Caveolin-1 (CAV1) has significant roles in many primary tumors and metastasis, despite the fact that malignant cells from different cancer types have different profiles of CAV1 expression. There is ...little information concerning CAV1 expression and role in hepatocellular carcinoma (HCC) progresion and metastasis. The role of CAV1 in HCC progression was explored in this study. We reported that CAV1 was overexpressed in highly invasive HCC cell lines compared with poorly invasive ones. The immunohistochemical staining was obviously stronger in metastatic HCC samples than in the non-metastatic specimens via tissue microarrays. Furthermore, CAV1 overexpression enhanced HCC cell invasiveness in vitro, and promoted tumorigenicity and lung metastasis in vivo. By contrast, CAV1 stable knockdown markedly reduced these malignant behaviors. Importantly, we found that CAV1 could induce EMT process through Wnt/β-catenin pathway to promote HCC metastasis. We also identify MMP-7 as a novel downstream target of CAV1. We have determined that CAV1 acts as a mediator between hyperactive ERK1/2 signaling and regulation of MMP-7 transcription. Together, these studies mechanistically show a previously unrecognized interplay between CAV1, EMT, ERK1/2 and MMP-7 that is likely significant in the progression of HCC toward metastasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The application of VEGF signaling inhibitors have been associated with more invasive or metastatic behavior of cancers including hepatocellular carcinoma (HCC). We explored the contribution of MET ...pathway to the enhanced HCC invasion and metastasis by VEGF signaling inhibition, and investigated the antitumor effects of NZ001, a novel dual inhibitor of MET and VEGFR2, in HCC.
Immunocompetent orthotopic mice model of hepal-6 was established to investigate the effects of either VEGF antibody alone or in combination with the selective MET inhibitor on tumor aggressiveness. The antitumor effects of NZ001 were examined in cultured HCC cells as well as in vivo models. MET gene amplification was determined by SNP 6.0 assay. MET/P-MET expression was detected by IHC.
Selective VEGF signaling inhibition by VEGF antibody significantly reduced in vivo tumor growth of the orthotopic mice models, simultaneously also enhanced tumor invasion and metastasis, but inhibiting MET signaling attenuated this side-effect. Further study revealed that hypoxia caused by VEGF signaling inhibition induced HIF-1α nuclear accumulation, subsequently leading to elevated total-MET expression, and synergized with HGF in inducing invasion. NZ001, a novel dual inhibitor of MET and VEGFR2, markedly inhibited both tumor growth and metastasis of HCC, which showed obvious advantages over sorafenib in not inducing more invasive and metastatic behaviors. This effect is more pronounced in HCC with MET amplification and overexpression.
The activation of MET is responsible for the metastasis-promoting effects induced by VEGF inhibition. MET and VEGFR2 dual blockade, NZ001, has advantages over sorafenib in not inducing more invasive and metastatic behaviors; MET amplification and overexpression can be used to identify the subgroup of patients most likely to get the optimal benefit from NZ001 treatment.
The variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged repeatedly, especially the Omicron strain which is extremely infectious, so early identification of patients ...who may develop critical illness will aid in delivering proper treatment and optimizing use of resources. We aimed to develop and validate a practical scoring model at hospital admission for predicting which patients with Omicron infection will develop critical illness.
A total of 2,459 patients with Omicron infection were enrolled in this retrospective study. Univariate and multivariate logistic regression analysis were performed to evaluate predictors associated with critical illness. Moreover, the area under the receiver operating characteristic curve (AUROC), continuous net reclassification improvement, and integrated discrimination index were assessed.
The derivation cohort included 1721 patients and the validation cohort included 738 patients. A total of 98 patients developed critical illness. Thirteen variables were independent predictive factors and were included in the risk score: age > 65, C-reactive protein > 10 mg/L, lactate dehydrogenase > 250 U/L, lymphocyte < 0.8*10^
/L, white blood cell > 10*10^
/L, Oxygen saturation < 90%, malignancy, chronic kidney disease, chronic cardiac disease, chronic obstructive pulmonary disease, diabetes, cerebrovascular disease, and non-vaccination. AUROC in the derivation cohort and validation cohort were 0.926 (95% CI, 0.903-0.948) and 0.907 (95% CI, 0.860-0.955), respectively. Moreover, the critical illness risk scoring model had the highest AUROC compared with CURB-65, sequential organ failure assessment (SOFA) and 4C mortality scores, and always obtained more net benefit.
