GPC3; glypican 3 (Xq26.1)

Gene Summary

Gene:GPC3; glypican 3
Aliases: SGB, DGSX, MXR7, SDYS, SGBS, OCI-5, SGBS1, GTR2-2
Summary:Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Updated:15 March, 2014


What does this gene/protein do?
GPC3 is implicated in:
- anatomical structure morphogenesis
- anchored to membrane
- anchored to plasma membrane
- anterior/posterior axis specification
- body morphogenesis
- bone mineralization
- branching involved in ureteric bud morphogenesis
- carbohydrate metabolic process
- cell proliferation involved in metanephros development
- chondroitin sulfate metabolic process
- coronary vasculature development
- embryonic hindlimb morphogenesis
- extracellular space
- glycosaminoglycan biosynthetic process
- glycosaminoglycan catabolic process
- glycosaminoglycan metabolic process
- Golgi lumen
- heparan sulfate proteoglycan binding
- integral to plasma membrane
- lung development
- lysosomal lumen
- lysosome
- mesenchymal cell proliferation involved in ureteric bud development
- mesonephric duct morphogenesis
- negative regulation of canonical Wnt receptor signaling pathway
- negative regulation of epithelial cell proliferation
- negative regulation of growth
- negative regulation of smoothened signaling pathway
- osteoclast differentiation
- peptidyl-dipeptidase inhibitor activity
- plasma membrane
- positive regulation of BMP signaling pathway
- positive regulation of endocytosis
- positive regulation of glucose import
- positive regulation of protein catabolic process
- positive regulation of smoothened signaling pathway
- positive regulation of Wnt receptor signaling pathway, planar cell polarity pathway
- protein binding
- proteinaceous extracellular matrix
- small molecule metabolic process
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 15 March 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Genetic Predisposition
  • Neoplasm Proteins
  • Oligonucleotide Array Sequence Analysis
  • Tumor Suppressor Gene
  • Transfection
  • Immunohistochemistry
  • Staging
  • Membrane Proteins
  • Lung Cancer
  • Breast Cancer
  • Smoking
  • Differential Diagnosis
  • Heparan Sulfate Proteoglycans
  • Cancer DNA
  • Childhood Cancer
  • DNA Primers
  • Gene Expression
  • DNA Sequence Analysis
  • X Chromosome
  • Promoter Regions
  • Transcription
  • Hepatocellular Carcinoma
  • Cell Proliferation
  • Liver Cancer
  • Thyroid Cancer
  • Wnt Proteins
  • Translocation
  • Wnt Signaling Pathway
  • Wilms Tumour
  • Messenger RNA
  • Vesicular Transport Proteins
  • GPC3
  • Mutation
  • Single Nucleotide Polymorphism
  • Polymerase Chain Reaction
  • DNA Methylation
  • Western Blotting
  • Glypicans
  • Gene Expression Profiling
  • Tumor Markers
Tag cloud generated 15 March, 2014 using data from PubMed, MeSH and CancerIndex


GPC3 and Liver Cancer

Related Publications (213)

GPC3 and Lung Cancer

Related Publications (13)

GPC3 targeted Immunotherapy Therapy

Related Publications (9)

GPC3 expression in Wilms' Tumor

Related Publications (8)

GPC3 and Breast Cancer

Related Publications (7)

GPC3 and Thyroid Cancer

Related Publications (3)

GPC3 Expression in Neuroblastoma

Related Publications (3)

Related Links

Latest Publications: GPC3 (cancer-related)

Gailey MP, Bellizzi AM
Immunohistochemistry for the novel markers glypican 3, PAX8, and p40 (ΔNp63) in squamous cell and urothelial carcinoma.
Am J Clin Pathol. 2013; 140(6):872-80 [PubMed] Related Publications
OBJECTIVES: To examine squamous cell carcinomas (SCCs) from diverse anatomic sites and invasive urothelial carcinomas (UCs) for expression of the oncofetal antigen glypican 3 (GPC3), the paired box transcription factor PAX8, and the ΔN isoform of p63 (p40).
METHODS: Immunohistochemistry for GPC3, PAX8, and p40 was performed on whole sections of 107 SCCs from 11 anatomic sites and 49 UCs; evaluation included extent and intensity of staining.
RESULTS: GPC3 was detected in 20% of SCCs and 12% of UCs and PAX8 in 3% of SCCs, limited to the uterine cervix, and 10% of UCs. p40 Was found in 99% of SCCs and 96% of UCs.
CONCLUSIONS: GPC3 expression is frequent in SCC/UC, awareness of which should guard against an incorrect diagnosis of hepatocellular carcinoma, while PAX8, limited in distribution, may have some use in suggesting a cervical or urothelial tract origin in a metastatic squamotransitional carcinoma of unknown primary. There is no drop-off in sensitivity for the diagnoses of SCC or UC with ΔNp63-specific immunohistochemistry, and if this performance can be extended to other applications, p40 may supplant the dominant "pan-p63" antibody clone.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Bladder Cancer Bladder Cancer - Molecular Biology

Feng M, Ho M
Glypican-3 antibodies: a new therapeutic target for liver cancer.
FEBS Lett. 2014; 588(2):377-82 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Glypican-3 (GPC3) is an emerging therapeutic target in hepatocellular carcinoma (HCC), even though the biological function of GPC3 remains elusive. Currently human (MDX-1414 and HN3) and humanized mouse (GC33 and YP7) antibodies that target GPC3 for HCC treatment are under different stages of preclinical or clinical development. Humanized mouse antibody GC33 is being evaluated in a phase II clinical trial. Human antibodies MDX-1414 and HN3 are under different stages of preclinical evaluation. Here, we summarize current evidence for GPC3 as a new target in liver cancer, discuss both its oncogenic function and its mode of actions for current antibodies, and evaluate potential challenges for GPC3-targeted anti-cancer therapies.

