Glypican 3 (GPC3) is a protein found within the human body, belonging to a family of cell surface molecules known as heparan sulfate proteoglycans. These proteins attach to the outer cell membrane, where they interact with various other proteins and play roles in biological processes. GPC3 is involved in regulating cell growth and division, as well as cell survival. Its presence and functions are particularly notable during the developmental stages before birth.
Understanding Glypican 3
GPC3 consists of a core protein linked to heparan sulfate chains, anchored to the cell’s outer membrane by a glycosylphosphatidylinositol (GPI) linkage. This structure allows GPC3 to interact with various signaling molecules outside the cell, influencing cellular communication. GPC3 is highly expressed in certain fetal tissues, including the liver, lungs, and kidneys, underscoring its involvement in embryonic development and organ formation.
Its functions are diverse and tissue-dependent, acting as a modulator in several signaling pathways. GPC3 can influence the Hedgehog signaling pathway, which is involved in cell proliferation and patterning during embryonic development. It also interacts with Wnt signaling proteins, which regulate cell growth and differentiation. GPC3’s heparan sulfate chains can bind to growth factors like fibroblast growth factor 2 (FGF-2), further modulating their activity and influencing cell growth.
Normal GPC3 expression is largely restricted to specific tissues in adults, with minimal presence in healthy adult organs. However, its re-expression or altered expression in certain conditions indicates its dynamic role in biological processes beyond development. While it can act as a growth inhibitor in some contexts, it may promote cell growth in others, such as in liver cells, by interacting with various growth factors.
Glypican 3’s Connection to Cancer
Glypican 3 gains significant attention due to its altered expression in various cancers, particularly hepatocellular carcinoma (HCC), the most common type of liver cancer. GPC3 is considered an oncofetal protein because it is normally present in fetal liver tissue but largely absent in the healthy adult liver. Its re-expression or overexpression in HCC tissues is a consistent finding, making it a reliable marker for this aggressive malignancy.
The overexpression of GPC3 in HCC contributes to tumor growth and progression by promoting cell proliferation and survival. It achieves this by activating the canonical Wnt signaling pathway, where GPC3 can form a complex with Wnt molecules and stimulate the binding of Wnt ligands to their Frizzled receptors. This activation leads to the expression of genes associated with uncontrolled cell division and survival, fostering the cancerous environment.
While HCC is the primary focus of GPC3’s cancer association, its expression has been identified in other malignancies as well. These include some cases of melanoma, lung squamous cell carcinoma, clear cell carcinoma of the ovary, and certain pediatric embryonal tumors like hepatoblastoma and Wilms’ tumor.
Glypican 3 as a Medical Tool
Glypican 3’s unique expression in cancer, particularly hepatocellular carcinoma (HCC), makes it a valuable medical tool. As a diagnostic biomarker for HCC, GPC3 can be detected in tissue samples using immunohistochemistry, which helps differentiate HCC from benign liver conditions.
GPC3 can also be found in a soluble form (sGPC3) in the peripheral blood of HCC patients, making it a non-invasive biomarker for diagnosis and prognosis. Combining sGPC3 detection with other established biomarkers, such as alpha-fetoprotein (AFP), can enhance the sensitivity of early HCC diagnosis. Its presence often correlates with a poorer prognosis for patients with HCC.
Beyond diagnosis, GPC3 is explored as a therapeutic target in cancer treatment. Its cell-surface location on HCC cells makes it accessible for antibody-based therapies. Approaches like anti-GPC3 monoclonal antibodies are being developed to specifically bind to GPC3 on cancer cells and trigger anti-tumor immune responses. Newer strategies include chimeric antigen receptor (CAR) T-cell therapies, where immune cells are engineered to recognize and destroy GPC3-expressing cancer cells, and antibody-drug conjugates that deliver toxic payloads directly to tumor cells.
Glypican 3 in Inherited Syndromes
Glypican 3 plays a direct role in certain inherited genetic conditions, most notably Simpson-Golabi-Behmel syndrome (SGBS). This X-linked overgrowth disorder results from mutations in the GPC3 gene, located on the X chromosome. Males are primarily affected because they have only one X chromosome; a deletion or point mutation in their GPC3 gene can lead to the syndrome. Mutations in the GPC3 gene prevent the production of functional glypican 3 or alter its structure, disrupting its ability to regulate cell growth. In SGBS, the loss of GPC3 function leads to the overactivity of signaling pathways, such as the Hedgehog pathway, resulting in increased cell proliferation and the characteristic pre- and postnatal overgrowth.
Individuals with SGBS often present with:
Pre- and postnatal overgrowth
A wide mouth, a broad nose with an upturned tip, and widely spaced eyes
Skeletal anomalies, such as extra spinal bones
Internal organ abnormalities, including kidney and heart defects
An increased risk for embryonal tumors, like Wilms’ tumor, in early childhood