Hepatocellular carcinoma may display elevated nestin expression in endothelial cells: experimental study

CONTEXT AND OBJECTIVE: Nestin, a class VI intermediate filament protein, is highly expressed in the portal mesenchyme and sinusoidal endothelium of the human fetal liver, but scarcely expressed in adult portal vessel endothelium. During experimental liver regeneration, an increased number of nestin-positive parenchymal cells have been observed in the zone adjacent to the Hering canals. These parenchymal cells are regarded as hepatic stem cells or hepatoblasts, which may be involved in hepatocellular carcinogenesis. In the light of recent reports describing nestin-positive parenchymal cells in hepatocellular carcinoma, we aimed to use this tumor type as a positive control for immunohistochemical detection of nestin. DESIGN AND SETTING: Experimental study conducted at a university hospital. METHODS: Hepatocellular carcinoma sections from one case were analyzed for nestin expression by immunohistochemistry using confocal microscopy. RESULTS: Surprisingly, a conspicuous pattern resembling liver sinusoid-like cytoarchitecture was observed upon nestin staining of endothelial cells. CONCLUSIONS: This pattern has not been previously described. The preliminary results shown here suggest that nestin-positive endothelial cells are located in niches of immature or proliferative cells. Moreover, nestin expression in endothelial cells of hepatocellular carcinoma enhances the role of angiogenesis in this tumor type, although the prevalence of this immunohistopathological pattern remains to be determined. Finally, hepatocellular carcinoma is an effective positive control for nestin staining in fluorescent immunohistochemistry.

Download Full-text

Localization of Nestin in Amygdaloid Kindled Rat: An Immunoelectron Microscopic Study

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100003747 ◽

2004 ◽

Vol 31 (4) ◽

pp. 514-519 ◽

Cited By ~ 6

Author(s):

Toshitaka Nakagawa ◽

Osamu Miyamoto ◽

Najma A. Janjua ◽

Roland N. Auer ◽

Seigo Nagao ◽

...

Keyword(s):

Electron Microscopy ◽

Endothelial Cells ◽

Piriform Cortex ◽

Light And Electron Microscopy ◽

Cell Types ◽

Perirhinal Cortex ◽

Intermediate Filament Protein ◽

Neural Cells ◽

Nestin Expression ◽

Filament Protein

Background:Nestin is a class VI intermediate filament protein, expressed during early embryonic development in mammals. Postnatally, nestin and its mRNA are down-regulated and gradually disappear. Recently, nestin expression has been detected in the adult nervous system, and it has been suggested that this protein may be related to neurogenesis, although, its role in the mechanism of neurogenesis is not known.Methods:The present study examined the localization of nestin in CNS tissue of the amygdaloid kindled rat by light and electron microscopy.Results:Kindled animals showed nestin expression mainly in the piriform cortex and the perirhinal cortex. By light microscopy, nestin was shown to be expressed in astrocytes, neurons, and endothelial cells. Electron microscopy demonstrated nestin expression in endothelial cells, astrocytic perivascular end feet, the rare pericyte, neurons and oligodendrocytes.Conclusion:We conclude that epilepsy causes widespread nestin expression in many cell types in the CNS, including non-neural cells.

Download Full-text

Deletion of MyD88 in non-parenchymal cells, but not in parenchymal cells attenuates the progression of hepatocellular carcinoma

Zeitschrift für Gastroenterologie ◽

10.1055/s-0037-1612767 ◽

2018 ◽

Vol 56 (01) ◽

pp. E2-E89

Author(s):

A Mohs ◽

N Kuttkat ◽

T Otto ◽

R Sonntag ◽

S Youssef ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Parenchymal Cells

Download Full-text

Experimental Models of Hepatocellular Carcinoma—A Preclinical Perspective

Cancers ◽

10.3390/cancers13153651 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3651

Author(s):

Alexandru Blidisel ◽

Iasmina Marcovici ◽

Dorina Coricovac ◽

Florin Hut ◽

Cristina Adriana Dehelean ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Prediction Models ◽

3D Models ◽

Experimental Models ◽

Health Concern ◽

Liver Carcinoma ◽

Tumor Type

Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.

Download Full-text

Neuropilin-1 on hematopoietic cells as a source of vascular development

Blood ◽

10.1182/blood-2002-01-0119 ◽

2003 ◽

Vol 101 (5) ◽

pp. 1801-1809 ◽

Cited By ~ 35

Author(s):

Yoshihiro Yamada ◽

Yuichi Oike ◽

Hisao Ogawa ◽

Yasuhiro Ito ◽

Hajime Fujisawa ◽

...

