Liver cancer is a global health issue, and its incidence is progressively increasing worldwide. It has been estimated that every year more than 800,000 people are diagnosed with liver cancer globally, and that by 2025 this disease will affect more than 1 million individuals. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer in adults, accounting for about 80% of cases (other forms include cholangiocarcinoma in 10–20% of cases). In the majority of cases, HCC is a direct consequence of chronic liver inflammation and cirrhosis, and major risk factors include persistent Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection, heavy alcohol consumption, ingestion of aflatoxin B1, smoking, and nonalcoholic fatty liver disease (NAFLD). This assay is for Research Use Only (RUO) and may not be used for diagnostic purposes.
View abstract on PubMed here.
Katharina Wiedemeyer, Martin Köbela, Holly Koelkebeck, Zhan Xiao, Kapil Vashisht
Department of Pathology and Laboratory Medicine, University of Calgary, and Alberta Public Laboratories, Calgary, Alberta, Canada and AstraZeneca, Gaithersburg, USA.
Highlights
•The oncofetal protein Glypican-3 is overexpressed in a subset of ovarian clear cell carcinomas.
•The membranous expression of Glypican-3 in ovarian clear cell carcinoma makes it an interesting immunotherapy target.
•The combination of ARID1A loss with Glypican-3 overexpression may identify a subgroup with particularly short survival.
Chimeric antigen receptor (CAR)-modified natural killer (NK) cells represent a promising immunotherapeutic modality for cancer treatment. However, their potential utilities have not been explored in hepatocellular carcinoma (HCC). Glypian-3 (GPC3) is a rational immunotherapeutic target for HCC. In this study, we developed GPC3-specific NK cells and explored their potential in the treatment of HCC. The NK-92/9.28.z cell line was established by engineering NK-92, a highly cytotoxic NK cell line with second-generation GPC3-specific CAR. Exposure of GPC3+ HCC cells to this engineered cell line resulted in significant in vitro cytotoxicity and cytokine production. In addition, soluble GPC3 and TGF-β did not significantly inhibit the cytotoxicity of NK-92/9.28.z cells in vitro, and no significant difference in anti-tumor activities was observed in hypoxic (1%) conditions. Potent anti-tumor activities of NK-92/9.28.z cells were observed in multiple HCC xenografts with both high and low GPC3 expression, but not in those without GPC3 expression. Obvious infiltration of NK-92/9.28.z cells, decreased tumor proliferation, and increased tumor apoptosis were observed in the GPC3+ HCC xenografts. Similarly, efficient retargeting on primary NK cells was achieved. These results justified clinical translation of this GPC3-specific, NK cell-based therapeutic as a novel treatment option for patients with GPC3+ HCC.
Carasquillo, JA et al., EJNMMI Res. 2018 Mar 5;8(1):20. doi: 10.1186/s13550-018-0374-8
I-124 codrituzumab (aka GC33), an antibody directed at Glypican 3, was evaluated in patients with hepatocellular carcinoma (HCC). Fourteen patients with HCC underwent baseline imaging with I-124 codrituzumab (~ 185 MBq, 10 mg). Seven of these patients undergoing sorafenib/immunotherapy with 2.5 or 5 mg/kg of cold codrituzumab had repeat imaging, with co-infusion of I-124 codrituzumab, as part of their immunotherapy treatment. Three patients who progressed while on sorafenib/immunotherapy were re-imaged after a 4-week washout period to assess for the presence of antigen. Serial positron emission tomography (PET) imaging and pharmacokinetics were performed following I-124 codrituzumab. An ELISA assay was used to determine "cold" codrituzumab serum pharmacokinetics and compare it to that of I-124 codrituzumab. Correlation of imaging results was performed with IHC. Short-term safety assessment was also evaluated.
Thirteen patients had tumor localization on baseline I-124 codrituzumab; heterogeneity in tumor uptake was noted. In three patients undergoing repeat imaging while on immunotherapy/sorafenib, evidence of decreased I-124 codrituzumab uptake was noted. All three patients who underwent imaging after progression while on immunotherapy continued to have I-124 codrituzumab tumor uptake. Pharmacokinetics of I-124 codrituzumab was similar to that of other intact IgG. No significant adverse events were observed related to the I-124 codrituzumab.