The risk scoring model based on the characteristics of patients at the time of admission to the hospital may help medical practitioners to identify critically ill patients and take prompt measures.
Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower ...response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
BackgroundOncolytic virotherapy has become an important branch of cancer immunotherapy. This study investigated the efficacy of an oncolytic adenovirus (OAV), OncoViron, with synergistic mechanisms ...in the treatment of multiple solid tumors.MethodsAn OAV, OncoViron, was constructed and investigated by cytological experiments and implanted tumor models of multiple solid tumor cell lines to certify its anticancer efficacy, the synergistic effects of viral oncolysis and transgene anticancer activity of OncoViron, as well as oncolytic virotherapy combined with immunotherapy, were also verified.ResultsThe selective replication of OncoViron mediated high expression of anticancer factors, specifically targeted a variety of solid tumors and significantly inhibited cancer cell proliferation. On a variety of implanted solid tumor models in immunodeficient mice, immunocompetent mice, and humanized mice, OncoViron showed great anticancer effects on its own and in combination with programmed death 1 (PD-1) antibody and chimeric antigen receptor (CAR) T cells. Pathological examination, single-cell sequencing, and spatial transcriptome analysis of animal implanted tumor specimens confirmed that OncoViron significantly altered the gene expression profile of infected cancer cells, not only recruiting a large number of lymphocytes, natural killer cells, and mononuclear macrophages into tumor microenvironment (TME) and activated immune cells, especially T cells but also inducing M1 polarization of macrophages and promoting the release of more immune cytokines, thereby remodeling the TME for coordinating PD-1 antibody or CAR T therapy.ConclusionsThe chimeric OncoViron is a novel broad-spectrum anticancer product with multiple mechanisms of synergistic and potentiated immunotherapy, creating a good opportunity for combined immunotherapy against solid tumors.
To study severe and rare complications of transarterial chemoembolization (TACE) for liver cancer.
Clinical records of severe and rare complications following TACE in 1348 cases of liver cancer from ...January 1997 to February 2004 were studied retrospectively.
A total of 2012 TACE procedures were performed for 1348 patients. There were 3 cases of spontaneous rupture of liver cancer, 1 case of perforation of duodenum, 3 cases of liver abscess (1 of them was associated with sepsis), 1 case of pulmonary embolism, 1 case of spasm of the hepatic artery, 40 cases of hepatic artery occlusion, 3 cases of femoral nerve injury, 1 case of bilioma and 1 case of acute renal failure.
Although the severe complications of TACE are rare, the procedure should be done cautiously including super selection of hepatic artery, slow infusion of lipiodol, careful postoperative observations and early detection and management of complications.
A series of new amphiphilic mPEG-PLA-SN38-conjugates were synthesized and formed micelles by self-assembly. Micelles of mPEG2K-PLA-SN38 have small size (∼20nm) and narrow size distribution. The ...lengths of mPEG and PLA chains had a major impact on the physicochemical characteristics and antitumor activity of SN38-conjugate micelles. The mPEG2K-PLA8·9k-SN38 micelles showed greater antitumor efficacy in HCT116 human colon cancer xenograft model.
Display omitted
•A series of amphiphilic mPEG-PLA-SN38-conjugates were synthesized and formed to micelles by self-assembly.•The lengths of mPEG and PLA chains had a major impact on the physicochemical characteristics and antitumor activity of mPEG-PLA-SN38 micelles.•mPEG2K-PLA8.9K-SN38 micelles are the most effective with complete regression of xenograft tumors.