Related: Liver Cancer

Bai S, Wei S, Pasha TL, et al.
Immunohistochemical studies of metastatic germ-cell tumors in retroperitoneal dissection specimens: a sensitive and specific panel.
Int J Surg Pathol. 2013; 21(4):342-51 [PubMed] Related Publications
Germ-cell tumors (GCTs) are the most common malignancies in adolescent and young men. These tumors are highly treatable, even at an advanced stage; therefore, accurate diagnosis is imperative. In this study, we evaluated immunohistochemical stains for SALL4, NANOG, glypican-3 (GPC3), D2-40, and CD30 with adequate control in retroperitoneal dissection specimens under the same laboratory conditions. The study groups included 31 cases of metastatic testicular GCTs with the following components: 11 seminomas, 14 embryonal carcinoma (ECs), 12 yolk sac tumor (YSTs), 8 teratomas, 10 cases of metastatic melanomas, 14 cases of malignant lymphomas, and 11 cases of metastatic, poorly differentiated carcinoma. SALL4 showed diffuse nuclear labeling for all seminomas, ECs, and YSTs. NANOG showed diffuse nuclear positivity in all seminomas and ECs. Metastatic carcinomas, melanomas, and malignant lymphomas were negative for these 2 markers. Gypican-3, D2-40, and CD30 showed sensitive staining for YSTs, seminomas, and ECs, respectively. In conclusion, SALL4 and NANOG are sensitive and specific markers for GCTs. GPC3, D2-40, and CD30 are sensitive but not specific for individual components of GCTs and may be useful in aiding in the differential diagnosis for the individual component of GCTs when the identity of GCT is established.

Liang J, Ding T, Guo ZW, et al.
Expression pattern of tumour-associated antigens in hepatocellular carcinoma: association with immune infiltration and disease progression.
Br J Cancer. 2013; 109(4):1031-9 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
BACKGROUND: The distinct expression pattern of tumour-associated antigens (TAAs) might be a critical reason for the inefficacy of immunity-based treatments and heterogeneous postsurgical recovery in patients with solid tumours, including hepatocellular carcinoma (HCC). However, little is known about the clinical value of the coexpression patterns of multiple TAAs.
METHODS: We determined the expression of multiple TAAs with identified immunogenicity (GPC3, AFP, SSX-2, NY-ESO-1, EpCAM, midkine) and the density of tumour-infiltrating immune cells by immunohistochemistry in a panel of 362 primary HCC patients. We evaluated the association between the TAAs, immune cell infiltration, clinicopathological parameters, and prognosis.
RESULTS: Patients who coexpressed more TAAs had better prognosis (P<0.00001, overall survival). The integrated pattern of TAA was associated with good differentiation and small tumour size, and with more CD57(+) natural killer and CD20(+) B-cell infiltration (P<0.05). Multivariate Cox proportional hazards analysis identified the TAA index as an independent prognostic indicator (hazard ratio 0.625; 95% confidence interval 0.467-0.837; P=0.002), and could further predict patient prognosis in collaboration with local immune infiltration.
CONCLUSION: Our results could provide new evidence for the improvement of prognostic molecular signatures in HCC, and a novel rationale for patient enrolment in future immunotherapeutic trials and/or clinical treatments.

Related: Liver Cancer AFP CTAG1B (CTAG, NY-ESO-1) EPCAM

Nault JC, Guyot E, Laguillier C, et al.
Serum proteoglycans as prognostic biomarkers of hepatocellular carcinoma in patients with alcoholic cirrhosis.
Cancer Epidemiol Biomarkers Prev. 2013; 22(8):1343-52 [PubMed] Related Publications
BACKGROUND: Proteoglycans are involved in neoangiogenesis and transduction of oncogenic signals, two hallmarks of carcinogenesis.
METHODS: This study sought to assess the prognostic value of serum levels of three proteoglycans (endocan, syndecan-1, and glypican-3) and VEGF in 295 patients with alcoholic cirrhosis: 170 without hepatocellular carcinoma, 58 with early hepatocellular carcinoma, and 67 with advanced hepatocellular carcinoma at inclusion. We analyzed the association between proteoglycan levels and prognosis using Kaplan-Meier and Cox methods.
RESULTS: Serum levels of the three proteoglycans and VEGF were increased in patients with advanced hepatocellular carcinoma compared with those without hepatocellular carcinoma or with early hepatocellular carcinoma. In multivariate analysis, high levels of serum endocan (>5 ng/mL) were independently associated with death [HR, 2.84; 95% confidence interval (CI,) 1.18-6.84; P = 0.02], but not with hepatocellular carcinoma occurrence, in patients without hepatocellular carcinoma at baseline. High serum endocan (>5 ng/mL) and syndecan-1 (>50 ng/mL) levels were significantly associated with greater risk of tumor recurrence (P = 0.025) in patients with early hepatocellular carcinoma treated by radiofrequency ablation. In patients with advanced hepatocellular carcinoma, high serum levels of endocan (P = 0.004) and syndecan-1 (P = 0.006) were significantly associated with less favorable overall survival. However, only a high level of serum syndecan-1 (>50 ng/mL) was independently associated with greater risk of death (HR, 6.21 95% CI, 1.90-20.30; P = 0.0025).
CONCLUSION: Serum endocan and syndecan-1 are easily assessable prognostic serum biomarkers of overall survival in alcoholic cirrhosis with and without hepatocellular carcinoma.
IMPACT: These new biomarkers will be useful to manage patients with hepatocellular carcinoma developed on alcoholic cirrhosis.

Related: Liver Cancer

Patra S, Vij M, Kota V, et al.
Pigmented perivascular epithelioid cell tumor of the liver: report of a rare case with brief review of literature.
J Cancer Res Ther. 2013 Apr-Jun; 9(2):305-7 [PubMed] Related Publications
The perivascular epithelioid cell tumor (PEComa) family of tumors includes angiomyolipoma, lymphangioleiomyomatosis, clear cell sugar tumor of the lung, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomical sites (PEComas-NOS). Among the PEComas-NOS, pigmented variants are extremely rare. The case concerns a 50-year-old female who presented with pain in right hypochondrium. The resected specimen included a 24 × 18 × 9 cm mass. The tumor was histologically characterized by both spindle and epithelioid cells with round to oval nuclei and clear to eosinophilic cytoplasm containing abundant melanin pigment. The stroma demonstrated intervening, thin, fibrovascular septa. Immunohistochemically, the tumor cells were strongly positive for HMB-45, weak positive for smooth muscle actin (SMA), and negative for Hep Par 1, Glypican 3, MUM-1, and S-100 protein. The patient had no evidence of disease 24 months after surgery. Pathologists and clinicians should know about the existence of pigmented perivascular epithelioid cell tumor of the liver.

