Targeting of hepatocellular carcinoma with glypican-3-targeting peptide ligand

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Abstract

Hepatocellular carcinoma is a common malignancy. The carcinoma cells express glypican-3 (GPC-3) on the cell membrane. GPC-3 is also expressed in melanoma cells. Therefore, GPC-3 might be a potential target for tumor imaging or therapy. Here, proteomic mass spectrometry was used to identify peptides that target GPC-3-expressing tumors. A mammalian expression vector expressing a FLAG-GPC-3 fusion protein was cloned for immunoprecipitation. With the use of liposomes, the vector was transfected into HepG2 (HepG2/FLAG-GPC-3) and HEK 293 cells, and the transfected cell lines were selected with geneticin. HepG2/FLAG-GPC-3 cells were used for immunoprecipitation of FLAG-GPC-3 fusion protein. Seven peptide candidates (L1-L7) were selected for GPC-3-targeting ligands by mass spectrometric analysis. The L5 peptide with 14 amino acids (Arg-Leu-Asn-Val-Gly-Gly-Thr-Tyr-Phe-Leu-Thr-Thr-Arg-Gln) showed selective binding to the GPC-3-expressing tumor cells, as did a shortened L5 peptide (L5-2) with seven amino acids (Tyr-Phe-Leu-Thr-Thr-Arg-Gln). These peptide ligands have potential as targeting moieties to GPC-3-expressing tumors for diagnostic and/or therapeutic purposes.

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Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders.

M Shady, Tonya A Lander, Ling Wang … (2001)

Hepatocellular carcinoma (HCC) is a common malignant tumour worldwide, and its differential diagnosis from benign lesions of the liver is often difficult yet of great clinical importance. In the present study, we analysed whether glypican-3 is useful in differentiating between benign and malignant liver diseases and whether it influences the growth behaviour of HCC. Northern blot analysis and in situ hybridisation. Northern blot analysis indicated that expression of glypican-3 mRNA was either low or absent in normal liver, in focal nodular hyperplasia (FNH), and in liver cirrhosis. In contrast, expression of glypican-3 mRNA was markedly increased in 20 of 30 and moderately increased in five of 30 HCC samples. The average increase in glypican-3 mRNA expression in HCC was significant compared with expression in normal liver (21.7-fold increase, p<0.01). In comparison with FNH or liver cirrhosis, glypican-3 mRNA expression in HCC was increased 7.2- (p<0.05) and 10.8-fold (p<0.01), respectively. In addition, pushing HCCs exhibited significantly higher glypican-3 mRNA expression than invading tumours (p<0.05). In situ hybridisation analysis demonstrated weak expression of glypican-3 mRNA in normal hepatocytes and bile ductular cells, and weak to occasionally moderate signals in hepatocytes forming nodules of liver cirrhosis and in regenerated hepatic nodules of FNH. In contrast, glypican-3 in situ hybridisation signals were intense in hepatic cancer cells with even higher levels in pushing HCCs than in invading HCCs. These findings suggest that glypican-3, in many cases, has the potential to differentiate between benign and malignant liver diseases.

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Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells.

Kiyotaka Nakano, Tetsuro Orita, Junichi Nezu … (2009)

Glypican 3 (GPC3), a GPI-anchored heparan sulfate proteoglycan, is expressed in the majority of hepatocellular carcinoma (HCC) tissues. Using MRL/lpr mice, we successfully generated a series of anti-GPC3 monoclonal antibodies (mAbs). GPC3 was partially cleaved between Arg358 and Ser359, generating a C-terminal 30-kDa fragment and an N-terminal 40-kDa fragment. All mAbs that induced antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) against cells expressing GPC3 recognized the 30-kDa fragment, indicating that the C-terminal region of GPC3 serves as an epitope for mAb with ADCC and/or CDC inducing activities. Chimeric mAbs with Fc replaced by human IgG1 were created from GC33, one of the mAbs that reacted with the C-terminal 30-kDa fragment. Chimeric GC33 induced not only ADCC against GPC3-positive human HCC cells but also was efficacious against the Huh-7 human HCC xenograft. Thus, mAbs against the C-terminal 30-kDa fragment such as GC33 are useful in therapy targeting HCC.

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Biomarkers for the lung cancer diagnosis and their advances in proteomics.

Hyeon Cho, Hye Sung (2008)

Over a last decade, intense interest has been focused on biomarker discovery and their clinical uses. This interest is accelerated by the completion of human genome project and the progress of techniques in proteomics. Especially, cancer biomarker discovery is eminent in this field due to its anticipated critical role in early diagnosis, therapy guidance, and prognosis monitoring of cancers. Among cancers, lung cancer, one of the top three major cancers, is the one showing the highest mortality because of failure in early diagnosis. Numerous potential DNA biomarkers such as hypermethylations of the promoters and mutations in K-ras, p53, and protein biomarkers; carcinoembryonic antigen (CEA), CYFRA21-1, plasma kallikrein B1 (KLKB1), Neuron-specific enolase, etc. have been discovered as lung cancer biomarkers. Despite extensive studies thus far, few are turned out to be useful in clinic. Even those used in clinic do not show enough sensitivity, specificity and reproducibility for general use. This review describes what the cancer biomarkers are for, various types of lung cancer biomarkers discovered at present and predicted future advance in lung cancer biomarker discovery with proteomics technology.