CD248, also known as Endosialin or Tumor Endothelial Marker 1 (TEM1), is a protein found on the surface of specific cells. While involved in normal biological processes, its presence and activity are notably altered in disease. This makes CD248 a subject of scientific interest, particularly as a potential target for new therapies.
The Basics of CD248
CD248 is a transmembrane glycoprotein, a protein spanning the cell membrane. It is encoded by the CD248 gene in humans and has a predicted molecular mass of 80.9 kDa, consisting of 757 amino acids. The protein structure includes a signal leader peptide, five globular extracellular domains (three of which are EGF repeats), a mucin-like region, a transmembrane domain, and a short cytoplasmic tail.
CD248 is found on specific cell types, such as fibroblasts and pericytes, often associated with blood vessels. Under healthy conditions in adult tissues, CD248 expression is at very low levels or absent. During embryonic development, its expression is high in mesenchymal tissues and vasculature. Its expression can be significantly upregulated under certain pathological conditions.
CD248’s Role in Body Processes
CD248 participates in several normal physiological processes, particularly those involving cell interactions and tissue organization. It is involved in cell adhesion, how cells attach to each other and their surroundings. This protein also plays a part in cell migration, the directed movement of cells, fundamental for development and tissue repair.
The protein contributes to the regulation of the extracellular matrix (ECM), the intricate network providing structural and biochemical support to cells. CD248’s involvement extends to processes like blood vessel formation, known as angiogenesis, essential for development and wound healing. It also participates in tissue remodeling, a process where tissues reorganize, important for maintaining integrity and repairing damage.
CD248 and Disease Development
CD248’s expression and function become altered in various disease states. Its heightened presence and activity contribute to the progression of several conditions.
Cancer
CD248 is highly expressed on tumor-associated stromal cells, cells surrounding a tumor, including pericytes and fibroblasts. This overexpression contributes to tumor growth by promoting processes within the tumor microenvironment. For instance, CD248 facilitates tumor cell migration and invasion, aiding in the spread of cancer. It also plays a role in angiogenesis within the tumor, the formation of new blood vessels that supply the tumor with nutrients and oxygen, supporting its growth and metastasis.
Fibrotic Diseases
CD248 is also implicated in fibrotic diseases, characterized by excessive tissue scarring from overproduction and accumulation of connective tissue. In conditions such as liver fibrosis, CD248 expression is upregulated on activated hepatic stellate cells, cells that contribute to scarring. In kidney fibrosis, CD248 is expressed by pericytes and stromal fibroblasts, and its expression increases with disease progression, contributing to the accumulation of myofibroblasts and microvascular rarefaction. CD248 promotes fibroblast activation and collagen deposition, key events in fibrosis development in organs like the lung, liver, and kidney.
Inflammation
CD248 has a role in chronic inflammatory conditions, contributing to tissue damage and remodeling. Its expression is re-activated in the presence of inflammation. CD248 participates in the inflammatory response and reorganization of the extracellular matrix, which can lead to tissue damage. Its presence in inflamed tissues suggests it contributes to persistent tissue changes in chronic inflammatory states.
Targeting CD248 for Treatment
CD248 is considered a promising therapeutic target because its expression is low in healthy adult tissues but significantly elevated in diseased states, allowing targeting of diseased cells while sparing healthy ones. This selective expression pattern offers a therapeutic window for intervention.
One strategy being explored involves antibody-drug conjugates (ADCs), designed to deliver potent drugs directly to CD248-expressing cells. These ADCs consist of an antibody that recognizes CD248, linked to a cytotoxic drug. Once the antibody binds to CD248 on the cell surface, the complex is internalized, releasing the drug inside the cell for its therapeutic effect. For example, a CD248-specific ADC has shown promise in inhibiting liver fibrosis by selectively killing CD248-positive hepatic stellate cells.
Immunotherapies are also being investigated, leveraging the body’s immune system to target CD248. This includes approaches like Chimeric Antigen Receptor (CAR)-T cell therapy, where T cells are engineered to recognize and attack CD248-expressing cells. This method aims to provide a highly specific and potent immune response against CD248-positive diseased cells, like those found in tumors.
Research is also underway to develop small molecule inhibitors that block CD248’s activity, interfering with its role in disease progression. These molecules aim to disrupt CD248’s interactions with other proteins or signaling pathways, mitigating its pro-disease effects. These therapeutic approaches hold promise for treating various cancers, as well as fibrotic diseases like liver and kidney fibrosis, by selectively targeting the cells that drive these conditions.