Related: Liver Cancer

Xu C, Yan Z, Zhou L, Wang Y
A comparison of glypican-3 with alpha-fetoprotein as a serum marker for hepatocellular carcinoma: a meta-analysis.
J Cancer Res Clin Oncol. 2013; 139(8):1417-24 [PubMed] Related Publications
BACKGROUNDS: Glypican-3(GPC3) has been reported as one of the most promising serum markers for hepatocellular carcinoma (HCC), while several studies have conflicting results for the diagnostic accuracy between GPC3 and alpha-fetoprotein (AFP).
METHODS: Studies that explored the diagnostic value of GPC3 and AFP in HCC were searched in MEDLINE, EMBASE, PUBMED, the Cochrane Library and Chinese biomedical literature database (CBM). Sensitivity, specificity and other measures about the accuracy of serum GPC3 and AFP in the diagnosis of HCC were pooled using random effects models. Summary receiver operating characteristic curve (sROC) analysis was used to summarize the overall test performance.
RESULTS: Ten studies were included in our meta-analysis. The pooled sensitivity for AFP and GPC3 is 51.9% (95% confidence interval (CI) 0.47-0.56) and 59.2% (95% CI 0.55-0.63), respectively, while the pooled specificity for AFP and GPC3 is 94% (95% CI 92.1-95.6%) and 84.8% (95% CI 82-87.3%), respectively. The pooled diagnostic odds ratio (DOR) for AFP and GPC3 were 23.4 (95% CI 10.3-53.2) and 17.99 (95% CI 5.4-60.4), respectively. Area under sROC for both AFP and GPC3 is 0.81 (95% CI 0.77-0.84).
CONCLUSIONS: GPC3 is comparable to AFP as a serum marker for the diagnosis of HCC, combination of AFP and GPC3 can elevate the sensitivity of diagnosis.

Related: Liver Cancer

Huang TS, Shyu YC, Turner R, et al.
Diagnostic performance of alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein, des-gamma carboxyprothrombin, and glypican-3 for the detection of hepatocellular carcinoma: a systematic review and meta-analysis protocol.
Syst Rev. 2013; 2:37 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
BACKGROUND: Diagnosis of early-stage hepatocellular carcinoma (HCC) followed by curative resection or liver transplantation offers the best chance for long-term patient survival. Clinically, ultrasonography has suboptimal sensitivity for detecting early-stage HCC. Several serological tests including alpha-fetoprotein (AFP), the ratio of lens culinaris agglutinin-reactive alpha-fetoprotein to total AFP (AFP-L3/AFP), des-gamma carboxyprothrombin (DCP), and glypican-3 (GPC-3) have been widely investigated as diagnostic biomarkers for early-stage HCC in at-risk populations. However, these tests are not recommended for routine HCC screening. Our objective is to determine the diagnostic performance of AFP, AFP-L3/AFP, DCP, and GPC-3 for the detection of HCC, particularly early-stage tumors meeting the Milan criteria.
METHODS/DESIGN: We will include cross-sectional studies that consecutively or randomly recruit target populations. We will search the Cochrane Library, Medline, Embase, Science Citation Index, and the Chinese National Knowledge Infrastructure. We will also search the MEDION and ARIF databases to identify diagnostic systematic reviews that include primary studies. Reference lists of relevant reviews will be searched for additional trials. Language restrictions will not be applied. Two reviewers will independently screen study eligibility and extract data. Methodological quality will be assessed according to the revised tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Two authors will apply the QUADAS-2 assessment to all the included studies, and any discrepancies will be resolved by the third author. The following test characteristics will be extracted into 2 × 2 tables for all included studies: true positives, false positives, true negatives, and false negatives. Study-specific estimates of sensitivity and specificity with 95% confidence intervals will be displayed in forest plots. When possible, we will use the bivariate random-effects model or the Rutter and Gatsonis hierarchical summary receiver operating characteristic model for statistical analysis. To investigate heterogeneity, we will include study designs, population characteristics, test characteristics, and types of reference standard as the study-level variables.
DISCUSSION: Our systematic review will allow patients, clinicians, and researchers to determine the diagnostic performance of AFP, AFP-L3/AFP, DCP, and GPC-3 for the detection of early-stage HCC and the potential roles of these diagnostic biomarkers in the existing diagnostic pathways.Systematic Review Registration: PROSPERO 2013; CRD42013003879.

Gupta A, Sheridan RM, Towbin A, et al.
Multifocal hepatic neoplasia in 3 children with APC gene mutation.
Am J Surg Pathol. 2013; 37(7):1058-66 [PubMed] Related Publications
Hepatoblastoma (HB), the most common hepatic neoplasm in children is associated with germline mutations in adenomatous polyposis coli tumor-suppressor gene that cause familial adenomatous polyposis syndrome. Individuals with familial adenomatous polyposis have a 750 to 7500× the risk of developing HB. We report 3 children with APC gene mutation, who underwent resection or liver transplant for HB. In addition to HB, all 3 patients had multiple independent adenoma-like nodules lacking qualities of intrahepatic metastases. Twenty-five nodules were subjected to immunohistochemical analysis using a panel of antibodies including glypican-3 (GPC3), β-catenin, cytokeratin AE1/AE3, CD34, Ki-67, glutamine synthetase (GS), and fatty acid binding protein. The nodules were round, ranged in size from 0.2 to 1.5 cm, and paler than the background liver. All lacked the chemotherapy effect. The nodules were circumscribed but nonencapsulated and composed of well-differentiated hepatocytes with occasional minor atypical features and absent or rare portal tracts. One lesion displayed a "nodule-within-nodule" pattern. The nodules demonstrated diffuse GS overexpression. Nine (36%) nodules were focally reactive for GPC3, and 1 (4%) displayed focal nuclear β-catenin expression. The associated HB showed diffuse expression of GS, GPC3, and β-catenin nuclear staining. We interpret these nodules as neoplastic with most being adenomas (GPC3 negative) that show features of independent origin and represent early stages of carcinogenesis, implying potential to progress to HB or hepatocellular carcinoma. To our knowledge, this is the first report of multifocal neoplasms in patients with HB and APC gene mutation.

