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Theranostics 2023: Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor...
: Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor thrombus (PVTT) in HCC remains unclear. As a consequence of myeloid cell developmental arrest, CD71 erythroid progenitor cells (EPCs) and myeloid-derived suppressor cells play important roles in HCC; however, their roles in PVTT remain unclear. The role of CD71 EPCs in the HCC tumor microenvironment (TME) was evaluated via morphological, RNA-sequencing, enzyme-linked immunosorbent assay, and flow cytometric analyses. Co-culture techniques were employed to assess the CD45 EPCs and their vascular compromising effect. Additionally, the PVTT-promoting function of CD45 EPCs was explored in a murine model. The CD45EPCs in HCC tissues exhibited increased myeloid cell features, including morphology, surface markers, transforming growth factor (TGF)-β generation, and gene expression, compared with those in circulation. Hence, a large proportion of CD45EPCs, particularly those in TMEs, comprise erythroid-transdifferentiated myeloid cells (EDMCs). Additionally, the expression of C-C chemokine receptor type 2 (CCR2) mRNA was upregulated in CD45EPCs within the TME. Tumor macrophages from HCC tissues induced substantial migration of CD45EPCs in a dose-dependent manner. Meanwhile, results from immunofluorescence analyses revealed that these two cell types are positively associated in the TME and circulation. That is, EDMCs are chemoattracted by HCC macrophages mainly via CCR2 from CD45 EPCs in the circulation. Additionally, the expressions of FX, FVII, FGB, C4b, CFB, and CFH were elevated in CD45EPCs within the TME compared with those in the spleen. The CD45EPCs from the HCC TME promoted vessel endothelial cell migration and compromised tube formation through TGF-β and FGB, respectively. Additionally, CD45EPCs from the TME induced HCC cell migration. HCC macrophage-induced CD45EPCs to exhibit higher levels of FX, FVII, FGB, and TGF-β. Meanwhile, upregulation of CCAAT/enhancer binding protein beta expression induced FGB and TGF-β generation in CD45EPCs in the TME. WTAP, a major RNA mA writer, stabilized and mRNA and enhanced their nuclear export in CD45EPCs from the TME. CD45EPCs from the TME were positively associated with PVTT and poor prognosis. Splenectomy reduced the level of CD45EPCs in the circulation and TME, as well as the incidence of microvascular invasion. The incidence of microvascular invasion increased following the transfer of HCC tissue CD45EPCs to splenectomized HCC-bearing mice. The CD45EPCs enriched in the HCC microenvironment are EDMCs, which are induced by HCC macrophages to migrate from the circulation to the TME. Subsequently, EDMCs promote PVTT by compromising the blood vessel endothelium, aggravating coagulation, and promoting HCC cell migration.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Portal Vein; Liver Neoplasms; Myeloid Cells; Thrombosis; Tumor Microenvironment
PubMed: 37649603
DOI: 10.7150/thno.82907 -
Journal of Cellular and Molecular... Aug 2023Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Portal vein tumour thrombus (PVTT) is considered one of most... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Portal vein tumour thrombus (PVTT) is considered one of most fearful complications of HCC and is strongly associated with a poor prognosis. Clarification of the mechanisms underlying the formation and development of PVTT is crucial for developing novel therapeutic strategies for HCC patients. Several studies have been made to uncover that tumour microenvironment, stem cells, abnormal gene expression and non-coding RNAs deregulation are associated with PVTT in patients with HCC in the last decade. However, the exact molecular mechanisms of PVTT in patients with HCC are still largely unknown. In the present review, we briefly summarized the molecular mechanisms underlying the formation and development of PVTT in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Portal Vein; Thrombosis; Chemoembolization, Therapeutic; Retrospective Studies; Treatment Outcome; Tumor Microenvironment
PubMed: 37349905
DOI: 10.1111/jcmm.17808 -
International Journal of Molecular... Aug 2023Vascular liver disorders (VLDs) comprise a wide spectrum of clinical-pathological entities that primarily affect the hepatic vascular system of both cirrhotic and... (Review)
Review
Vascular liver disorders (VLDs) comprise a wide spectrum of clinical-pathological entities that primarily affect the hepatic vascular system of both cirrhotic and non-cirrhotic patients. VLDs more frequently involve the portal and the hepatic veins, as well as liver sinusoids, resulting in an imbalance of liver homeostasis with serious consequences, such as the development of portal hypertension and liver fibrosis. Surprisingly, many VLDs are characterized by a prothrombotic phenotype. The molecular mechanisms that cause thrombosis in VLD are only partially explained by the alteration in the Virchow's triad (hypercoagulability, blood stasis, and endothelial damage) and nowadays their pathogenesis is incompletely described and understood. Studies about this topic have been hampered by the low incidence of VLDs in the general population and by the absence of suitable animal models. Recently, the role of coagulation imbalance in liver disease has been postulated as one of the main mechanisms linked to fibrogenesis, so a novel interest in vascular alterations of the liver has been renewed. This review provides a detailed analysis of the current knowledge of molecular mechanisms of VLD. We also focus on the promising role of anticoagulation as a strategy to prevent liver complications and to improve the outcome of these patients.
