Glypican-3 (GPC3) is a protein located on the surface of cells, playing a role in regulating various cellular processes. It is a member of the glypican family, a group of six mammalian proteins (GPC1-6) that are characterized as heparan sulfate proteoglycans. These proteins are anchored to the cell’s outer membrane through a special lipid structure called a glycosylphosphatidylinositol (GPI) linkage. This attachment allows GPC3 to interact with the extracellular environment and influence cell behavior.
As a glypican, GPC3 contributes to the intricate network of cell communication and regulation. Its presence on the cell surface enables it to modulate the activity of several growth factors, which are molecules that stimulate cell growth, proliferation, and differentiation. This regulatory capacity highlights GPC3’s involvement in fundamental biological functions that maintain tissue integrity and development.
Understanding GPC3’s Biological Role
GPC3 is classified as a heparan sulfate proteoglycan, meaning it consists of a protein core with attached heparan sulfate sugar chains. The human GPC3 gene encodes a 70-kilodalton (kDa) core protein that is subsequently cleaved into two subunits: a 40-kDa N-terminal subunit and a 30-kDa C-terminal subunit. These subunits remain associated and are tethered to the cell membrane by a GPI anchor, positioning GPC3 to interact with external cellular signals.
Under normal physiological conditions, GPC3 is widely present on the membranes of various embryonic cells, but its expression significantly diminishes or becomes undetectable in many adult tissues, including the normal adult liver. It is particularly expressed at high levels in developing lung, liver, and kidney tissues. This pattern of expression underscores its involvement in the intricate processes of organismal development and tissue formation.
The normal functions of GPC3 involve regulating several crucial signaling pathways that govern cell growth and differentiation. It modulates the activity of Wnt, Hedgehog, fibroblast growth factors (FGFs), and bone morphogenetic proteins (BMPs). For instance, GPC3 can regulate Wnt/β-catenin and Yap signaling pathways, which are fundamental to cell proliferation and tissue patterning.
GPC3 plays a part in various developmental processes such as limb patterning, skeletal development, and renal branching morphogenesis. It also contributes to coronary vascular development and cell movements during gastrulation. The protein can also inhibit the activity of dipeptidyl peptidase 4 (DPP4), an enzyme involved in metabolic regulation.
GPC3 in Disease Development
GPC3’s normal regulatory functions can become disrupted, leading to its involvement in disease progression, particularly in certain cancers. Its dysregulation often involves an altered expression pattern, where it is found at abnormally high levels in diseased tissues. This overexpression can significantly contribute to the uncontrolled growth and proliferation characteristic of cancerous cells.
A prominent example of GPC3’s role in disease is its strong association with hepatocellular carcinoma (HCC), the most common type of liver cancer. While GPC3 is absent in normal adult liver tissue, it is consistently overexpressed in a large majority of HCC cases, ranging from 70% to 100% of instances. This stark difference in expression makes GPC3 a distinctive marker for this aggressive cancer.
In HCC, the overexpression of GPC3 actively promotes tumor growth by enhancing specific cellular signaling pathways. It stimulates canonical Wnt signaling, a pathway frequently implicated in cancer development, by potentially increasing the binding of Wnt proteins to their Frizzled receptors on the cell surface. This heightened Wnt signaling drives the proliferation of liver cancer cells.
Beyond Wnt signaling, GPC3’s heparan sulfate chains can interact with other growth factors like fibroblast growth factors (FGF) and hepatocyte growth factor (HGF), influencing their effects on cell proliferation and migration. Studies indicate that GPC3 expression can also influence the ERK signaling pathway and is negatively correlated with E-cadherin, a protein involved in cell adhesion, in HCC cell lines. These interactions further contribute to the aggressive nature of HCC.
The presence of elevated GPC3 levels in HCC is also linked to a less favorable prognosis for patients. Those with GPC3-positive HCC often experience shorter overall survival and disease-free survival compared to those with GPC3-negative tumors. This correlation underscores GPC3’s involvement not only in the development but also in the aggressive behavior of HCC.
GPC3’s involvement is not exclusive to HCC, though it is the most well-studied and prominent association. It has been observed to a lesser extent in other malignancies, including melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms’ tumor cells, and lung squamous cell carcinoma. In these contexts, GPC3’s presence may similarly contribute to abnormal cell growth and disease progression.
GPC3 as a Medical Tool
The distinct expression pattern of GPC3 in disease, particularly its overexpression in hepatocellular carcinoma, has made it a useful tool in medical diagnostics and therapeutics. GPC3 is utilized as a biomarker, assisting in the diagnosis and monitoring of HCC. Its presence can be detected through immunostaining of tissue biopsies, providing a valuable aid in confirming HCC diagnosis and differentiating it from benign liver lesions.
Beyond tissue analysis, soluble forms of GPC3 (sGPC3) can be found in the bloodstream, allowing for its use as a non-invasive serum biomarker. Elevated sGPC3 levels in blood tests can indicate the presence of HCC, serving as a method for early detection or monitoring disease recurrence after treatment. GPC3 has shown promise as a more reliable tumor marker than alpha-fetoprotein (AFP) in some cases, and its combination with AFP can significantly improve diagnostic sensitivity for HCC.
The unique expression of GPC3 on cancerous cells, while being largely absent in healthy adult tissues, also positions it as a promising target for cancer therapies. Researchers are developing treatments that specifically aim to target GPC3-expressing cells, minimizing harm to normal cells. This targeted approach seeks to deliver therapeutic agents directly to the tumor.
One therapeutic strategy involves the use of humanized monoclonal antibodies, such as GC33, designed to bind specifically to GPC3 on the surface of HCC cells. These antibodies can inhibit tumor growth by triggering the body’s immune response to destroy the cancer cells through antibody-dependent cellular cytotoxicity. Clinical trials are currently evaluating the effectiveness of such antibody-based treatments.
Other approaches include cancer vaccines that induce cytotoxic T lymphocytes (CTLs) against GPC3-derived peptides, and Chimeric Antigen Receptor (CAR) T-cell therapies that engineer a patient’s T-cells to specifically recognize and attack GPC3-expressing tumor cells. These innovative strategies highlight GPC3’s potential as a focal point for developing more precise and effective treatments for HCC and certain pediatric cancers.