Related: Liver Cancer

Yao S, Zhang J, Chen H, et al.
Diagnostic value of immunohistochemical staining of GP73, GPC3, DCP, CD34, CD31, and reticulin staining in hepatocellular carcinoma.
J Histochem Cytochem. 2013; 61(9):639-48 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
It has been reported that Golgi protein-73 (GP73), glypican-3 (GPC3), and des-γ-carboxy prothrombin (DCP) could serve as serum markers for the early detection of hepatocellular carcinoma (HCC). This study aimed to evaluate a panel of immunostaining markers (including GP73, GPC3, DCP, CD34, and CD31) as well as reticulin staining to distinguish HCC from the mimickers. Our results revealed that CD34 immunostaining and reticulin staining were highly sensitive for the diagnosis of HCC. A special immunoreaction pattern of GP73--a diffuse coarse-block pattern in a perinuclear region or a concentrated cluster-like or cord-like pattern in a certain part of the cytoplasm--was observed in HCC cells, in contrast to the cytoplasmic fine-granular pattern in surrounding non-tumor cells and non-malignant nodules. This coarse-block pattern correlated significantly with less differentiated HCC. In comparison, GPC3 displayed a good advantage in diagnosing well-differentiated HCC. In our study, DCP and CD31 showed little diagnostic value for HCC as an immunostaining marker. When GP73, GPC3, and CD34 were combined, the specificity improved to 96.6%. Our findings demonstrate for the first time that the immunohistochemical panel of GP73, GPC3, and CD34 as well as reticulin staining is highly specific for the pathological diagnosis of HCC.

Related: Liver Cancer

Chen M, Li G, Yan J, et al.
Reevaluation of glypican-3 as a serological marker for hepatocellular carcinoma.
Clin Chim Acta. 2013; 423:105-11 [PubMed] Related Publications
BACKGROUND: Glypican-3 (GPC3) is a novel histochemical marker of hepatocellular carcinoma (HCC). However, its utility as a serologic marker for HCC is not conclusive.
METHODS: A total of 1037 subjects, including 155 patients with HCC, 180 with chronic hepatitis, 124 with liver cirrhosis, 442 with non-HCC cancer and 136 healthy controls, were analyzed for serum GPC3 (sGPC3) by an ELISA constructed with 2 monoclonal antibodies.
RESULTS: The average level of sGPC3 in HCC patients was 99.94±267.2ng/ml, which was significantly higher than in patients with chronic hepatitis (10.45±46.02ng/ml, P<0.0001), liver cirrhosis (19.44±50.88ng/ml, P=0.0013), non-HCC cancer (20.50±98.33ng/ml, P<0.0001) and healthy controls (4.14±31.65ng/ml, P<0.0001). The sensitivity of sGPC3 in HCC diagnosis was 40.0%, whereas the specificity was 98.5%, 94.4% and 87.1% in healthy controls, chronic hepatitis patients and liver cirrhosis patients, respectively. In addition, 13.5% (28/207) of lung cancer patients and 13.2% (9/68) of thyroid cancer patients had positive results with sGPC3.
CONCLUSION: Serum GPC3 is a potential marker for HCC. However, the presence of sGPC3 in patients with lung cancer and thyroid cancer might limit its application as a single marker in the diagnosis of HCC.

Related: Liver Cancer Cancer Prevention and Risk Reduction

Morita S, Yoshida A, Goto A, et al.
High-grade lung adenocarcinoma with fetal lung-like morphology: clinicopathologic, immunohistochemical, and molecular analyses of 17 cases.
Am J Surg Pathol. 2013; 37(6):924-32 [PubMed] Related Publications
Low-grade lung adenocarcinoma of fetal lung type, which is well characterized by its unique clinicopathologic and molecular features, is recognized as a distinct variant of lung cancer. In contrast, high-grade lung adenocarcinoma with fetal lung-like morphology (HG-LAFM) has not been studied widely. To characterize this subset better, we analyzed 17 high-grade adenocarcinomas with at least focal component resembling a developing epithelium in the pseudoglandular phase of the fetal lung. These rare (ca. 0.4%) carcinomas occurred predominantly in elderly men with a heavy smoking history, who showed elevated serum α-fetoprotein in 4 of 5 cases tested. Histologic examination revealed a fetal lung-like component as a focal finding accounting for 5% to 60% of the total tumor volume. It was invariably admixed with tissues having a morphology not resembling that of a fetal lung. A coexisting non-fetal lung-like element was quite heterogenous in appearance, showing various growth patterns. However, clear-cell (88%), hepatoid (29%), and large cell neuroendocrine carcinoma (24%) histology seemed overrepresented. HG-LAFM was characterized immunohistochemically by frequent expression of α-fetoprotein (41%), glypican-3 (88%), SALL-4 (59%), neuroendocrine markers (82%), CDX-2 (35%), and p53 (65%). HG-LAFM was molecularly heterogenous in that EGFR or KRAS mutation was observed in 22% of cases tested for both. Our data indicate that HG-LAFMs might form a coherent subgroup of lung adenocarcinomas. However, the uniformly focal nature of the fetal lung-like element, widely diverse coexisting non-fetal lung-like histology, and inhomogenous molecular profiles lead us to believe that HG-LAFM is best regarded as a morphologic pattern showing characteristic association with several clinicopathologic parameters rather than a specific tumor entity.

Related: Lung Cancer KRAS gene

Fu SJ, Qi CY, Xiao WK, et al.
Glypican-3 is a potential prognostic biomarker for hepatocellular carcinoma after curative resection.
Surgery. 2013; 154(3):536-44 [PubMed] Related Publications
BACKGROUND: Glypican-3 (GPC3), an oncofetal protein, is overexpressed in hepatocellular carcinoma (HCC). The diagnostic efficacy of GPC3 for HCC has been evaluated intensively in recent years; however, the prognostic value of GPC3 for HCC has not been well clarified. The purpose of this study was to investigate the relationship between GPC3 and postoperative patient survival in a prospective database.
METHODS: GPC3 protein was detected by immunohistochemistry. The relationship between GPC3 expression level and patients' clinicopathologic factors was analyzed. Kaplan-Meier survival analysis was used to calculate patients' survival and was compared by using the log rank test. The Cox regression model was used to identify the risk factors associated with prognosis.
RESULTS: GPC3 was expressed in 84% of HCC tissues. GPC3 protein expression was correlated with the number of tumors (P = .015), serum alpha-fetoprotein (AFP) level (P = .011), and TNM stage (P = .006). High GPC3 expression was an independent risk factor for poor postoperative disease-free survival (hazard ratio [HR] = 0.469; 95% confidence interval [CI] 0.303-0.727; P = .001); and overall survival (HR = 0.435; 95% CI, 0.257-0.736; P = .002). Stratification analysis indicated that GPC3 had a good predictive value for tumor recurrence in patients with HCC who have normal serum AFP levels. Also, GPC3 expression status could predict the outcomes of patients with stage I disease.
CONCLUSION: GPC3 is a potential and reliable biomarker for predicting tumor recurrence and overall survival in HCC patients after curative resection.

