Portal Vein Tumor Thrombus Formation Research Articles

Identification of key molecules in the formation of portal vein tumor thrombus in hepatocellular carcinoma based on single cell transcriptomics and in vitro experiments.

The presence of portal vein tumor thrombus (PVTT) is a significant indicator of advanced-stage hepatocellular carcinoma (HCC). Unfortunately, the prediction of PVTT occurrence remains challenging, and there is a lack of comprehensive research exploring the underlying mechanisms of PVTT formation and its association with immune infiltration. Our approach involved analyzing single-cell sequencing data, applying high dimensional weighted gene co-expression network analysis (hdWGCNA), and identifying key genes associated with PVTT development. Furthermore, we constructed competing endogenous RNA (ceRNA) networks and employed weighted gene co-expression network analysis (WGCNA), as well as three machine-learning techniques, to identify the upstream regulatory microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) of the crucial mRNAs. We employed fuzzy clustering of time series gene expression data (Mfuzz), gene set variation analysis (GSVA), and cell communication analysis to uncover significant signaling pathways involved in the activation of these important mRNAs during PVTT development. In addition, we conducted immune infiltration analysis, survival typing, and drug sensitivity analysis using The Cancer Genome Atlas (TCGA) cohort to gain insights into the two patient groups under study. Through the implementation of hdWGCNA, we identified 110 genes that was closely associated with PVTT. Among these genes, TMEM165 emerged as a crucial candidate, and we further investigated its significance using COX regression analysis. Furthermore, through machine learning techniques and survival analysis, we successfully identified the upstream regulatory miRNA (hsa-miR-148a) and lncRNA (LINC00909) that targeted TMEM165. These findings shed light on the complex regulatory network surrounding TMEM165 in the context of PVTT. Moreover, we conducted CIBERSORT analysis, which unveiled correlations between TMEM165 and immune infiltration in HCC patients. Specifically, TMEM165 exhibited associations with various immune cell populations, including memory B cells and CD8+ T cells. Additionally, we observed implications for immune function, particularly in relation to immune checkpoints, within the context of HCC. The regulatory axis involving TMEM165, hsa-miR-148a, and LINC00909 emerges as a crucial determinant in the development of PVTT in HCC patients, and it holds significant implications for prognosis. Furthermore, alterations in the TMEM165/hsa-miR-148a/LINC00909 regulatory axis exhibit a strong correlation with immune infiltration within the HCC tumor microenvironment, leading to immune dysfunction and potential failure of immunotherapy.

Progress on the molecular mechanism of portal vein tumor thrombosis formation in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, with poor prognosis and high mortality. Early-stage HCC has no obvious clinical symptoms, and most patients are already at an advanced stage when they are diagnosed. Portal vein tumor thrombus (PVTT) is the most common complication and a poor prognostic factor for HCC, which frequently leads to portal vein hypertension, ascites, gastrointestinal bleeding, and tumor metastasis. The formation of PVTT is related to the complex structure and hemodynamic changes of the portal vein and is closely related to changes at the cellular and molecular levels. The differentially-expressed genes (DEGs) between PVTT and primary tumor (PT) suggest that the two tissues may have different clonal origins. Epigenetic and proteomic analyses also suggest complex and diverse mechanisms for the formation of PVTT. In addition, the tumor microenvironment and energy metabolism pathways are interrelated in regulating the invasion and progression of PVTT. Aerobic glycolysis and the tumor immune microenvironment have been the focus of recent studies on PVTT. In this review, we summarize the mechanism of PVTT formation at the cellular and molecular levels to provide information to guide better prevention and treatment of PVTT in the clinic.

Screening potential prognostic biomarkers for portal vein emboli in patients with hepatocellular carcinoma.

The formation of portal vein tumor thrombus (PVTT) is closely related to the prognosis of patients with hepatocellular carcinoma (HCC). However, the mechanisms by which PVTTs form and the biomarkers involved are still little understood. The Genome Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to obtain transcriptome data from normal tissue, HCC tissue, primary tumors (PTs) of HCC, and paired PVTT tissue. Differentially expressed genes (DEGs) in PTs and PVTTs were analyzed. The differentially expressed immune genes were further investigated in terms of their prognostic significance, immune infiltration, function. Finally, we explored the relationship between risk scores and drug sensitivity based on the R package. In the two datasets, there were 458 DEGs identified in the PT and PVTT tissues, of which, 58 were immune-related genes. The differentially expressed immune genes may promote the progression of PVTT by participating in the regulation of non-cellular components such as the extracellular matrix, inflammatory factors, and chemokines. Furthermore, the immune genes KDR, AKT3, FCGR2B, KIAA1429, and TPT1 were correlated with the prognosis of HCC in patients with PVTT. Using this data, a model was constructed to predict the prognosis of patients, thus allowing for the identification of high- and low-risk patients. This study demonstrated that immune-related genes may be involved in the regulation of the extracellular matrix and acellular components, and subsequently, in the formation of PVTT. These five genes KDR, AKT3, FCGR2B, KIAA1429, and TPT1 may be potential prognostic biomarkers and treatment targets for HCC patients with PVTT.

