic changes in tumors. CnP is a promising therapeutic strategy to overcome refractory pancreatic cancers through the suppression of CAF.
Background
Liver resection is the most effective procedure for colorectal cancer liver metastasis (CRLM); however, early recurrence is an important problem that affects the postoperative prognoses of ...patients with CRLM. We previously suggested a therapeutic algorithm for CRLM using fluorodeoxyglucose-positron emission tomography (FDG-PET) and revealed the applicability of FDG-PET in predicting the prognosis after liver resection of CRLM. In this study, we assessed the correlation between FDG-PET and biological viability such as proliferation or metabolic activity.
Methods
We retrospectively evaluated 61 patients who underwent hepatectomy for CRLM. We assessed hypoxia inducible factor-1α (HIF-1α), pyruvate kinase isozyme M2 (PKM2), glucose transporter 1 (GLUT1), and Ki-67 expression via immunohistochemistry and evaluated the correlation between standardized uptake value (SUV) and these factors.
Results
High HIF-1α, PKM2, and GLUT1 expression were positively correlated with high SUV expression (
P
= 0.0444, 0.0296, and 0.0245, respectively). Ki-67 and SUV were also positively correlated (
P
= 0.00164). HIF-1α expression and PKM2 expression were significantly correlated (
P
= 0.0430), and PKM2 expression and GLUT1 expression were extremely significantly correlated (
P
< 0.0001).
Conclusion
SUV reflected tumor proliferation or metabolic factors in CRLM. FDG-PET could be a useful modality for assessing tumor viability and may provide useful information regarding the appropriate treatment strategy for CRLM.
Treatment of hepatocellular carcinoma (HCC) is currently challenging. Cancer-associated fibroblasts (CAFs) promote the malignancy of HCC cells via production of cytokines. Conophylline (CnP), a vinca ...alkaloid obtained from
leaves, has been reported to suppress activation of hepatic stellate cells and liver fibrosis in rats. We examined the efficacy of CnP in suppressing tumor growth in HCC. Specifically, we investigated whether CnP could inhibit CAFs, which were derived from HCC tissues
and
Same as previous reports, CAFs promoted proliferative and invasive ability of HCC cells. CnP suppressed α-smooth muscle actin expression of CAFs, and inhibited their cancer-promoting effects. CnP significantly suppressed CAFs producting cytokines such as IL6, IL8, C-C motif chemokine ligand 2, angiogenin, and osteopontin (OPN). Combined therapy with sorafenib and CnP against HCC cells and CAFs
showed to inhibit tumor growth the most compared with controls and single treatment with CnP or sorafenib. Transcriptome analysis revealed that GPR68 in CAFs was strongly suppressed by CnP. The cancer-promoting effects of cytokines were eliminated by knockdown of GPR68 in CAFs. CnP inhibited the HCC-promoting effects of CAFs by suppressing several HCC-promoting cytokines secreted by CAFs expressing GPR68. Combination therapy with CnP and existing anticancer agents may be a promising strategy for treating refractory HCC associated with activated CAFs.
Background
The ratio of creatinine and cystatin C estimated glomerular filtration rates (eGFRcre/eGFRcys) is significantly positively correlated with sarcopenia. However, there are no published ...reports on the relationship between eGFRcre/eGFRcys and long‐term prognosis in patients after hepatic resection for hepatocellular carcinoma (HCC).
Methods
A total of 157 patients who had undergone curative hepatic resection for HCC were retrospectively reviewed. Cystatin C levels were measured in serum samples that had been frozen after collection at surgery. We aimed to investigate the significance of cystatin C in prognostic value following hepatic resection for HCC.
Results
The best cut‐off eGFRcre/eGFRcys value for overall survival after hepatic resection for HCC was 1.0025. High eGFRcre/eGFRcys was significantly associated with poor liver function, low skeletal muscle mass, large tumor size, large ascitic volume, worse overall and recurrence‐free survival. The eGFRcre/eGFRcys was significantly related to severe recurrence patterns (multiple liver recurrences, distant metastasis).
Conclusions
Preoperative eGFRcre/eGFRcys can predict overall and recurrence‐free survival in HCC patients undergoing hepatic resection. The eGFRcre/eGFRcys is a simple and reliable surrogate marker that indicates eligibility for hepatic resection for HCC.
Harimoto and colleagues found that the preoperative ratio of creatinine and cystatin C estimated glomerular filtration rates (eGFRcre/eGFRcys) can predict overall and recurrence‐free survival in hepatocellular carcinoma patients undergoing hepatic resection. High eGFRcre/eGFRcys was significantly associated with poor liver function, low skeletal muscle mass, large tumor size and large ascitic volume.
CKLF‐like MARVEL transmembrane domain–containing protein 6 (CMTM6) maintains membrane PD‐L1 expression by controlling its endosomal recycling. However, in patients with hepatocellular carcinoma ...(HCC), the correlation among CMTM6, B7 family ligands, and CD8‐positive cytotoxic T lymphocytes (CTLs), and the molecular function of CMTM6 in HCC have not been established. We performed immunohistochemistry to evaluate the relationships among CMTM6 expression, clinicopathological factors, B7 family ligands expression, and CTL infiltration in HCC samples. Moreover, we established CMTM6‐knockout human HCC cell lines to evaluate the function of human CMTM6 in immune regulation and tumor viability. CMTM6 expression was positively associated with membrane B7 family ligands expression and CTL infiltration in HCC samples. High CMTM6 expression in HCC tissues was associated with the expression of the proliferation marker Ki‐67 and shorter recurrence‐free survival. In vitro analysis showed the downregulation of membrane B7 family ligands and proliferation potency in the CMTM6‐knockout human HCC cell line. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family ligands expression. Thus, CMTM6 might be a biomarker to predict the risk of HCC recurrence and a therapeutic target to suppress tumor growth and increase CTL activity.
CMTM6 expression was positively associated with B7 family ligand expression and cytotoxic T lymphocyte (CTL) infiltration in hepatocellular carcinoma (HCC) samples. The CMTM6‐knockout human HCC cell line showed the downregulation of membrane B7 family ligands expression and proliferation potency. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family expression.
PDF