7-Ethyl-10-hydroxy-comptothecin (SN38) is an active metabolite of irinotecan (CPT-11) and the clinical application of SN38 is limited by its hydrophobicity and instability. To address these issues, a series of novel amphiphilic mPEG-PLA-SN38-conjugates were synthesized by linking SN38 to mPEG-PLA-SA, and they could form micelles by self-assembly. The effects of mPEG-PLA composition were studied in vitro and in vivo. The mean diameters of mPEG2K-PLA-SN38 micelles and mPEG4K-PLA-SN38 micelles were 10–20nm and 120nm, respectively, and mPEG2K-PLA-SN38 micelles showed greater antitumor efficacy than mPEG4K-PLA-SN38 micelles both in vitro and in vivo. These data suggest that the lengths of mPEG and PLA chains had a major impact on the physicochemical characteristics and antitumor activity of SN38-conjugate micelles.
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive solid malignant tumors worldwide. Increasing investigations demonstrate that long non-coding RNAs (lncRNAs) ...expression is abnormally dysregulated in cancers. It is crucial to identify and predict the prognosis of patients for the selection of further therapeutic treatment.
Methods:
PDAC lncRNAs abundance profiles were used to establish a signature that could better predict the prognosis of PDAC patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied to establish a multi-lncRNA signature in the TCGA training cohort (
N
= 107). The signature was then validated in a TCGA validation cohort (
N
= 70) and another independent Fudan cohort (
N
= 46).
Results:
A five-lncRNA signature was constructed and it was significantly related to the overall survival (OS), either in the training or validation cohorts. Through the subgroup and Cox regression analyses, the signature was proven to be independent of other clinic-pathologic parameters. Receiver operating characteristic curve (ROC) analysis also indicated that our signature had a better predictive capacity of PDAC prognosis. Furthermore, ClueGO and CluePedia analyses showed that a number of cancer-related and drug response pathways were enriched in high risk groups.
Conclusions:
Identifying the five-lncRNA signature (RP11-159F24.5, RP11-744N12.2, RP11-388M20.1, RP11-356C4.5, CTC-459F4.9) may provide insight into personalized prognosis prediction and new therapies for PDAC patients.
Background
Fibroblast activation protein (FAP) is commonly expressed in activated stromal fibroblasts in various epithelial tumours. Recently,
68
Ga-FAPI-04 has been used for tumour imaging in ...positron emission tomography/computed tomography (PET/CT). This study aimed to compare the diagnostic performances of
68
Ga-FAPI-04 PET/CT and
18
F-FDG PET/CT in hepatocellular carcinoma (HCC), and to assess factors associated with
68
Ga-FAPI-04 uptake in HCC.
Materials and Methods
Twenty-nine patients with suspiciously HCC who received both
18
F-FDG and
68
Ga-FAPI-04 PET/CT were included in this retrospective study. The results were interpreted by two experienced nuclear medicine physicians independently. The maximum and mean standardized uptake values (SUV
max
and SUV
mean
) were measured in the lesions and liver background, respectively. The tumour-to-background ratio (TBR) was then calculated as lesion’s SUV
max
divided by background SUV
mean
.
Results
A total of 35 intrahepatic lesions in 25 patients with HCC were finally involved in the statistical analysis.
68
Ga-FAPI-04 PET/CT showed a higher sensitivity than
18
F-FDG PET/CT in detecting intrahepatic HCC lesions (85.7%
vs
. 57.1%,
P
= 0.002), including in small (≤ 2 cm in diameter; 68.8%
vs
. 18.8%,
P
= 0.008) and well- or moderately-differentiated (83.3%
vs
. 33.3%,
P
= 0.031) tumors. SUV
max
was comparable between
68
Ga-FAPI-04 and
18
F-FDG (6.96 ± 5.01
vs
. 5.89 ± 3.38,
P
> 0.05), but the TBR was significantly higher in the
68
Ga-FAPI-04 group compared with the
18
F-FDG group (11.90 ± 8.35
vs
. 3.14 ± 1.59,
P
< 0.001). SUV
max
and the TBR in
68
Ga-FAPI-04 positive lesions were associated with tumour size (both
P
< 0.05), but not the remaining clinical and pathological features (all
P
> 0.05).
Conclusions
68
Ga-FAPI-04 PET/CT is more sensitive than
18
F-FDG PET/CT in detecting HCC lesions, and
68
Ga-FAPI-04 uptake is correlated mainly with tumour size.
PDF