Identification of prognostic biomarkers associated with the occurrence of portal vein tumor thrombus in hepatocellular carcinoma.

The occurrence of portal vein tumor thrombus (PVTT) is strongly correlated to the staging and poor prognosis of hepatocellular carcinoma (HCC) patients. However, the mechanisms of PVTT formation remain unclear. This study aimed to investigate differentially expressed genes (DEGs) between primary tumor (PT) and PVTT tissues and comprehensively explored the underlying mechanisms of PVTT formation. The DEGs between PT and paired PVTT tissues were analyzed using transcriptional data from the Gene Expression Omnibus (GEO) database. The expression, clinical relevance, prognostic significance, genetic alternations, DNA methylation, correlations with immune infiltration, co-expression correlations, and functional enrichment analysis of the DEGs were explored using multiple databases. As result, 12 DEGs were commonly down-expressed in PVTT compared with PT tissues among three datasets. The expression of DCN, CCL21, IGJ, CXCL14, FCN3, LAMA2, and NPY1R was progressively decreased from normal liver, PT, to PVTT tissues, whose up-expression associated with favorable survivals of HCC patients. The genetic alternations and DNA methylation of the DEGs frequently occurred, and several methylated CpG sites of the DEGs significantly correlated with outcomes of HCC patients. The immune infiltration in the tumor microenvironment of HCC was correlated with the expression level of the DEGs. Besides, the DEGs and their co-expressive genes participated in the biological processes of extracellular matrix (ECM) organization and focal adhesion. In summary, this study indicated the dysregulation of ECM and focal adhesion might contribute to the formation of PVTT. And the above seven genes might serve as potential biomarkers of PVTT occurrence and prognosis of HCC patients.

S100P as a novel biomarker of microvascular invasion and portal vein tumor thrombus in hepatocellular carcinoma.

Portal vein tumor thrombus (PVTT) and microvascular invasion (MVI) are types of intrahepatic vascular metastasis of hepatocellular carcinoma (HCC) and are highly correlated with poor prognosis. However, the underlying biomarkers of PVTT and MVI are unclear. We identified a PVTT/MVI-associated gene S100P by cDNA microarray analysis, and assess the potential value of serum S100P measurement in the differential diagnosis of HCC and prediction of MVI status with large retrospective and perspective cohort studies. The mRNA and protein of S100P was increased in HCCs with PVTT or MVI. High S100P immunostaining in tumors was correlated with inferior tumor-free survival. Serum S100P values discriminated patients with HCCs from those with benign liver tumors, and it showed predictive potential of MVI status in both retrospective and perspective cohorts. S100P may regulate HCC tumorigenicity and invasive ability; S100P also was associated with up-regulation of CD44, which may mediate HCC cell adhesion to form PVTT/MVI. Serum S100P may be a novel differential diagnostic marker for HCC and a potential predictor of MVI status pre-surgery for HCC patients. S100P overexpression in HCC is highly correlated with the formation of PVTT and MVI, which may make S100P as a potential therapeutic target for HCC metastasis.

The correlations between hepatitis B virus infection and hepatocellular carcinoma with portal vein tumor thrombus or extrahepatic metastasis.

Portal vein tumor thrombus (PVTT) and extrahepatic metastasis are associated with the prognosis of hepatocellular carcinoma (HCC). We aimed to investigate the effect of hepatitis B virus (HBV) infection on HCC patients with PVTT or extrahepatic metastasis. The clinical data of 639 patients with HCC from our hospital were retrospectively analyzed to analyze the correlation between HBV and HCC with PVTT or extrahepatic metastasis. Univariate analysis revealed that positive hepatitis B virus surface antigen (HBsAg), a detectable serum hepatitis B virus DNA load (>500 IU/ml), cirrhosis and ascites were associated with the presence of PVTT. Positive hepatitis B virus e antigen (HBeAg), cirrhosis and ascites were associated with the presence of extrahepatic metastasis. In a multivariate regression analysis carried out a detectable serum hepatitis B virus DNA load, cirrhosis and ascites were independent risk factors of PVTT. Ascites was an independent risk factor of extrahepatic metastasis. The patients in the PVTT of type III/IV group and the PVTT of type I/II group had a significantly higher rate of positive serum HBsAg, a detectable serum hepatitis B virus DNA load (>500 IU/ml) and HBsAg + HBeAb + HBcAb test positive compared with those in the PVTT-negative group. HBsAg + HBeAb + HBcAb test positive was significantly associated with the presence of extrahepatic metastasis (P=0.028). HBV infection and replication status are associated with the formation of PVTT or extrahepatic metastasis in patients with HCC.

