Novel Glypican-3-Binding Peptide for in Vivo Hepatocellular Carcinoma Fluorescent Imaging
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Glypican-3 (GPC3) is a key member of the glypican family that is expressed on the cell surface by a glycosyl-phosphatidyl-inositol (GPI) anchor. It plays a significant role in hepatocellular carcinoma (HCC) development, angiogenesis, and metastasis. Most HCC overexpress GPC3, whereas little GPC3 can be detected in normal adult liver and benign liver lesions. Therefore, it is important to understand the function of GPC3 in HCC tumor development as the GPC3 ligand may facilitate detection of HCC. In this study, a 12-mer peptide with the sequence of DHLASLWWGTEL (denoted as TJ12P1) was identified by screening a phage display peptide library that demonstrated ideal GPC3 binding affinity. We used TJ12P1 conjugated with near-infrared fluorescent (NIFR) dye Cy5.5 for tumor imaging. After intravenous injection of the imaging agent, TJ12P1, xenografts of high GPC3 expressing hepatocellular carcinoma cell line, HepG2, demonstrated significantly higher tumor accumulation (tumor/muscle ratio: 3.98 ± 0.36) than those of low GPC3 expressing prostate cancer cell line, PC3 (tumor/muscle ratio: 2.03 ± 0.23). More importantly, GPC3 expression in tumor samples of patients could be visualized using TJ12P1, suggesting the potential use of this peptide as a probe for HCC detection. Our study has successfully identified a promising GPC3-binding peptide ligand for detecting the GPC3 expression in HCC not only in vitro but also in vivo by its noninvasive imaging.Keywords:
Glypican 3
Glypican-3 (GPC3) is a cell surface oncofetal proteoglycan that is anchored by glycosylphosphatidylinositol. Whereas GPC3 is abundant in fetal liver, its expression is hardly detectable in adult liver. Importantly, GPC3 is overexpressed in hepatocellular carcinoma (HCC), and several immunohistochemical studies reported that overexpression predicts a poorer prognosis for HCC patients. Therefore, GPC3 would serve as a useful molecular marker for HCC diagnosis and also as a target for therapeutic intervention in HCC. Indeed, some immunotherapy protocols targeting GPC3 are under investigations; those include humanized anti-GPC3 cytotoxic antibody, peptide vaccine and immunotoxin therapies. When considering the clinical requirements for GPC3-targeting therapy, companion diagnostics to select the appropriate HCC patients are critical, and both immunohistochemical analysis of tissue sections and measurement of serum GPC3 level have been suggested for this purpose. This review summarizes current knowledge regarding the clinical implication of GPC3 detection and targeting in the management of patients with HCC.
Glypican 3
Oncofetal antigen
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ヒトの肝細胞癌組織と正常組織におけるcDNAマイクロアレイ解析により，肝細胞癌に高発現する遺伝子としてGlypican-3 (GPC3）を同定した．GPIアンカー膜蛋白質であるGPC3は，肝細胞癌患者の約40%の血清中に検出される新規癌胎児性抗原であり，αフェト蛋白，PIVKA-IIにつぐ肝細胞癌の第3の腫瘍マーカーとして有用であることを示した．また，マウスにGPC3ペプチドを負荷した樹状細胞を投与した後に，マウスGPC3を発現する癌細胞株を移植すると，自己免疫現象を伴うことなく著明な腫瘍の増殖抑制と生存期間の延長を誘導できた．さらに，HLA-A2トランスジェニックマウスや，癌患者の血液検体を利用して，HLA-A2あるいはA24によりヒト・キラーT細胞に提示されるGPC3ペプチドを同定した．これらのペプチドで癌患者のリンパ球を刺激することにより，GPC3発現ヒト肝細胞癌細胞株を傷害するヒト・キラーT細胞を誘導できた．これらのGPC3ペプチドを用いた，肝細胞癌の免疫療法に関する臨床試験を開始した．また，我々はマウス胚性幹（ES）細胞から樹状細胞（ES-DC）を分化誘導する方法を開発し，マウスGPC3を発現するES-DCをマウスに免疫したところ，GPC3発現マウス癌細胞株に対するin vivo抗腫瘍効果の誘導が観察された．
Glypican 3
Oncofetal antigen
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In recent years,the study about the relationship between Glypican-3(GPC3) and hepatocellular carcinoma(HCC) increased year by year.GPC3 has higher expression in the blood serum and tumor tissues of patients with HCC,and it has higher sensitivity and specificity in the diagnosis of HCC.The expression of GPC-3 also has a certain relationship with the prognosis of HCC.Meanwhile,GPC3 provided a novel for the treatment of HCC.
