Glypican-3: a new target for cancer immunotherapy.

Hepatocellular carcinoma (HCC) remains a common malignant cancer worldwide. There is an urgent need to identify new molecular targets for the development of novel therapeutic approaches. Herein, we review the structure, function and biology of glypican-3 (GPC3) and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy. GPC3 is a cell-surface protein that is over-expressed in HCC. Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS), a rare X-linked overgrowth condition. GPC3 binds Wnt and Hedgehog (Hh) signalling proteins. GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulphate glycan chains. GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC. An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanised IgG molecule is currently undergoing clinical evaluation in patients with HCC. There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC.

[1]  D. Schlessinger,et al.  Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling. , 2002, Developmental biology.

[2]  M. Evans,et al.  Glypican‐3 protein expression in primary and metastatic melanoma , 2009, Cancer.

[3]  Masamichi Sugimoto,et al.  Histopathological analyses of the antitumor activity of anti-glypican-3 antibody (GC33) in human liver cancer xenograft models: The contribution of macrophages. , 2009, Cancer biology & therapy.

[4]  Ping Xu,et al.  Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. , 2008, Developmental cell.

[5]  Ximing J. Yang,et al.  Expression of glypican 3 in hepatoblastoma: an immunohistochemical study of 65 cases. , 2008, Human pathology.

[6]  M. Kojima,et al.  Glypican‐3 expression is correlated with poor prognosis in hepatocellular carcinoma , 2009, Cancer science.

[7]  Wei Cheng,et al.  Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. , 1997, Cancer research.

[8]  Yusuke Nakamura,et al.  Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. , 2003, Biochemical and biophysical research communications.

[9]  D. Sinnett,et al.  Expression of glypican 3 (GPC3) in embryonal tumors , 2000, International journal of cancer.

[10]  C. McKerlie,et al.  Glypican-3–Deficient Mice Exhibit Developmental Overgrowth and Some of the Abnormalities Typical of Simpson-Golabi-Behmel Syndrome , 1999, The Journal of cell biology.

[11]  H. Kataoka,et al.  The expression profile of glypican‐3 and its relation to macrophage population in human hepatocellular carcinoma , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[12]  H. Aburatani,et al.  Glypican-3 expression in clear cell adenocarcinoma of the ovary , 2009, Modern Pathology.

[13]  H. Aburatani,et al.  Identification of Soluble NH2-Terminal Fragment of Glypican-3 as a Serological Marker for Early-Stage Hepatocellular Carcinoma , 2004, Cancer Research.

[14]  Y. Nishimura,et al.  HLA-A2 and -A24-restricted glypican-3-derived peptide vaccine induces specific CTLs: preclinical study using mice. , 2008, International journal of oncology.

[15]  J. Filmus,et al.  Soluble glypican 3 inhibits the growth of hepatocellular carcinoma in vitro and in vivo , 2008, International journal of cancer.

[16]  Charles A Powell,et al.  The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor. , 2003, American journal of respiratory cell and molecular biology.

[17]  W. Skarnes,et al.  glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development. , 2000, Developmental biology.

[18]  H. Hsu,et al.  Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway , 2008, Carcinogenesis.

[19]  Hong-Yang Wang,et al.  Upregulation of Glypican‐3 expression in hepatocellular carcinoma but downregulation in cholangiocarcinoma indicates its differential diagnosis value in primary liver cancers , 2005, Liver international : official journal of the International Association for the Study of the Liver.

[20]  P. Tangkijvanich,et al.  Diagnostic role of serum glypican‐3 in differentiating hepatocellular carcinoma from non‐malignant chronic liver disease and other liver cancers , 2010, Journal of gastroenterology and hepatology.

[21]  D. Schlessinger,et al.  Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome , 1996, Nature Genetics.

[22]  Masamichi Sugimoto,et al.  Histopathological analyses of the antitumor activity of anti-glypican-3 antibody (GC33) in human liver cancer xenograft models: The essential role of macrophages , 2009 .

[23]  Yusuke Nakamura,et al.  Mouse Homologue of a Novel Human Oncofetal Antigen, Glypican-3, Evokes T-Cell–Mediated Tumor Rejection without Autoimmune Reactions in Mice , 2004, Clinical Cancer Research.

