Glypicans in Cancer

Proteoglycans (PGs) are glycoproteins that contain long, covalently-linked unbranched chains of repeating disaccharides. HSPGs, proteoglycans with heparan sulfate (HS) glycosaminoglycan (GAG) chains, are abundant components of cells and the extracellular matrix (ECM) and as such serve diverse roles in development and pathophysiology.¹ HSPGs act as signaling co-receptors for growth factors and morphogens, regulate the stability and distribution of signaling molecules in the ECM and chemokine gradients at sites of injury, modulate cell adhesion and motility, and affect intracellular membrane trafficking.² There are three classes of HSPGs: the secreted extracellular matrix proteoglycans, the transmembrane syndecans, and the GPI-linked glypicans.^{1, 2} In mammals, six glypicans (GPC1-6) have been identified. All have a 60-70 kDa protein core, are glycosyl phosphatidylinositol (GPI)-linked to the cell membrane, and due to their globular structure are restricted to HS-type GAG attachments.^{1, 2, 3}

Since glypicans act as co-receptors by facilitating the formation of ligand-receptor complexes and effectively lowering the required concentration of ligand, it is not surprising that they are expressed in the tumor environment.⁴ Glypican-1, -3 and -5 have all been associated with the tumorigenic process, mostly by affecting growth factor signaling and cell proliferation. GPC1 shows increased expression in human gliomas and glioma-derived cell lines, and acts by enhancing fibroblast growth factor (FGF) basic signaling and mitogenesis.⁵ Likewise, in pancreatic and breast cancer cells GPC1 is over-produced, and affects regulation of FGF basic and heparin-binding EGF-like growth factor (HB-EGF) signaling.^{6, 7} Antisense depletion of GPC1 in pancreatic cancer cells also reduces their ability to form tumors in vivo.⁸ Another example of glypican-promoted proliferation of tumor cells involves GPC5. Its upregulation has a strong association with the appearance and increased cell proliferation of rhabdomyosarcoma, a malignant skeletal muscle tumor. The mechanism involves GPC5-mediated activity of FGF basic, hepatocyte growth factor (HGF), and Wnt-1.⁹

View Larger Image

Figure 1. The six members of the vertebrate glypican family share a characteristic structure. Glypicans are anchored to the cell surface via a GPI linkage, have a conserved pattern of 14 cysteine residues, which contribute to intramolecular disulfide linkages, and display GAG attachment sites predominantly near the membrane. Alternative names and molecular weight of the core proteins are also indicated. (Figure is adapted from references 15 and 16).

Interestingly, the role glypican-3 plays in tumorigenesis is less straightforward. On the one hand, GPC3 is overexpressed in and promotes the growth of hepatocellular carcinoma.^{10, 11} It does so by attenuating FGF basic and bone morphogenetic protein-7 (BMP-7) signaling, yet stimulating canonical Wnt signaling.^{10, 11} On the other hand, knock-down of GPC3 function in HepG2 hepatoma cells promotes their growth, and GPC3 is frequently silenced in mesotheliomas, ovarian cancer, and breast cancer cell lines.^{3, 12} A further indication that GPC3 may act as an inhibitor of cell proliferation comes from the clinical characteristics of Simpson-Golabi-Behmel syndrome, which renders GPC3 non-functional. Patients display a variety of abnormalities, including pre- and postnatal overgrowth and a susceptibility to certain malignancies.¹³ While negatively charged sulfate groups on HS chains interact with basic amino acids on ligands, it appears that the simple immobilization of growth factors on HS is insufficient to fully explain the role of glypicans in growth factor-mediated signal transduction. For instance, the location and amount of sulfation impacts the ability of FGF Receptor 2c to interact with heparan sulfate. This requires the presence of both 2-O- or 6-O-sulfated residues.¹⁴ There is also evidence that the HS chains are not required for all proteoglycan activities and that the protein core interacts with growth factors independently of HS chains.^{1, 3} In addition, glypicans can be secreted, and perhaps act through a different mechanism than membrane-bound forms.³ Nonetheless, proteoglycan regulation of growth factor sequestration and signaling makes glypicans (and other glycans) attractive targets for cancer therapeutics.⁴

References

1. Bishop, J.R. et al. (2007) Nature 446:1030.
2. Kirkpatrick, C.A. & S.B. Selleck (2007) J. Cell Sci. 120:1829.
3. Fimus, J. (2001) Glycobiology 11:19R.
4. Fuster, M.M. & J.D. Esko (2005) Nat. Rev. Cancer 5:526.
5. Su, G. et al. (2006) Am. J. Pathol. 168:2014.
6. Kleeff, J. et al. (1998) J. Clin. Invest. 102:1662.
7. Matsuda, K. et al. (2001) Cancer Res. 61:5562.
8. Kleeff, J. et al. (1999) Pancreas 19:281.
9. Williamson, D. et al. (2007) Cancer Res. 67:57.
10. Midorikawa, Y. et al. (2003) Int. J. Cancer 103:455.
11. Capurro, M.I. et al. (2005) Cancer Res. 65:6245.
12. Sung, Y.K. et al. (2003) Exp. Mol. Med. 35:257.
13. Jakubovic, B.D. & S. Jothy (2007) Exp. Mol. Pathol. 82:184.
14. Pye, D.A. et al. (1998) J. Biol. Chem. 273:22936.
15. Rosenberg, R.D. et al. (1997) J. Clin. Invest. 100:S67.
16. Vengelers, M. et al. (1999) J. Biol. Chem. 274:26968.

This symbol denotes references that cite the use of R&D Systems products.