High SPINK1 Expression Predicts Poor Prognosis and Promotes Cell Proliferation and Metastasis of Hepatocellular Carcinoma

Background Serine protease inhibitor Kazal type I (SPINK1) is highly expressed and promotes tumor progress in different cancers. This study aimed to evaluate SPINK1’s prognostic value and its role in hepatocellular carcinoma (HCC) progress. Methods We use tissue micro-arrays containing 273 tumor and paired para-tumor tissues to evaluate SPINK1’s prognostic value in HCC. CCK8 cell proliferation assay, wound healing assays, transwell migration and invasion assays were performed to explore the effect of SPINIK1 on HCC cells. The Cancer Genome Atlas (TCGA) database and Gene set enrichment analysis (GSEA) were used to verify the prognosis value of SPINK1 in HCC and explore the underlying mechanisms. Results SPINK1 expression was significantly higher in tumor tissues than paired para-tumor tissues (P < 0.001). Higher SPINK1 expression in tumor was significantly associated with portal vein tumor thrombus formation (P = 0.019) and shorter overall survival (P = 0.029). SPINK1 expression in tumor tissue was an independent predictor for overall survival. SPINK1 increased proliferation (P < 0.001), enhanced migration and invasion ability of HCC cell lines (P < 0.001). GSEA revealed that glycine, serine, threonine and bile acid metabolism may be the underlying mechanism of SPINK1 in HCC. Conclusions In conclusion, high SPINK1 expression is associated with poor prognosis of HCC. SPINK1 promotes proliferation, migration and invasion ability of HCC cells.

Macrovascular Endothelial Cells Enhance the Motility of Liver Cancer Cells by Up-regulation of MMP-3, Activation of Integrin/FAK Signaling Pathway and Induction of Non-classical Epithelial-mesenchymal Transition.

Background: Liver cancer with portal vein tumor thrombus (PVTT) indicates a serious prognosis. The molecular mechanism of PVTT formation is not totally clarified, the invasion of blood vessels by liver cancer cells is the key step and portal vein endothelial cells plays critical role.Methods: Conditioned medium (CM) of human umbilical vein endothelial cells (HUVEC) were used to culture liver cancer cells and prostate cancer cells for cell motility and viability analysis for the purpose of simulating the role of macrovascular endothelial cells in the development of liver cancer.Results: HUVEC-CM caused long spindle-shaped changes in liver cancer cells; the invasion and migration ability of Bel-7402 and MHCC-LM3 (cultured in HUVEC-CM) increased significantly. Integrins/FAK (focal adhesion kinase) signaling pathway was activated and MMP-3 was up-regulated. However, classical epithelial-mesenchymal transition (EMT) did not involve. HUVEC-CM caused a decrease of cell population in G1- and S-phase of Bel-7402, it also caused an accumulation of cell population in G1 phase and a decrease of cell population in S-phase of MHCC-LM3, MHCC-97L and DU-145. HUVEC-CM promotes apoptosis of Bel-7402 and MHCC-97L and the nude mouse tumorigenic experiment did not find that the HUVEC-CM increase the tumorigenic ability of liver cancer cells.Conclusion: HUVEC may provide an easy-to-adhere roadbed for liver cancer cells invasion of blood vessels by altering extracellular matrix (ECM), activating integrins/FAK pathway and inducing non-classical EMT. The effect of HUVEC-CM on cell viability was cancer cell type dependent. It is a meaningful glance at the mechsanism of PVTT.

