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Activation of Hepatic Stellate Cells During Liver Carcinogenesis Requires Fibrinogen/Integrin αvβ5 in Zebrafish
- Source :
- Neoplasia (New York, N.Y.), Neoplasia: An International Journal for Oncology Research, Vol 20, Iss 5, Pp 533-542 (2018)
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Hepatocellular carcinoma (HCC) is one of the most common cancers and it usually develops from a background of liver fibrosis or inflammation. The crosstalk between tumor cells and stromal cells plays an important and stimulating role during tumor progression. Previously we found in a krasV12–induced zebrafish HCC model that oncogenic hepatocytes activate hepatic stellate cells (HSCs) by up-regulation of serotonin and activate neutrophils and macrophages by up-regulation of cortisol. In the present study, we found a novel signaling transduction mechanism between oncogenic hepatocytes and HSCs. After krasV12 induction, fibrinogen was up-regulated in oncogenic hepatocytes. We reasoned that fibrinogen may bind to integrin αvβ5 on HSCs to activate HSCs. Consistent with this notion, pharmaceutical treatment using an antagonist of integrin αvβ5, cilengitide, significantly blocked HSC activation and function, accompanied by attenuated proliferation of oncogenic hepatocytes and progression of liver fibrosis. On the contrary, adenosine 5’-diphosphate, an agonist of αvβ5, activated HSCs significantly that further stimulated the tumor progression and liver fibrosis. Interestingly, in human liver disease samples, we detected an increased level of fibrinogen during tumor progression which indicated the potential role of fibrinogen signaling in HCC progression. Thus, we concluded a novel interaction between oncogenic hepatocytes and HSCs through the fibrinogen related pathway in both the zebrafish HCC model and human liver disease samples.
- Subjects :
- WT, wild type
Liver Cirrhosis
0301 basic medicine
Cancer Research
Carcinogenesis
Fibrinogen
Gfap, glial fibrillary acidic protein
OH, oncogenic hepatocyte
FACS, fluorescence-activated cell sorting
Zebrafish
biology
Chemistry
Liver Neoplasms
TME, tumor microenvironment
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
HSC, hepatic stellate cell
Liver
dpf, day post fertilization
Disease Progression
medicine.symptom
IHC, immunohistochemistry
Signal Transduction
medicine.drug
dox, doxycycline
Original article
Carcinoma, Hepatocellular
Stromal cell
Integrin
Inflammation
lcsh:RC254-282
03 medical and health sciences
Hepatic Stellate Cells
medicine
Animals
Humans
IF, immunofluorescence
Receptors, Vitronectin
Tumor microenvironment
a-Sma, alpha-smooth muscle actin
Oncogenes
biology.organism_classification
dpi, day post induction
030104 developmental biology
Tumor progression
H&E, hematoxylin and eosin
Hepatocytes
Hepatic stellate cell
Cancer research
biology.protein
HCC, hepatocellular carcinoma
Subjects
Details
- ISSN :
- 14765586
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Neoplasia
- Accession number :
- edsair.doi.dedup.....e82b7750b0f198d48bdff552870bd625