[24]  H. Aburatani,et al.  Glypican 3‐expressing gastric carcinoma: Distinct subgroup unifying hepatoid, clear‐cell, and α‐fetoprotein‐producing gastric carcinomas , 2009, Cancer science.

[25]  J. Filmus,et al.  The Loss of Glypican-3 Induces Alterations in Wnt Signaling* , 2005, Journal of Biological Chemistry.

[26]  M. Tsuchiya,et al.  Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization , 2010, Anti-cancer drugs.

[27]  Wen Shi,et al.  Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. , 2003, Gastroenterology.

[28]  S. Jhanwar,et al.  Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma , 2000, Oncogene.

[29]  J. Filmus,et al.  Processing by Convertases Is Not Required for Glypican-3-induced Stimulation of Hepatocellular Carcinoma Growth* , 2005, Journal of Biological Chemistry.

[30]  D. Schlessinger,et al.  Frequent silencing of the GPC3 gene in ovarian cancer cell lines. , 1999, Cancer research.

[31]  S. Ishikawa,et al.  Glypican‐3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP‐7 signaling , 2003, International journal of cancer.

[32]  H. Kataoka,et al.  Optimization of tissue processing for immunohistochemistry for the detection of human glypican-3. , 2010, Acta histochemica.

[33]  J. Filmus,et al.  Glypicans in growth control and cancer. , 2001, Glycobiology.

[34]  K. Wakamatsu,et al.  Identification of Glypican-3 as a Novel Tumor Marker for Melanoma , 2004, Clinical Cancer Research.

[35]  H. Terashima,et al.  Involvement of glypican-3 in the recruitment of M2-polarized tumor-associated macrophages in hepatocellular carcinoma , 2009, Cancer biology & therapy.

[36]  L. Terracciano,et al.  Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues: a tissue microarray analysis of 4,387 tissue samples. , 2008, American journal of clinical pathology.

[37]  H. Aburatani,et al.  Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer. , 2008, Cancer research.

[38]  H. Aburatani,et al.  Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells. , 2009, Biochemical and biophysical research communications.

[39]  Ximing J. Yang,et al.  Glypican 3: A Novel Marker in Testicular Germ Cell Tumors , 2006, The American journal of surgical pathology.

[40]  P. Marynen,et al.  Characterization of glypican-5 and chromosomal localization of human GPC5, a new member of the glypican gene family. , 1997, Genomics.

[41]  H. Moch,et al.  Glypican-3 Expression in Primary and Recurrent Ovarian Carcinomas , 2007, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[42]  B. Peers,et al.  Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements , 2003, The Journal of cell biology.

[43]  Hiroyuki Aburatani,et al.  The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma , 2005, Modern Pathology.

[44]  S. Senju,et al.  Identification of HLA-A2- or HLA-A24-Restricted CTL Epitopes Possibly Useful for Glypican-3-Specific Immunotherapy of Hepatocellular Carcinoma , 2006, Clinical Cancer Research.

[45]  C. Lobe,et al.  Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. , 2005, Cancer research.

[46]  Mitchell Ho,et al.  Recombinant soluble glypican 3 protein inhibits the growth of hepatocellular carcinoma in vitro , 2011, International journal of cancer.

[47]  T. Longacre,et al.  Oncofetal Protein Glypican-3 Distinguishes Yolk Sac Tumor From Clear Cell Carcinoma of the Ovary , 2008, The American journal of surgical pathology.

[48]  J. Church,et al.  Isolation of a cDNA corresponding to a developmentally regulated transcript in rat intestine , 1988, Molecular and cellular biology.

[49]  J. Filmus,et al.  Overgrowth of a mouse model of Simpson– Golabi–Behmel syndrome is partly mediated by Indian Hedgehog , 2009, EMBO reports.

[50]  J. Filmus,et al.  OCI-5/Rat Glypican-3 Binds to Fibroblast Growth Factor-2 but Not to Insulin-like Growth Factor-2* , 1997, The Journal of Biological Chemistry.

[51]  J. Filmus,et al.  Glypican-3 expression is silenced in human breast cancer , 2001, Oncogene.