Glypican 3

Schematic of the glypican-3 (GPC3) protein[9]

The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40 kDa and the C-terminal subunit is ~30 kDa.[9] Six glypicans (GPC1-6) have been identified in mammals. 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.[7] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[10][11] The core protein of GPC3 may serve as a co-receptor or a receiver for Wnt. A cysteine-rich domain at the N-lobe of GPC3 has been identified as a hydrophobic groove that interacts with Wnt3a.[11] Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation.[11] Wnt also recognizes a heparan sulfate structure on GPC3 , which contains IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to heparan sulfate.[12]

Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome.[13]

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC)[14] and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[15] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.[16] The YP7 murine antibody has been humanized and named as 'hYP7'.[17] GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors.[9] However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.

GPC3 is a promising therapeutic target for treating liver cancer.[18] Several therapeutic anti-GPC3 antibodies have been developed, including GC33[19] and YP7.[16][17] The laboratory of Dr. Mitchell Ho at the National Cancer Institute, NIH (Bethesda, Maryland, US) has generated YP7 and other murine monoclonal antibodies that recognize the C-lobe of GPC3 by hybridoma technology.[16] These antibodies have been humanized (e.g. hYP7) using antibody engineering for clinical applications.[17] The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3[20] targeting the N-lobe of GPC3 [11] and the human monoclonal antibody HS20[21][22] targeting the heparan sulfate chains on GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3,[23][24][25] the antibody-drug conjugates based on hYP7[26] and the T-cell engaging bispecific antibodies derived from YP7[27] and GC33,[28] have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33,[29] hYP7[30][31] and HN3[32] are being developed at various stages for treating liver cancer. In mice with xenograft or orthoptic liver tumors, CAR (hYP7) T cells can eliminate GPC3-positive cancer cells, by inducing perforin- and granzyme-mediated cell death and reducing Wnt signaling in tumor cells.[31]

• Glypican

• GeneReviews/NIH/NCBI/UW entry on Simpson-Golabi-Behmel Syndrome