Related: Liver Cancer

Witjes CD, ten Kate FJ, Verhoef C, et al.
Immunohistochemical characteristics of hepatocellular carcinoma in non-cirrhotic livers.
J Clin Pathol. 2013; 66(8):687-91 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers. In the absence of risk factors, for example, cirrhosis or hepatitis B or C virus infection, HCC diagnosis might be difficult. We aimed to explore the value of immunohistochemical characteristics to diagnostics and prognosis, and whether these immunohistochemical characteristics differ from those of HCC in a cirrhotic liver, possibly indicating an aberrant pathogenetic pathway. Paraffin-embedded, formalin-fixed tissue slides from liver resection specimens of the patients with HCC in a non-cirrhotic liver were analysed. From January 2000 through April 2011, 799 patients with HCC were admitted to our hospital; in total, 47 patients with 50 HCCs in a non-cirrhotic liver were operated. These tumours were stained positive for α-fetoprotein (AFP) in 30%, CD34 in 88%, cytokeratine 7 (CK7) in 44%, CK19 in 12%, glypican-3 (GPC-3) in 40%, glutamine synthetase in 62% and β-catenin in 32%. There was similarity in immunohistochemical expression of several markers comparing HCC in a non-cirrhotic liver with HCC in a cirrhotic liver. Moderate or poorly differentiated HCC more often expressed β-catenin and GPC-3 and showed a higher percentage of MIB-1-positive hepatocytes. A positive AFP immunohistochemical staining was significantly related with a high preoperative AFP serum level (p=0.001). None of the immunohistochemical stainings were associated with a worse overall survival. Of the patients treated with a surgical resection, 17 had recurrence of HCC and these patients more often had a positive CK19 staining (p=0.048). In conclusion, immunohistochemical expression of several markers in HCC in a non-cirrhotic and cirrhotic liver was comparable. Immunohistochemical markers have limited additional value to characterise HCC in non-cirrhoitc livers.

Related: MKI67 Liver Cancer

Yao M, Yao DF, Bian YZ, et al.
Values of circulating GPC-3 mRNA and alpha-fetoprotein in detecting patients with hepatocellular carcinoma.
Hepatobiliary Pancreat Dis Int. 2013; 12(2):171-9 [PubMed] Related Publications
BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) is poor and its early diagnosis is of the utmost importance. This study aimed to investigate the values of glypican-3 (GPC-3) expression in the liver and sera and its gene transcription for diagnosis and monitoring of metastasis of HCC.
METHODS: Liver GPC-3 was analyzed in HCC tissues from 36 patients by immunohistochemistry and Western blotting. GPC-3 mRNA from circulating peripheral blood mononuclear cells from 123 HCC patients or 246 patients with other diseases or 36 HCC tissues was amplified by RT-PCR, quantitative real-time PCR, and confirmed by DNA sequencing. Circulating GPC-3 level was detected by ELISA.
RESULTS: The increasing expression of GPC-3 was observed from non-cancerous to cancerous tissues, with brown granule-like staining localized in tumor parts of atypical hyperplasia and HCC formation. The positive rate of GPC-3 was 80.6% in HCC, 41.7% in their paracancerous tissues, and none in distal cancerous tissues (P<0.001), with no significant difference in differentiation grade and tumor number except for size (Z=2.941, P=0.003). Serum GPC-3 was detected only in HCC (52.8%) and significant difference was found between GPC-3 and tumor size (X2=6.318, P=0.012) or HBV infection (X2=23.362, P<0.001). Circulating GPC-3 mRNA was detected in 70.7% of HCC tissues, with relation to TNM stage, periportal cancerous embolus, and extra-hepatic metastasis (P<0.001). The combination of circulating GPC-3, GPC-3 mRNA and alpha-fetoprotein is of complementary value for HCC diagnosis (94.3%).
CONCLUSION: Both GPC-3 overexpression and GPC-3 mRNA abnormality could be used as markers for the diagnosis of HCC and monitoring its metastasis.

Related: Liver Cancer AFP

Jin GZ, Dong H, Yu WL, et al.
A novel panel of biomarkers in distinction of small well-differentiated HCC from dysplastic nodules and outcome values.
BMC Cancer. 2013; 13:161 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
BACKGROUND: Differential diagnosis of high-grade dysplastic nodules (HGDN) and well-differentiated hepatocellular carcinoma (WDHCC) represents a challenge to experienced hepatic clinicians, radiologists and hepatopathologists.
METHODS: The expression profiles of aminoacylase-1 (ACY1), sequestosome-1 (SQSTM1) and glypican-3 (GPC3) in low-grade dysplastic nodules (LGDN), HGDN and WDHCC were assessed by immunohistochemistry. The differential diagnostic performances of these three markers alone and in combination for HGDN and WDHCC were investigated by logistic regression models (HGDN = 21; WDHCC = 32) and validated in an independent test set (HGDN, n = 21; WDHCC n = 24). Postoperative overall survival and time to recurrence were evaluated by univariate and multivariate analyses in an independent set of 500 patients.
RESULTS: ACY1, SQSTM1 and GPC3 were differentially expressed in each group. For the differential diagnosis of WDHCC from HGDN, the sensitivity and specificity of the combination of ACY1 + SQSTM1 + GPC3 for detecting WDHCC were 93.8% and 95.2% respectively in the training set, which were higher than any of the three two-marker combinations. The validities of the four diagnostic models were further confirmed in an independent test set, and corresponding good sensitivity and specificity were observed. Interestingly, GPC3 expression in HCC tissues combined with serum α-fetoprotein (AFP) was found to be an independent predictor for overall survival and time to recurrence.
CONCLUSIONS: ACY1 + SQSTM1 + GPC3 combination represents a potentially valuable biomarker for distinguishing between WDHCC and HGDN using immunohistochemistry. Meanwhile, low GPC3 staining combined with positive serum AFP may play a practical role in predicting poor postoperative outcome and high tumor recurrence risk.