Research progress on mechanisms of hepatic portal vein tumor thrombus formation

Hepatic portal vein tumor thrombosis (PVTT) is the common complication of late liver cancer and the main route of intrahepatic metastasis, which is defined as liver cancer cells invade the hepatic portal system under different factors and proliferate in portal vein to form a carcinoma embolus. The formation of PVTT not only leads to insufficient blood supply in the portal vein and decreased liver function, but also courses many symptoms such as portal hypertension, peritoneal effusion, and gastrointestinal bleeding. In recent years, domestic and foreign scholars have actively explored mechanisms of PVTT formation and have achieved great progress. In this paper, the research status and progress of PVTT formation mechanisms are reviewed from the aspects of hemodynamics, molecular biology and liver cancer microenvironment. Key words: Hepatocellular carcinoma; Portal vein tumor thrombus; Formation mechanism; Research progress

14-3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α.

Portal vein tumor thrombus (PVTT) is a type of intrahepatic metastasis arising from hepatocellular carcinoma (HCC) and is highly correlated with a poor prognosis. Hypoxia is common in solider tumors, including HCC, where it alters the behavior of HCC cells. We asked whether and how hypoxia contributes to PVTT formation. We demonstrated that increased intratumoral hypoxia is strongly associated with PVTT formation in HCC. We also showed that 14-3-3ζ is induced by hypoxia in HCC cells and correlates with PVTT formation in clinical HCC samples. In addition, 14-3-3ζ up-regulates HIF-1α expression by recruiting HDAC4, which prevents HIF-1α acetylation, thereby stabilizing the protein. Under hypoxic conditions in vitro, 14-3-3ζ knockdown inhibits hypoxia-induced HCC invasion by the HIF-1α/EMT pathway. Blockade of 14-3-3ζ in HCC cells reduces PVTT formation and distant lung metastasis in vivo. Moreover, a combination of 14-3-3ζ and HIF-1α expression is more prognostic for HCC patients than either protein alone. These results suggest that the hypoxia/14-3-3ζ/HIF-1α pathway plays an important role in PVTT formation and HCC metastasis.

RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription

Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), which are responsible for tumor relapse and metastases. Portal vein tumor thrombus (PVTT) is raised from HCC and strongly correlated to a poor prognosis. However, the mechanism underling the formation of PVTT is largely unknown. Herein, we provide evidence that RNA polymerase II subunit 5 (RPB5)-mediating protein (RMP) was progressively upregulated in PVTT and overexpressed RMP appeared to increase T-ICs self-renewal. Moreover, RMP promoted metastases of PVTT cells and HCC cells in vitro and in vivo. Knockdown of RMP attenuated T-ICs self-renewal and reversed epithelial-mesenchymal transition (EMT) in HCC and PVTT cells. The neutralizing assays suggested that interleukin-6 (IL-6) had an indispensable role in RMP regulating metastases and self-renewal of HCC cells. Furthermore, the transcription of IL-6 was verified to be modulated by RMP via interaction with p65 and RPB5, through which expanding the T-IC/cancer stem cell populations, as well as inducing EMT was promoted. These results suggested that RMP may promote PVTT formation by promoting IL-6 transcription. Thus, RMP serves as a potent factor contributed to develop PVTT and a promising therapeutic target for HCC patients.

Treatment of portal vein tumor thrombus using125Iodine seed implantation brachytherapy

We reported two cases of liver metastasis with portal vein tumor thrombus that developed after liver transplantation for hepatocellular carcinoma (HCC). Both the patients were women aged 43 and 55 years, who had liver metastasis and portal vein tumor thrombus formation after liver transplantations for HCC. For the treatment of portal vein tumor thrombus, (125)I seeds were implanted into the hepatic tissue under the guidance of preoperative computed tomography (CT) images with a total radiation dose of 130 Gy. Enhanced spiral CT scan was performed for evaluation of the liver at 12 and 16 wk after treatment. Thereafter, upper abdominal CT examination was performed every 2-3 mo. No severe complications associated with the (125)I seeds were seen in these two patients. The upper abdominal CT images (obtained after 3 and 4 mo of treatment) showed that the thrombosis reactions were complete reaction and restoration of the patency of the partially obstructed portal vein with partial obstruction. In the case with complete obstruction of the portal vein, the thrombosis was resolved completely, but blood flow could not be restored. After this treatment, one of the patients is still alive, while the other died within 6 mo after the treatment due to lung metastasis complicated with lung infection, leading to respiratory failure.

