Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma

Zheng, Xiufeng; Liu, Xun; Lei, Yanna; Wang, Gang; Liu, Ming

doi:10.3389/fonc.2022.824208

Cited by 55 publications

(35 citation statements)

References 118 publications

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“…To further characterize the identified clusters, we performed differentially expressed gene (DEG) analysis and profiled the featured DEGs in each cluster at the set of log-fold change (log FC) thresholds of 0.25 ( Figure S1 A). We examined the spatial expression of marker genes previously reported for common cell types in two samples to assess the sensitivity of the method of detecting the transcripts per spot, and the results confirmed that ALB and CYP2E1 14 were highly expressed in para-carcinoma regions; GPC3 26 and AKR1B10 27 in carcinoma regions; ACTA2 and COL1A1 (markers typically associated with activated fibroblasts or cancer-associated fibroblasts) 28 in the fiber cord and stromal regions, and the above also confirmed the reliability of ST sequencing results. We also detected the spatial distribution of PTPRC (leukocyte marker) 29 , CD2 (T cell and NK cell marker) 30 , and LYZ (myeloid cell marker) 31 in two samples (Figure 1 E); however, no evident spatial characteristics of these markers were found.…”

Section: Resultsmentioning

confidence: 74%

Spatial maps of hepatocellular carcinoma transcriptomes reveal spatial expression patterns in tumor immune microenvironment

Wang¹,

Yuan²,

Jiang³

et al. 2022

Theranostics

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Rationale: Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant disease with the complex immune microenvironment, which ultimately influence clinic outcomes of patients. However, the spatial expression patterns of diverse immune cells among tumor microenvironment remain to be further deciphered. Methods: Spatial transcriptomics sequencing (ST) was implemented on two portions of HCC specimens. Differentially expressed genes, cell cycle phases, epithelial-mesenchymal features, pseudo-time and immune infiltration analysis were applied to demonstrate the intratumor heterogeneity and define the specific immune-related regions, and the results were further validated by a second analysis on another ST study. In vitro and in vivo experiments were conducted to confirm the functional mechanisms of key molecules such as CCL15, CCL19 and CCL21. Clinical tissue samples were used to assess their potential prognostic and therapeutic values. Results: Totally, 7553 spots were categorized into 15 subsets by hierarchical clustering, and malignant subsets with intratumor heterogeneity phenotypes were identified. Spatial heterogeneity from distinct sectors highlights specific chemokines: CCL15 is remarkable in the core region of the carcinoma sector and facilitates the immunosuppressive microenvironment by recruiting and polarizing M2-like macrophages in vitro and in vivo ; High expression of CCL15 and CD163 respectively predicts poor prognosis of HCC patients, and the combined application of them has better predictive value. CCL19 and CCL21, sharing similar spatial expression patterns, are highly-correlated and prominent in the immune infiltration enrichment and recruit CD3 + T cells and CD20 + B cells to inhibit the growth of HCC, indicating a good prognosis of HCC patients. Conclusions: Taken together, our studies preliminarily reveal intratumor heterogeneity of HCC based on ST techniques and unravel the previously unexplored spatial expression patterns in the immune microenvironment. We also highlight the clinical significance and spatial discrepancy of key molecules, providing novel insight for further developing therapeutic strategies in HCC.

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Section: Resultsmentioning

confidence: 74%

Spatial maps of hepatocellular carcinoma transcriptomes reveal spatial expression patterns in tumor immune microenvironment

Wang¹,

Yuan²,

Jiang³

et al. 2022

Theranostics

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“…Importantly, it is specifically present in HCC tissue [ 38 , 90 , 113 ]. Among these several valuable TAAs, GPC3 was counted as a promising target protein for diagnosis, treatment, and drug delivery approaches thanks to its specificity for HCC tissue [ 122 , 123 , 124 ].…”