Related: Liver Cancer

Chan ES, Pawel BR, Corao DA, et al.
Immunohistochemical expression of glypican-3 in pediatric tumors: an analysis of 414 cases.
Pediatr Dev Pathol. 2013 Jul-Aug; 16(4):272-7 [PubMed] Related Publications
Glypican-3 (GPC3) is a proteoglycan thought to play an important role during development. Germline GPC3 mutations are seen in the rare Simpson-Golabi-Behmel syndrome (SGBS), which predisposes patients to Wilms tumor, hepatoblastoma, and neuroblastoma. While numerous adult tumors have been evaluated by immunohistochemistry for GPC3, no comprehensive assessment has been done in pediatric tumors. We therefore investigated GPC3 expression in 143 pediatric central nervous system (CNS) tumors and 271 non-CNS tumors. Among non-CNS tumors, GPC3 expression was seen in 9/9 (100%) hepatoblastomas, 4/6 (67%) malignant rhabdoid tumors, 5/13 (38%) Wilms tumors, 11/37 (30%) alveolar rhabdomyosarcomas, and 8/45 (18%) embryonal rhabdomyosarcomas. All 136 neuroblastomas, 14 Ewing sarcoma/primitive neuroectodermal tumors, and 11 synovial sarcomas were immunonegative for GPC3. Among CNS tumors, GPC3 had restricted expression, with positivity in 6/6 (100%) atypical teratoid rhabdoid tumors and 1/4 (25%) craniopharyngiomas. The remaining 136 CNS tumors-23 medulloblastomas, 21 pilocytic astrocytomas, 13 gangliogliomas, 12 ependymomas, 12 glioblastomas, 11 choroid plexus neoplasms, 10 diffuse astrocytomas (grade II/III), 10 meningiomas, 8 dysembryoplastic neuroepithelial tumors, 8 oligodendrogliomas, 3 craniopharyngiomas, 3 germinomas, and 2 neurocytomas-were entirely negative for GPC3. These results showed GPC3 positivity in a number of non-CNS tumors, with no consistent discrimination between tumors that were or were not associated with SGBS. Within the CNS, GPC3 positivity was limited to a small subset of CNS neoplasms and may thus serve as a useful positive diagnostic biomarker (P < 0.0001) in addition to negative INI1/BAF47/SMARCB1 staining to differentiate atypical teratoid rhabdoid tumors from other high-grade pediatric brain tumors.

Related: Cancer Prevention and Risk Reduction Children's Cancer Web: Home Page

Marquardt JU, Fischer K, Baus K, et al.
Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients.
Hepatology. 2013; 58(3):1054-64 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+-dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down-regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3-week-old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed up-regulation of established hepatocellular carcinoma (HCC) biomarkers alpha-fetoprotein (Afp), insulin-like growth factor 2 (Igf2), H19, and glypican-3. Furthermore, decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis-insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes, such as global hypomethylation, as well as metabolic changes, such as hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had a prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we demonstrated that the Sirt6-KO signature possessed a predictive value for tumors other than HCC (e.g., breast and lung cancer). Conclusion: Loss of SIRT6 induces epigenetic changes that may be relevant to chronic liver disease and HCC development. Down-regulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype that ultimately has relevance for outcome of HCC and other cancer patients.

Related: Liver Cancer Signal Transduction

Yu J, Ma Q, Zhang B, et al.
Clinical application of specific antibody against glypican-3 for hepatocellular carcinoma diagnosis.
Sci China Life Sci. 2013; 56(3):234-9 [PubMed] Related Publications
Glypican-3 (GPC3) is a promising tumor marker for hepatocellular carcinoma (HCC) diagnosis with high sensitivity and specificity. The aim of this study was to establish an immunohistochemical detection method for GPC3 using the 7D11 monoclonal antibody (7D11 mAb) and evaluate its application for HCC diagnosis. The feasibility of the 7D11 mAb was evaluated by immunohistochemistry performed on adjacent normal liver and intrahepatic cholangiocarcinoma (ICC) samples, Furthermore, the serum GPC3 levels were evaluated in 40 HCC patients, 7 ICC patients and 50 healthy donors. The results showed that GPC3 was expressed in 85% of HCC tissues (34/40), but was undetectable in ICC tissues and adjacent normal tissues.GPC3 was significantly increased in the serum of HCC patients (17/40, 42.5%) but was undetectable in the serum of ICC patients (0/7, 0%) and healthy donors(0/50, 0%). This prospective study evaluated the clinical usefulness of 7D11 mAb for GPC3 detection in HCC patients. In conclusion, the use of 7D11 mAb might be good for GPC3 large-scale applications for clinical diagnosis of HCC.

Related: Monoclonal Antibodies Liver Cancer

Giunchi F, Vasuri F, Baldin P, et al.
Primary liver sarcomatous carcinoma: report of two cases and review of the literature.
Pathol Res Pract. 2013; 209(4):249-54 [PubMed] Related Publications
Primary liver sarcomatous carcinomas (PLSCs) are very aggressive tumors. They are characterized by a fast clinical course, and therefore need a prompt histological diagnosis. Here, we report two cases of PLSC. One arises in a non-cirrhotic liver and the other in cirrhosis, with differences in onset and histological features. Special emphasis is put on the expression of albumin and HCC markers, and their possible usefulness in the diagnosis. The English literature of the last 20 years was revised (92 cases). Immunohistochemistry was performed manually or automatically; in situ hybridization (ISH) technique for albumin mRNA detection was carried out. The sarcomatoid components in both cases were immunoreactive for K8/18, Glutamine Synthetase and EZH2, and negative for Glypican 3, SMA, caldesmon, desmin, DOG-1, CD34, CD31, CD117, CD56, and alpha-fetoprotein. The detection of albumin mRNA by ISH was negative in the sarcomatoid component in both cases. PLSC represents a diagnostic challenge for pathologists, especially in its "pure" form: neither albumin mRNA detection nor HCC markers are useful for the diagnosis: positivity for K8/18 and the negativity for the mesenchymal markers seem to represent the main tools for the histological diagnosis.

Related: Liver Cancer Soft Tissue Sarcomas

Feng M, Gao W, Wang R, et al.
Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma.
Proc Natl Acad Sci U S A. 2013; 110(12):E1083-91 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
Glypican-3 (GPC3) has emerged as a candidate therapeutic target in hepatocellular carcinoma (HCC), but the oncogenic role of GPC3 in HCC is poorly understood. Here, we report a human heavy-chain variable domain antibody, HN3, with high affinity (Kd = 0.6 nM) for cell-surface-associated GPC3 molecules. The human antibody recognized a conformational epitope that requires both the amino and carboxy terminal domains of GPC3. HN3 inhibited proliferation of GPC3-positive cells and exhibited significant inhibition of HCC xenograft tumor growth in nude mice. The underlying mechanism of HN3 action may involve cell-cycle arrest at G1 phase through Yes-associated protein signaling. This study suggests a previously unrecognized mechanism for GPC3-targeted cancer therapy.