Topics: Humans; Animals; Thrombosis; Vascular Diseases; Liver Cirrhosis; Hypertension, Portal
PubMed: 37628933
DOI: 10.3390/ijms241612754 -
World Journal of Gastroenterology Sep 2023Splanchnic vein thrombosis (SVT) is a manifestation of venous thromboembolism in an unusual site. Portal, mesenteric, and splenic veins are the most common vessels... (Review)
Review
Splanchnic vein thrombosis (SVT) is a manifestation of venous thromboembolism in an unusual site. Portal, mesenteric, and splenic veins are the most common vessels involved in SVT which occurs mainly in patients with liver cirrhosis, although non-cirrhotic patients could be affected as well. Thrombosis of hepatic veins, also known as Budd-Chiari syndrome, is another manifestation of SVT. Prompt diagnosis and intervention are mandatory in order to increase the recalization rate and reduce the risk of thrombus progression and hypertensive complications. Traditional anticoagulation with heparin and vitamin-K antagonists is the treatment of choice in these cases. However, recent studies have shown promising results on the efficacy and safety of direct oral anticoagulants (DOACs) in this setting. Available results are mainly based on retrospective studies with small sample size, but first clinical trials have been published in the last years. This manuscript aims to provide an updated overview of the current evidence regarding the role of DOACs for SVT in both cirrhotic and non-cirrhotic patients.
Topics: Humans; Retrospective Studies; Anticoagulants; Heparin; Budd-Chiari Syndrome; Venous Thromboembolism
PubMed: 37731994
DOI: 10.3748/wjg.v29.i33.4962 -
Indian Journal of Pathology &... 2023Liver involvement is commonly seen in various haematological disorders. They present clinically with elevation of liver enzymes and organomegaly, with or without mass... (Review)
Review
Liver involvement is commonly seen in various haematological disorders. They present clinically with elevation of liver enzymes and organomegaly, with or without mass lesions. However, liver involvement may be silent in many hematological disorders or there may be specific findings in liver biopsy that can lead to the diagnosis of clinically inapparent hematological disorders. Present review highlights features of hepatic manifestations in various hematological diseases with special emphasis on histopathological findings. Among RBC disorders, secondary hemochromatosis is the commonest among patients with hemolytic anemia; whereas Sickle Cell Hepatopathy is a well known complication in Sickle Cell Disease, characterised by sequestration of sickled RBCs in sinusoids. Vascular complications such as Budd Chiari syndrome and portal venopathy with portal vein thrombosis are seen in patients with myeloproliferative neoplasms. However, sometimes primary hematological disease may remain occult. Various lymphomas show characteristic pattern of hepatic involvement, most common being sinusoidal and portal infiltration. Pattern of infiltration may give clues to different types of lymphomas. Amongst all lymphomas, Diffuse large B cell lymphoma is the most common lymphoma involving liver. Disseminated intravascular coagulation is a fatal systemic condition and liver involvement by widespread fibrin thrombi, is not an exception. Assessing liver histopathology in context of hematological conditions makes better understanding of pathophysiology and progress of these diseases. It is important for hematologists and hepatologist to be aware of possible liver involvement in various hematological diseases presenting with elevated LFTs and have a logical approach to abnormal LFTs.
Topics: Humans; Liver; Budd-Chiari Syndrome; Thrombosis; Myeloproliferative Disorders; Lymphoma
PubMed: 38084516
DOI: 10.4103/ijpm.ijpm_856_22 -
Metabolites Oct 2023Hypoglycemia occurs frequently in people with type 1 and type 2 diabetes. Hypoglycemia activates the counter-regulatory response. Besides peripheral glucose sensors... (Review)
Review
Hypoglycemia occurs frequently in people with type 1 and type 2 diabetes. Hypoglycemia activates the counter-regulatory response. Besides peripheral glucose sensors located in the pancreas, mouth, gastrointestinal tract, portal vein, and carotid body, many brain regions also contain glucose-sensing neurons that detect this fall in glucose. The autonomic nervous system innervates the heart, and during hypoglycemia, can cause many changes. Clinical and animal studies have revealed changes in electrocardiograms during hypoglycemia. Cardiac repolarization defects (QTc prolongation) occur during moderate levels of hypoglycemia. When hypoglycemia is severe, it can be fatal. Cardiac arrhythmias are thought to be the major mediator of sudden death due to severe hypoglycemia. Both the sympathetic and parasympathetic nervous systems of the brain have been implicated in regulating these arrhythmias. Besides cardiac arrhythmias, hypoglycemia can have profound changes in the heart and most of these changes are exacerbated in the setting of diabetes. A better understanding of how the brain regulates cardiac changes during hypoglycemia will allow for better therapeutic intervention to prevent cardiovascular death associated with hypoglycemia in people with diabetes. The aim of this paper is to provide a narrative review of what is known in the field regarding how the brain regulates the heart during hypoglycemia.