Section: Tumor-associated Antigens Useful For Hcc Treatmentmentioning

confidence: 99%

Novel Nanotechnology Approaches to Overcome Drug Resistance in the Treatment of Hepatocellular Carcinoma: Glypican 3 as a Useful Target for Innovative Therapies

Mossenta

Busato

et al. 2022

IJMS

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Hepatocellular carcinoma (HCC) is the second most lethal tumor, with a 5-year survival rate of 18%. Early stage HCC is potentially treatable by therapies with curative intent, whereas chemoembolization/radioembolization and systemic therapies are the only therapeutic options for intermediate or advanced HCC. Drug resistance is a critical obstacle in the treatment of HCC that could be overcome by the use of targeted nanoparticle-based therapies directed towards specific tumor-associated antigens (TAAs) to improve drug delivery. Glypican 3 (GPC3) is a member of the glypican family, heparan sulfate proteoglycans bound to the cell surface via a glycosylphosphatidylinositol anchor. The high levels of GPC3 detected in HCC and the absence or very low levels in normal and non-malignant liver make GPC3 a promising TAA candidate for targeted nanoparticle-based therapies. The use of nanoparticles conjugated with anti-GPC3 agents may improve drug delivery, leading to a reduction in severe side effects caused by chemotherapy and increased drug release at the tumor site. In this review, we describe the main clinical features of HCC and the common treatment approaches. We propose the proteoglycan GPC3 as a useful TAA for targeted therapies. Finally, we describe nanotechnology approaches for anti-GPC3 drug delivery systems based on NPs for HCC treatment.

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“…GALAD in NAFLD patients was found to predict the probability of developing NASH and HCC with more sensitivity compared to both US scanning and all serum biomarkers alone. Hence, the GALAD score may be a reliable tool for HCC surveillance and may be exploited to identify patients at higher risk of NASH and HCC [56] .…”

Section: Des-gamma-carboxy Prothrombinmentioning

confidence: 99%

Old-fashioned and newly discovered biomarkers: the future of NAFLD-related HCC screening and monitoring

Piciotti¹,

Longo²,

Agresta³

et al. 2022

Hepatoma Res

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Nonalcoholic fatty liver disease (NAFLD) is the major contributor to the global burden of chronic liver diseases and ranges from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may progress into cirrhosis and hepatocellular carcinoma (HCC). HCC represents the most common liver cancer, and it is a leading cause of death worldwide with an increasing trend for the future. Due to late diagnosis, non-responsiveness to systemic therapy, and high cancer heterogeneity, the treatment of this malignancy is challenging. To date, liver biopsy and ultrasound (US) are the gold standard procedures for HCC diagnosis and surveillance, although they are not suitable for mass screening. Therefore, it is impelling to find new, less invasive diagnostic strategies able to detect HCC at an early stage as well as monitor tumor progression and recurrence. Common and rare inherited variations that boost the switching from NASH to liver cancer may help to predict tumor onset. Furthermore, epigenetic changes which reflect intertumoral heterogeneity occur early in tumorigenesis and are highly stable under pathologic conditions. The severity of hepatic injuries can be detected through the analysis of cell circulating tumor DNAs (ctDNAs), microRNAs (miRNAs), and noncoding RNAs (ncRNAs), which are involved in several pathological processes that feature cancer, including cell growth, survival, and differentiation, thus representing appealing biomarkers for HCC. Therefore, this review discusses the current options for HCC surveillance, focusing on the role of genetic and epigenetic biomarkers as new strategies to refine HCC management.

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Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma

Cited by 55 publications

References 118 publications

Spatial maps of hepatocellular carcinoma transcriptomes reveal spatial expression patterns in tumor immune microenvironment

Spatial maps of hepatocellular carcinoma transcriptomes reveal spatial expression patterns in tumor immune microenvironment

Novel Nanotechnology Approaches to Overcome Drug Resistance in the Treatment of Hepatocellular Carcinoma: Glypican 3 as a Useful Target for Innovative Therapies

Old-fashioned and newly discovered biomarkers: the future of NAFLD-related HCC screening and monitoring

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