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Hepatocellular carcinoma (HCC) is a malignant tumor with a fairly poor prognosis (5-year survival of less than 50%). Using sorafenib, the only food and drug administration (FDA)-approved drug, HCC cannot be effectively treated; it can only be controlled at most for a couple of months. There is a great need to develop efficacious treatment against this debilitating disease. Glypican-3 (GPC3), a member of the glypican family that attaches to the cell surface by a glycosylphosphatidylinositol anchor, is overexpressed in HCC cases and is elevated in the serum of a large proportion of patients with HCC. GPC3 expression contributes to HCC growth and metastasis. Furthermore, several different types of antibodies targeting GPC3 have been developed. The aim of this review is to summarize the current literatures on the GPC3 expression in human HCC, molecular mechanisms of GPC3 regulation and antibodies targeting GPC3.
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This cross-sectional study was performed in the Department of Hepatology, Bangabandhu Sheikh Mujib Medical University. The purpose of this study was to assess the diagnostic value of serum Glypican-3 in detecting hepatocellular carcinoma. It was conducted during January 2015 to December 2016. Through convenience sampling technique, 30 diagnosed patients of hepatocellular carcinoma were enrolled in this study. Mean age was 50.26 ± 14.7 years. Males were the predominant gender in the study, which was 86.7%. Among the 30 respondents, 76.7% had HBsAg positive, 10% had anti HCV antibodies present. Mean serum glypican 3 level was 378.00 ± 168.42 ng/ml. Significant association of Alfa-fetoprotein and serum Glypican 3 in hepatocellular carcinoma patients was found. Serum Alfa-fetoprotein and serum Glypican 3 both were significantly detected in hepatocellular carcinoma but Glypican 3 was more sensitive and specific to detect hepatocellular carcinoma.
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Glypican 3
Sinusoid
Oncofetal antigen
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Liver disease
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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.
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Intrahepatic Cholangiocarcinoma
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Glypican-3 has been reported to be one of the most promising serum markers for hepatocellular carcinoma. This study aimed to assess the clinical utility of serum glypican 3 for the diagnosis of hepatocellular carcinoma. We recruited consecutive patients on a large scale, 283 with hepatocellular carcinoma, 445 with chronic hepatic diseases, and 162 normal controls, to assess the diagnostic accuracy of serum glypican 3 for hepatocellular carcinoma by enzyme-linked immunosorbent assay. In addition, we further analyzed the relationship between the serum levels of α-fetoprotein and glypican-3 in patients with hepatocellular carcinoma. The results indicated that serum glypican 3 was elevated in patients with hepatocellular carcinoma (0 ng/mL, range = 0-14.0 ng/mL, P = .033) and liver cirrhosis (0 ng/mL, range = 0-12.5 ng/mL, P = .001) compared to the levels in normal control (0 ng/mL, range = 0-4.3 ng/mL), but there was no difference between hepatocellular carcinoma and liver cirrhosis ( P = .097). The area under the curve of the receiver–operating characteristics curve for hepatocellular carcinoma versus all controls was 0.519, with a sensitivity of 39.9%, a specificity of 60.6%, and an optimal cutoff value of 0.002 ng/mL. The positive and negative predictive values were 32.0% and 68.3%, respectively. No significant correlation in serum levels was observed between glypican 3 and α-fetoprotein ( P > .05). The diagnostic sensitivity for hepatocellular carcinoma increased to 72.8% (206 of the 283) when glypican 3 was combined with α-fetoprotein. Glypican 3 was not a promising serum maker for the diagnosis of hepatocellular carcinoma alone, but it could be complementary to α-fetoprotein and elevate the sensitivity of hepatocellular carcinoma diagnosis.
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Research of the Glypican-3 Expression in Hepatocelluar Carcinoma and its Clinicopathogical Relevance
Objective To observe the expressions of Glypican-3 in hepatocellular carcinoma,paraneoplastic,cirrhosis and normal tissue so as to observe its relationship to clinicopathogical characteristics in hepatocellular carcinoma( HCC),and to provide the prognosis evaluation in HCC. Methods Immunohistochemistry was used on the screened 43 cases of patients with hepatocellular carcinoma to detect the expression of Glypican-3 in hepatocellular carcinoma,cirrhosis and normal controls,carcinoma tissues according to their clinical and pathological data while analyzing the GPC3 and AFP positive expression rate in hepatocellular carcinoma( HCC). Results 1. Expression of GPC3 in tumor was significantly higher than those in paraneoplastic,cirrhosis and normal tissue.( P 0. 05) 2. GPC3 expressions in carcinoma tissues were correlated with differentiation( P 0. 05). 3. Compared with AFP,GPC3 was more sensitive for the immunohistochemistry diagnosis of HCC( P 0. 05). Conclusion 1. Compared with the wildly used immune marker AFP,GPC3 is more sensitive and could be used as a new immune marker for the immunohistochemistry diagnosis and differential diagnosis of HCC. 2. GPC3 may be related to the differentiation of tumor cells.
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