Related: Liver Cancer

Mateos ME, Beyer K, López-Laso E, et al.
Simpson-Golabi-Behmel syndrome type 1 and hepatoblastoma in a patient with a novel exon 2-4 duplication of the GPC3 gene.
Am J Med Genet A. 2013; 161A(5):1091-5 [PubMed] Related Publications
Mutations in the gene encoding glypican (GPC) 3 appear to be responsible for most cases of Simpson-Golabi-Behmel syndrome type 1. Duplication of the GPC4 gene has also been associated to this syndrome; however, no duplications involving GPC3 have been related. We describe a family that harbors a novel exon 2-4 duplication event leading to a truncating germline mutation of the GPC3 gene that, to our knowledge, has not been previously reported. GPC3 transcripts that carry this duplication bear non-functional proteins making its pathogenic role highly probable. The absence of a functional GPC3 may alter the normal differentiation of embryonal mesodermal tissues predisposing to the development of embryonal tumors, as the index case studied who developed a hepatoblastoma at age 9 months.

Related: Liver Cancer

Li H, Deng Q, Huang L, et al.
[Expression of glypican-3 in lung squamous cell carcinoma and adenocarcinoma and its relation with prognosis].
Nan Fang Yi Ke Da Xue Xue Bao. 2013; 33(2):212-5 [PubMed] Related Publications
OBJECTIVE: To study the different expressions of glypican-3 in lung squamous cell carcinoma and adenocarcinoma and explore the association of glypican-3 with the prognosis of the patients.
METHODS: Glypican-3 expression was detected immunohistochemically in the tumor tissues and adjacent tissues from 48 cases of lung squamous cell carcinoma and adenocarcinoma. Kaplan-Meier method and log-rank test were used for survival analysis of the patients.
RESULTS: Glypican-3 expression was detected in the tumor tissues in 29.2% (14/48) of the cases, but not in the adjacent tissues. Of the 22 patients with lung squamous cell carcinoma, 12 (54.5%) showed positive glypican-3 expression in the tumor tissue, a rate significantly higher than that in patients with lung adenocarcinoma [7.7% (2/26), P<0.01]. In all the glypican-3-positive cases, the tumor tissues showed stronger glypican-3 expression in cases with lymph node metastasis or poor tumor differentiation. Kaplan-Meier survival analysis did not indicate a significant correlation of glypican-3 expression with the prognosis of the lung cancer patients.
CONCLUSION: Patients with lung squamous cell carcinoma have higher glypican-3 expressions in the tumor tissues than those with lung adenocarcinoma, suggesting the value of glypican-3 protein as a potential marker to detect lung squamous cell carcinoma.

Related: Lung Cancer

Nobuoka D, Yoshikawa T, Sawada Y, et al.
Peptide vaccines for hepatocellular carcinoma.
Hum Vaccin Immunother. 2013; 9(1):210-2 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
Immunotherapy is a potentially attractive treatment option for patients with hepatocellular carcinoma (HCC). We have reported that glypican-3 (GPC3) is an ideal target for anticancer immunotherapy against HCC because its expression is specifically detected in > 80% of HCCs, even during the early stages. Further, increased GPC3 expression is correlated with a poor prognosis. Based on results obtained from a preclinical study using mice, we conducted a phase I clinical trial using a GPC3-derived peptide vaccine. Phase I results showed that the GPC3-derived peptide vaccine was well tolerated. Furthermore, this was the first study to show that the frequency of peptide-specific cytotoxic T lymphocytes was correlated with overall survival in patients with HCC receiving a peptide vaccine. Next, we conducted a phase II clinical trial using the GPC3-derived peptide vaccine in patients with HCC after surgery or radiofrequency ablation (adjuvant setting). We are currently evaluating a third trial involving liver biopsies removed from patients with advanced HCC before and after GPC3-derived peptide vaccination. We expect that the results of these trials will result in future drug development.

Zhu AX, Gold PJ, El-Khoueiry AB, et al.
First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma.
Clin Cancer Res. 2013; 19(4):920-8 [PubMed] Related Publications
PURPOSE: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC.
EXPERIMENTAL DESIGN: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5-20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria.
RESULTS: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P = 0.033).
CONCLUSION: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation.

Related: Monoclonal Antibodies Liver Cancer

Iwama T, Horie K, Yoshikawa T, et al.
Identification of an H2-Kb or H2-Db restricted and glypican-3-derived cytotoxic T-lymphocyte epitope peptide.
Int J Oncol. 2013; 42(3):831-8 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
Glypican-3 (GPC3) is overexpressed in human hepatocellular carcinoma (HCC) but not expressed in normal tissues except for placenta and fetal liver and therefore is an ideal target for cancer immunotherapy. In this study, we identified an H2-Kb or H2-Db restricted and murine GPC3 (mGPC3)-derived cytotoxic T-lymphocyte (CTL) epitope peptide in C57BL/6 (B6) mice, which can be used in the design of preclinical studies of various therapies with GPC3-target immunotherapy in vivo. First, 11 types of 9- to 10-mer peptides predicted to bind with H2-Kb or H2-Db were selected from the mGPC3 amino acid sequence based on the binding score as calculated by the BIMAS software. We evaluated the peptide-binding affinity and confirmed that all peptides were able to bind to H2-Kb or H2-Db by in vitro cellular binding assay. Subsequently, a mixed peptide vaccine and single peptide vaccine were given to B6 mice to evaluate immunogenic potential of the 11 selected peptides. Using the splenocytes from peptide-vaccinated mice, interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assays showed that mGPC3-1127-136 (AMFKNNYPSL) peptide was the most efficient for inducing CTLs among the 11 peptides. Next, we demonstrated that the mGPC3-1 peptide-specific CTL line could recognize mGPC3-expressing cancer cells, suggesting that mGPC3-1 peptide was an endogenously presented peptide. In conclusion, we identified mGPC3-1 as an H2-Kb or H2-Db restricted, mGPC3-derived CTL epitope peptide.