PubMed: 37887414
DOI: 10.3390/metabo13101089 -
Annals of Gastroenterological Surgery Nov 2023Resection is the only potential curative treatment for perihilar cholangiocarcinoma (PHC); however, complete resection is often technically challenging due to the... (Review)
Review
Resection is the only potential curative treatment for perihilar cholangiocarcinoma (PHC); however, complete resection is often technically challenging due to the anatomical location. Various innovative approaches and procedures were invented to circumvent this limitation but the rates of postoperative morbidity (20%-78%) and mortality (2%-15%) are still high. In patients diagnosed with resectable PHC, deliberate and coordinated preoperative workup and optimization of the patient and future liver remnant are crucial. Biliary drainage is recommended to relieve obstructive jaundice and optimize the clinical condition before liver resection. Biliary drainage for PHC can be performed either by endoscopic biliary drainage or percutaneous transhepatic biliary drainage. To date there is no consensus about which method is preferred. The volumetric assessment of the future remnant liver volume and optimization mainly using portal vein embolization is the gold standard in the management of the risk to develop post hepatectomy liver failure. The improvement of systemic chemotherapy has contributed to prolong the survival not only in patients with unresectable PHC but also in patients undergoing curative surgery. In this article, we review the literature and discuss the current surgical treatment of PHC.
PubMed: 37927920
DOI: 10.1002/ags3.12734 -
Surgical Endoscopy Jul 2023Extrahepatic transection of the right hepatic artery and right portal vein before parenchymal dissection is a widely used standard for minimal invasive right...
BACKGROUND
Extrahepatic transection of the right hepatic artery and right portal vein before parenchymal dissection is a widely used standard for minimal invasive right hepatectomy. Hereby, hilar dissection represents a technical difficulty. We report our results of a simplified approach in which the hilar dissection is omitted and the line of dissection is defined with ultrasound.
METHODS
Patients undergoing minimally invasive right hepatectomy were included. Ultrasound-guided hepatectomy (UGH) was defined by the following main steps: (1) ultrasound-guided definition of the transection line, (2) dissection of the liver parenchyma according to the caudal approach, (3) intraparenchymal transection of the right pedicle and (4) of the right liver vein, respectively. Intra- and postoperative outcomes of UGH were compared to the standard technique. Propensity score matching was performed to adjust for parameters of perioperative risk.
RESULTS
Median operative time was 310 min in the UGH group compared to 338 min in the control group (p = 0.013). No differences were observed for Pringle maneuver duration (35 min vs. 25 min; p = ns) nor postoperative transaminases levels (p = ns). There was a trend toward a lower major complication rate in the UGH group (13 vs. 25%) and a shorter median hospital stay (8 days vs. 10 days); however, both being short of statistical significance (p = ns). Bile leak was observed in zero cases of UGH compared to 9 out of 32 cases (28%) for the control group (p = 0.020).
CONCLUSIONS
UGH appears to be at least comparable to the standard technique in terms of intraoperative and postoperative outcomes. Accordingly, transection of the right hepatic artery and right portal vein prior to the transection phase can be omitted, at least in selected cases. These results need to be confirmed in a prospective and randomized trial.
Topics: Humans; Hepatectomy; Liver Neoplasms; Prospective Studies; Hepatic Veins; Laparoscopy
PubMed: 37029324
DOI: 10.1007/s00464-023-09996-7 -
Liver International : Official Journal... Sep 2023PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these...
BACKGROUND & AIMS
PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen.
METHODS
Wall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non-disruptive tag in native PIEZO1 or endothelial-specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively.
RESULTS
PIEZO1 activation leads to nitric oxide synthase- and endothelium-dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium-dependent but independent of nitric oxide synthase. The TRPV4-mediated contraction is suppressed by inhibitors of phospholipase A and cyclooxygenases and mimicked by prostaglandin E , suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo-osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses.
CONCLUSIONS
The portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures.
Topics: Animals; Male; Mice; Endothelium; Nitric Oxide; Nitric Oxide Synthase; Osmotic Pressure; Portal Vein; TRPV Cation Channels; Vasodilation; Ion Channels
PubMed: 37349903
DOI: 10.1111/liv.15646