Keyword(s):

Endothelial Cells ◽

Fetal Liver ◽

Vascular Development ◽

Hematopoietic Cells ◽

Vegf Receptor ◽

Knock Out ◽

Neuropilin 1 ◽

Vasculogenesis And Angiogenesis

Neuropilin-1 (NP-1) is a receptor for vascular endothelial growth factor-165 (VEGF165) and acts as a coreceptor that enhances the function of VEGF165 through VEGF receptor-2 (VEGFR-2). Studies using transgenic and knock-out mice of NP-1 indicated that this molecule is important for vascular development as well as neuronal development. We recently reported that clustered soluble NP-1 phosphorylates VEGFR-2 on endothelial cells with a low dose of VEGF165 and rescues the defective vascularity of the NP-1−/− embryo in vitro and in vivo. Here we show that NP-1 is expressed by CD45+ hematopoietic cells in the fetal liver, can bind VEGF165, and phosphorylates VEGFR-2 on endothelial cells. CD45+NP-1+ cells rescued the defective vasculogenesis and angiogenesis in the NP-1−/− P-Sp (para-aortic splanchnopleural mesodermal region) culture, although CD45+NP-1− cells did not. Moreover, CD45+NP-1+ cells together with VEGF165 induced angiogenesis in an in vivo Matrigel assay and cornea neovascularization assay. The extracellular domain of NP-1 consists of “a,” “b,” and “c” domains, and it is known that the “a” and “c” domains are necessary for dimerization of NP-1. We found that both the “a” and “c” domains are essential for such rescue of defective vascularities in the NP-1 mutant. These results suggest that NP-1 enhances vasculogenesis and angiogenesis exogenously and that dimerization of NP-1 is important for enhancing vascular development. In NP-1−/− embryos, vascular sprouting is impaired at the central nervous system (CNS) and pericardium where VEGF is not abundant, indicating that NP-1–expressing cells are required for normal vascular development.

Download Full-text

Human Chorionic Gonadotropin Induces Nestin Expression in Endothelial Cells of the Ovary via Vascular Endothelial Growth Factor Signaling

Endocrinology ◽

10.1210/en.2007-0774 ◽

2007 ◽

Vol 149 (1) ◽

pp. 253-260 ◽

Cited By ~ 10

Author(s):

Noriyuki Takahashi ◽

Masanori T. Itoh ◽

Bunpei Ishizuka

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Chorionic Gonadotropin ◽

Growth Factor Signaling ◽

Vascular Endothelial ◽

Nestin Expression ◽

Capillary Endothelial Cells ◽

Theca Interna ◽

Endothelial Growth Factor

The intermediate filament protein nestin was originally found to be expressed in neuronal progenitor cells, but recent studies have shown that other cell types, including endocrine and vascular endothelial cells, express nestin. In the present study, we examined the expression and localization of nestin in the ovaries of developing, peripubertal, and adult rats. RT-PCR and Western blot analyses revealed that nestin mRNA and proteins were expressed in adult rat ovaries. Immunohistochemical analyses using adult rat ovaries showed that nestin was mainly localized to capillary endothelial cells of theca interna in follicles with more than two layers of granulosa cells and that its expression increased with follicle growth. Ontogenetically, ovarian nestin expression started at the peripubertal period when the first gonadotropin surge occurs. To test the possibility that gonadotropins induce nestin expression, prepubertal (postnatal d 21) rats were sc injected with equine chorionic gonadotropin (eCG) and/or human chorionic gonadotropin (hCG). A single injection of hCG, but not eCG, was sufficient to induce nestin expression in follicles, mainly in capillary endothelial cells of theca interna. Furthermore, pretreatment with an inhibitor of vascular endothelial growth factor receptor prevented the induction of the nestin expression by hCG. These findings demonstrate that the endogenous LH surge induces nestin expression in capillary endothelial cells of theca interna via the vascular endothelial growth factor signaling pathway. Nestin may be involved in angiogenesis in growing follicles, which is followed by follicle maturation and subsequent ovulation.