I-124 codrituzumab detected tumor localization in most patients with HCC. Pharmacokinetics was similar to that of other intact iodinated humanized IgG. No visible cross-reactivity with normal organs was observed.
Abstract here...
Court, CM et al., Liver Transpl. 2018 Apr 6. doi: 10.1002/lt.25062
Current clinicopathologic staging systems and serum biomarkers poorly discriminate tumor biology in hepatocellular carcinoma (HCC), with high recurrence rates following curative-intent surgical resection and liver transplantation (LT). Identification of accurate biomarkers for improved prognostication and treatment selection is a critical unmet need. We sought to develop a novel "liquid-biopsy" assay capable of detecting HCC circulating tumor cells (CTCs), and characterizing phenotypic subpopulations with prognostic significance. Utilizing HCC cell lines, a tissue microarray, and human blood samples, an antibody cocktail targeting the cell-surface markers asialoglycoprotein receptor (ASGPR), Glypican-3,
... in the tumor cellular origin theoretical system for hepatocellular carcinoma progression.
Ran Xue et al.
Glypican-3 (GPC3) expression is correlated with poor prognosis and progression in hepatocellular carcinoma (HCC). HCC progression can be associated with the differentiation status of tumor cell before malignant transformation. Our aim was to investigate the dynamic expression of GPC3 during tumor cells differentiation and to explore the role and theoretical significance of GPC3 in malignant essence of HCC.
The expressions of tissue GPC3 and alpha fetoprotein (AFP) were detected by immunohistochemical staining.
Lower respiratory infections are among the top ten causes of death worldwide. Since pathogen to cell adhesion is a crucial step in the infection progress, blocking the interaction between eukaryotic receptors and bacterial ligands may enable the pathogenesis process to be stopped. Cell surface glycosaminoglycans (GAGs) are known to be mediators in the adhesion of diverse bacteria to different cell types, making it of interest to examine their involvement in the attachment of various pathogenic bacteria to lung cells, including epithelial cells and fibroblasts.
Oncotarget. 2017 Jun 28. doi: 10.18632/oncotarget.18799. [Epub ahead of print]
Prediction of early recurrence of hepatocellular carcinoma within the Milan criteria after radical resection.
Feng J, Chen J, Zhu R, Yu L, Zhang Y, Feng D, Kong H, Song C, Xia H, Wu J, Zhao D.
Abstract
Approximately 50% hepatocellular carcinoma patients meeting the Milan criteria utilized to develop an improved prognostic model for predicting the recurrence in these patients. Using univariate and multivariate analysis, cytokeratin-19 and glypican-3 expression patterns, tumor number and histological grading from eight putative prognostic factors comprised the risk factor scoring model to predict the tumor recurrence. In the training cohort, the area under roc curve (AUC) value of the model was 0.715 [95% confidence interval (CI) = 0.645-0.786, P<0.001], which was the highest among all the parameters. The performance of the model was assessed using an independent validation cohort, wherein the AUC value was 0.760 (95% CI=0.647-0.874, P<0.001), which was higher than the other factors. The results indicated that model had high performance with adequate discrimination ability. Moreover, it significantly improved the predictive capacity for the recurrence in patients with hepatocellular carcinoma within the Milan criteria after radical resection.
Few tissue markers are currently available to pathologists in the study of hepatocellular tumors. These markers should be used carefully taking into consideration not only morphology but also, and sometimes even more important, the clinical setting where the lesion to be diagnosed had developed. Glypican-3, heat shock protein 70, and glutamine synthetase (GS) are markers currently used...
BACKGROUND:
Glypican-3 is a cell surface proteoglycan that is found in embrionary tissues, and there are no studies investigating this protein in odontogenic tumor. Thus, the aim of this study was to investigate glypican-3 in a series of aggressive and non-aggressive odontogenic tumors.
METHODS:
Fifty-nine cases of tumors were divided into aggressive odontogenic tumors (20 solid ameloblastomas, four unicystic ameloblastoma, 28 KOTs including five associated with Gorlin-Goltz syndrome) and non-aggressive odontogenic tumors....
PAX8 is a thyroid-specific transcription factor whose expression is dysregulated in thyroid cancer. A recent study using a conditional knock-out mouse model identified 58 putative PAX8 target genes. In the present study, we evaluated the expression of 11 of these genes in normal and tumoral thyroid tissues from patients with papillary thyroid cancer (PTC).