Related: Liver Cancer

Krings G, Ramachandran R, Jain D, et al.
Immunohistochemical pitfalls and the importance of glypican 3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma.
Mod Pathol. 2013; 26(6):782-91 [PubMed] Related Publications
Scirrhous hepatocellular carcinoma is a rare ill-defined morphological subtype of hepatocellular carcinoma characterized by marked stromal fibrosis. This variant can be difficult to distinguish from intrahepatic cholangiocarcinoma and metastatic adenocarcinoma, especially on needle biopsies. We performed immunohistochemistry for hepatocellular and adenocarcinoma-associated markers on 20 scirrhous hepatocellular carcinoma cases and compared the results with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Scirrhous hepatocellular carcinomas were significantly less likely to be HepPar-1 positive than classical hepatocellular carcinomas (26% and 74%, respectively; P<0.001) and were significantly more likely to express adenocarcinoma-associated markers such as epithelial cell adhesion molecule (63 vs 11%; P<0.001), cytokeratin 19 (26 vs 2%; P<0.001), and cytokeratin 7 (53 vs 2%; P<0.001). At least one of these adenocarcinoma-related markers was positive in 80% of scirrhous hepatocellular carcinoma cases. Glypican 3 and arginase were positive in 79% and 85% of cases of scirrhous hepatocellular carcinoma, respectively; the combined use of these two markers yielded 100% sensitivity for scirrhous hepatocellular carcinoma. In conclusion, the scirrhous morphology, absence of HepPar-1 staining, and frequent positivity with adenocarcinoma-related markers in scirrhous hepatocellular carcinoma can lead to an erroneous diagnosis of adenocarcinoma. Glypican 3 and arginase are the most reliable markers for identifying hepatocellular differentiation in this setting.

Related: Liver Cancer

Young RH, Ulbright TM, Policarpio-Nicolas ML
Yolk sac tumor with a prominent polyvesicular vitelline pattern: a report of three cases.
Am J Surg Pathol. 2013; 37(3):393-8 [PubMed] Related Publications
We report 3 cases of the rare polyvesicular vitelline variant of ovarian yolk sac tumor (YST). The patients were 23, 29, and 43 years old, and all presented with large unilateral adnexal masses confined to the ovary. One tumor was predominantly cystic, and the other 2 had prominent cystic components; all 3 also had solid components. Microscopic examination of the cystic regions showed dilated cysts that largely effaced the stroma resulting in a honeycomb-like appearance. The solid foci were characterized predominantly by small tubules in a fibrous stroma; the tubules exhibited variably conspicuous cystic dilatation to merge with the microcystic appearance. The tumor cells varied from large and primitive-appearing to flattened and deceptively innocuous when lining large cysts. They were immunoreactive for α-fetoprotein and glypican-3. Non-polyvesicular vitelline components of YST were present focally in 2 cases (hepatoid in one, reticular and endometrioid like in the second). Two patients are disease free after 20 and 26 years, respectively; disease-free follow-up is of short duration in the third case (2 years). The good long-term outcome in 2 cases supports prior evidence that suggests that the natural history of this form of YST may be more indolent than conventional forms of the tumor.

Related: Ovarian Cancer

Pan Z, Chen C, Long H, et al.
Overexpression of GPC3 inhibits hepatocellular carcinoma cell proliferation and invasion through induction of apoptosis.
Mol Med Rep. 2013; 7(3):969-74 [PubMed] Related Publications
Glypican‑3 (GPC3) is a membrane heparan sulfate proteoglycan involved in cell proliferation, differentiation, adhesion, migration and the development of the majority of mesodermal tissues and organs. GPC3 has been found to be important for the occurrence and development of hepatocellular carcinoma (HCC). Therefore, it may be suitable for use as a novel molecular marker for the diagnosis of primary liver cancer. In the present study, the role of GPC3 in the occurrence and development of HCC was determined. GPC3 recombinant vector was transfected into two HCC cell lines, Huh7 and SK‑HEP‑1, to upregulate the expression of GPC3 and examine changes in the biological behavior of the cells. Results indicate that overexpression of GPC3 in Huh7 and SK‑HEP‑1 cells effectively inhibited cell proliferation and cell invasion through induction of apoptosis. However, cotreatment of the cells with insulin‑like growth factor 2 (IGF2) and fibroblast growth factor 2 (FGF2) was found by Annexin V‑PI flow cytometric analysis to significantly inhibit the apoptotic cell death induced by GPC3 overexpression. These observations indicate that GPC3 may act as a negative regulator of IGF2 and FGF2 pathways. Taken together, these results demonstrate that overexpression of GPC3 inhibits the occurrence and development of HCC.

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Fernández-Vega I, García O, Crespo A, et al.
Specific genes involved in synthesis and editing of heparan sulfate proteoglycans show altered expression patterns in breast cancer.
BMC Cancer. 2013; 13:24 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
BACKGROUND: The expression of a specific set of genes controls the different structures of heparan sulfate proteoglycans (HSPGs), which are involved in the growth, invasion and metastatic properties of cancerous cells. The purpose of this study is to increase knowledge of HSPG alterations in breast cancer.
METHODS: Twenty-three infiltrating ductal adenocarcinomas (IDCs), both metastatic and non-metastatic were studied. A transcriptomic approach to the structure of heparan sulfate (HS) chains was used, employing qPCR to analyze both the expression of the enzymes involved in their biosynthesis and editing, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate chains, we extended the study to include the genes involved in the biosynthesis of these glycosaminoglycans. Histochemical techniques were also used to analyze tissular expression of particular genes showing significant expression differences, of potential interest.
RESULTS: No significant change in transcription was detected in approximately 70% of analyzed genes. However, 13 demonstrated changes in both tumor types (40% showing more intense deregulation in the metastatic), while 5 genes showed changes only in non-metastatic tumors. Changes were related to 3 core proteins: overexpression of syndecan-1 and underexpression of glypican-3 and perlecan. HS synthesis was affected by lower levels of some 3-O-sulfotransferase transcripts, the expression of NDST4 and, only in non metastatic tumors, higher levels of extracellular sulfatases. Furthermore, the expression of chondroitin sulfate also was considerably affected, involving both the synthesis of the saccharidic chains and sulfations at all locations. However, the pro-metastatic enzyme heparanase did not exhibit significant changes in mRNA expression, although in metastatic tumors it appeared related to increased levels of the most stable form of mRNA. Finally, the expression of heparanase 2, which displays anti-metastatic features, experienced a strong deregulation in all patients analyzed.
CONCLUSIONS: IDCs show alterations in the expression of HSPG genes; principally the expression and localization of proteoglycans and the sulfation patterns of glycosaminoglycan chains, depending on the metastatic nature of the tumor. In addition, the anti-proliferative molecule heparanase 2 experiences strong deregulation, thus highlighting it as a potentially interesting diagnostic factor.

Related: Breast Cancer SDC1


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