Download Full-text

Expression of human thrombomodulin on porcine endothelial cells can reduce platelet aggregation but did not reduce activation of complement or endothelium – an experimental study

Transplant International ◽

10.1111/tri.13573 ◽

2020 ◽

Vol 33 (4) ◽

pp. 437-449

Author(s):

Wolf Ramackers ◽

Dennis Rataj ◽

Sonja Werwitzke ◽

Sabine Bergmann ◽

Michael Winkler ◽

...

Keyword(s):

Experimental Study ◽

Endothelial Cells ◽

Platelet Aggregation ◽

Reduce Platelet Aggregation ◽

Porcine Endothelial Cells

Download Full-text

Identification of human chronic myelogenous leukemia progenitor cells with hemangioblastic characteristics

Blood ◽

10.1182/blood-2004-07-2514 ◽

2005 ◽

Vol 105 (7) ◽

pp. 2733-2740 ◽

Cited By ~ 59

Author(s):

Baijun Fang ◽

Chunmei Zheng ◽

Lianming Liao ◽

Qin Han ◽

Zhao Sun ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Progenitor Cells ◽

Chronic Myelogenous Leukemia ◽

Blood Cells ◽

Fusion Gene ◽

Fetal Liver ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Leukemic Cells

AbstractOverwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. Interestingly, the BCR/ABL fusion gene, which is present in chronic myelogenous leukemia (CML), was also detected in the endothelial cells of patients with CML, suggesting that CML might originate from hemangioblastic progenitor cells that can give rise to both blood cells and endothelial cells. Here we isolated fetal liver kinase-1–positive (Flk1+) cells carrying the BCR/ABL fusion gene from the bone marrow of 17 Philadelphia chromosome–positive (Ph+) patients with CML and found that these cells could differentiate into malignant blood cells and phenotypically defined endothelial cells at the single-cell level. These findings provide direct evidence for the first time that rearrangement of the BCR/ABL gene might happen at or even before the level of hemangioblastic progenitor cells, thus resulting in detection of the BCR/ABL fusion gene in both blood and endothelial cells.

Download Full-text

The distribution, induction and isoenzyme profile of glutathione S-transferase and glutathione peroxidase in isolated rat liver parenchymal, Kupffer and endothelial cells

Biochemical Journal ◽

10.1042/bj2640737 ◽

1989 ◽

Vol 264 (3) ◽

pp. 737-744 ◽

Cited By ~ 18

Author(s):

P Steinberg ◽

H Schramm ◽

L Schladt ◽

L W Robertson ◽

H Thomas ◽

...

Keyword(s):

Endothelial Cells ◽

Glutathione Peroxidase ◽

Rat Liver ◽

Peroxidase Activity ◽

Cell Types ◽

Transferase Activity ◽

Glutathione Peroxidase Activity ◽

Glutathione S Transferase ◽

Liver Parenchymal ◽

Parenchymal Cells

The distribution and inducibility of cytosolic glutathione S-transferase (EC 2.5.1.18) and glutathione peroxidase (EC 1.11.1.19) activities in rat liver parenchymal, Kupffer and endothelial cells were studied. In untreated rats glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene and 4-hydroxynon-2-trans-enal as substrates was 1.7-2.2-fold higher in parenchymal cells than in Kupffer and endothelial cells, whereas total, selenium-dependent and non-selenium-dependent glutathione peroxidase activities were similar in all three cell types. Glutathione S-transferase isoenzymes in parenchymal and non-parenchymal cells isolated from untreated rats were separated by chromatofocusing in an f.p.l.c. system: all glutathione S-transferase isoenzymes observed in the sinusoidal lining cells were also detected in the parenchymal cells, whereas Kupffer and endothelial cells lacked several glutathione S-transferase isoenzymes present in parenchymal cells. At 5 days after administration of Arocolor 1254 glutathione S-transferase activity was only enhanced in parenchymal cells; furthermore, selenium-dependent glutathione peroxidase activity decreased in parenchymal and non-parenchymal cells. At 13 days after a single injection of Aroclor 1254 a strong induction of glutathione S-transferase had taken place in all three cell types, whereas selenium-dependent glutathione peroxidase activity remained unchanged (endothelial cells) or was depressed (parenchymal and Kupffer cells). Hence these results clearly establish that glutathione S-transferase and glutathione peroxidase are differentially regulated in rat liver parenchymal as well as non-parenchymal cells. The presence of glutathione peroxidase and several glutathione S-transferase isoenzymes capable of detoxifying a variety of compounds in Kupffer and endothelial cells might be crucial to protect the liver from damage by potentially hepatotoxic substances.

Download Full-text