Portal vein tumor thrombus ablation of new method Experimental Study

Objective To Explore the effective interventional therapy for portal vein tumor thrombus, and to reduce the recurrence rate after liver resection or transplantation. Methods At ultrasound-guided VX2 cancer cells will be injected into New Zealand white rabbits with portal vein, portal vein tumor thrombus forma-tion. after the Animal model of portal vein tumor thrombus is set up. At ultrasound-guided portal vein puncture into 7 FVTCD tubes,inset the special microwave radiation ablation electrode from the PTCD tube, and ablation. At the same time by PTCD needle to inject the chemotherapy drugs fluorouracil and cisplatin. Through ultra-sonography, CT scan and pathology to determine the effect. Results After ablation, the thrombus echo of ultra-sound scan, contrast-enhanced ultrasound and CT scan is enhance than before ablation; It shows that cancer cells have apoptosis, the rate of abnormal liver function is both reached 100% before and after the ablation, However,the ALT, AST after ablation is decreased significantly than before ablation; At the same time,the por-tal vein wall and the surrounding liver tissue damage less. Conclusion At ultrasound-guided portal vein tumor thrombus within the microwave ablation United inject chemotherapy drugs probably is a safe, effective method. Key words: Portal vein tumor thrumbus; Interventional therapy; Microwave; Ablation; Rabbit

The potential of plasma thrombomodulin as a biomarker of portal vein tumor thrombus in hepatocellular carcinoma.

To study the relationship between thrombomodulin (TM) plasma levels and the formation of portal vein tumor thrombus (PVTT) in patients with hepatocellular carcinoma (HCC). Pre- and-postoperative plasma TM levels of 45 patients with HCC and six patients with benign liver-occupying lesion were measured by enzyme-linked immunosorbent assay (ELISA), and the expression of TM in human HCC tissues was determined by immunohistochemistry assay. The preoperative plasma TM level of patients with HCC (10.2+/-5.7 ng/ml) was significantly higher than that of those patients with benign liver-occupying lesion (6.1+/-2.2 ng/ml) and that of normal controls (5.7+/-1.0 ng/ml), respectively (P<0.05). The postoperative TM level of 40 patients with HCC whose tumors had been removed decreased significantly than the preoperative TM level (10.8+/-5.3 ng/ml versus 7.6+/-4.2 ng/ ml, P < 0.05), whereas there was no significant difference between the preoperative and postoperative TM level of six patients with benign liver-occupying lesion (6.1+/-2.2 ng/ml versus 5.9+/-1.8 ng/ml, P>0.05). The preoperative plasma TM level of patients with single HCC (11.5+/-5.9 ng/ml) or no PVTT (11.4+/-5.6 ng/ml) was significantly higher than that of those patients with multiple HCC (8.1+/-4.6 ng/ml) or PVTT (6.9+/-4.5 ng/ ml), respectively (P<0.05). The preoperative plasma TM level of the patients with HCC tissue that stained positive for TM was significantly higher than those with tissue that stained negative for TM (12.2+/-6.5 ng/ ml versus 8.7+/-4.6 ng/ml, P<0.05). The postoperative plasma TM level showed no difference between the patients with HCC tissue stained positive and negative for TM (8.3+/-4.1 ng/ml versus 7.6+/-4.4 ng/ml, P>0.05). There was also no significant difference between the plasma TM level and other clinicopathological futures. Plasma TM increases in patients with HCC and can be a biomarker of the formation of PVTT.

Expression of platelet-derived endothelial cell growth factor and vascular endothelial growth factor in hepatocellular carcinoma and portal vein tumor thrombus

Both platelet-derived endothelial cell growth factor (PD-ECGF) and vascular endothelial growth factor (VEGF) are known to promote the development of new blood vessels, which are fundamental to tumor growth and metastasis. We aimed at evaluating the gene expression of PD-ECGF and VEGF in hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). Surgical specimens (28 HCC, 28 nontumorous liver tissues and 18 PVTT) were studied by Northern blot analysis. The levels of PD-ECGF mRNA and VEGF mRNA expression were measured by densitometric scanning of the autoradiographs, and they were normalized to the level of expression of an internal control (glyceraldehydephosphate dehydrogenase) mRNA. The expression rates of PD-ECGF mRNA in PVTT, HCC and nontumorous liver tissues were 77.8% (14/18), 67.9% (19/28) and 35.7% (10/28), being 88.9% (16/18), 75.0% (21/28) and 17.9% (5/28) respectively for VEGF mRNA. The expressions of PD-ECGF mRNA and VEGF mRNA were higher in HCC with PVTT than when PVTT was absent (P < 0.05). The PVTT was more often seen in patients with positive expression of both PD-ECGF mRNA and VEGF mRNA in HCC than in patients who were positive for only one of these factors or negative for both (P < 0.05). Both PD-ECGF and VEGF correlated well with the formation of PVTT of HCC.