HGNC Approved Gene Symbol: GPC1
Cytogenetic location: 2q37.3 Genomic coordinates (GRCh38): 2:240,435,663-240,468,076 (from NCBI)
Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Two different cell surface heparan sulfate proteoglycan families can be distinguished: the syndecan-like integral membrane proteoglycans (SLIPS), with a core protein spanning the cytoplasmic membrane, and the glypican-related integral membrane proteoglycans (GRIPS), with a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol. GPC1 belongs to the GRIPS family (Vermeesch et al., 1995).
Endostatin (120328), a collagen XVIII fragment, is a potent antiangiogenic protein. Karumanchi et al. (2001) showed that alkaline phosphatase-tagged endostatin bound endothelial cells, revealing 2 binding affinities. Expression cloning identified glypican, specifically glypican-1 or glypican-4 (GPC4; 300168), as the lower-affinity receptor. Biochemical and genetic studies indicated that the heparan sulfate glycosaminoglycans of glypican were critical for endostatin binding. Furthermore, endostatin selected a specific octasulfated hexasaccharide from a sequence in heparin. Karumanchi et al. (2001) also demonstrated a role for endostatin in renal tubular cell branching morphogenesis and showed that glypicans serve as low-affinity receptors for endostatin in these cells, as in endothelial cells. Antisense experiments suggested the critical importance of glypicans in mediating endostatin activities.
Aikawa et al. (2008) found that both cancer cell-derived and host cell-derived GPC1 were crucial for efficient growth, metastasis, and angiogenesis of human and mouse cancer cells. Downregulation of GPC1 by antisense RNA in a human pancreatic cancer cell line resulted in prolonged doubling times and decreased anchorage-independent growth in vitro, as well as attenuated tumor growth, angiogenesis, and metastasis following transplant into athymic mice. Moreover, athymic mice lacking Gpc1 exhibited decreased tumor angiogenesis and metastases following intrapancreatic implantation with human pancreatic cancer cells and fewer pulmonary metastases following intravenous injection of mouse melanoma cells. Hepatic endothelial cells isolated from these mice exhibited an attenuated mitogenic response to Vegfa (VEGF; 192240).
Using mass spectrometry analyses, Melo et al. (2015) identified a cell surface proteoglycan, GPC1, specifically enriched on cancer cell-derived exosomes. GPC1-positive circulating exosomes were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1-positive circulating exosomes were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1-positive circulating exosomes correlated with tumor burden and the survival of pre- and post-surgical patients. GPC1-positive circulating exosomes from patients and from mice with spontaneous pancreatic tumors carry specific KRAS (190070) mutations, and reliably detected pancreatic intraepithelial lesions in mice despite negative signals by MRI. Melo et al. (2015) concluded that GPC1-positive circulating exosomes may serve as a potential noninvasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
By fluorescence in situ hybridization, Vermeesch et al. (1995) assigned the GPC1 gene to chromosome 2q35-q37.
Aikawa, T., Whipple, C. A., Lopez, M. E., Gunn, J., Young, A., Lander, A. D., Korc, M. Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells. J. Clin. Invest. 118: 89-99, 2008. [PubMed: 18064304] [Full Text: https://doi.org/10.1172/JCI32412]
Karumanchi, S. A., Jha, V., Ramchandran, R., Karihaloo, A., Tsiokas, L., Chan, B., Dhanabal, M., Hanai, J., Venkataraman, G., Shriver, Z., Keiser, N., Kalluri, R., and 9 others. Cell surface glypicans are low-affinity endostatin receptors. Molec. Cell 7: 811-822, 2001. [PubMed: 11336704] [Full Text: https://doi.org/10.1016/s1097-2765(01)00225-8]
Melo, S. A., Luecke, L. B., Kahlert, C., Fernandez, A. F., Gammon, S. T., Kaye, J., LeBleu, V. S., Mittendorf, E. A., Weitz, J., Rahbari, N., Reissfelder, C., Pilarsky, C., Fraga, M. F., Piwnica-Worms, D., Kalluri, R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523: 177-182, 2015. Note: Erratum: Nature 610: E15-E17, 2022. [PubMed: 26106858] [Full Text: https://doi.org/10.1038/nature14581]
Vermeesch, J. R., Mertens, G., David, G., Marynen, P. Assignment of the human glypican gene (GPC1) to 2q35-q37 by fluorescence in situ hybridization. Genomics 25: 327-329, 1995. [PubMed: 7774946] [Full Text: https://doi.org/10.1016/0888-7543(95)80152-c]