Podoplanin is a protein, specifically a glycoprotein, found on the surface of various specialized cells throughout the human body. As a type I transmembrane glycoprotein, it passes through the cell membrane once, with its larger N-terminal end located outside the cell. It consists of 162 amino acids, with 128 residues extending beyond the cell surface. This mucin-containing protein is characterized by a large number of O-glycoside chains, contributing to its structure and functions.
The Normal Functions of Podoplanin
Podoplanin plays diverse roles in healthy bodily functions, particularly within the lymphatic system, kidneys, and lungs. In the lymphatic system, podoplanin on lymphatic endothelial cells helps ensure the separation of blood and lymphatic vessels during embryonic development. It also maintains fluid balance by facilitating lymphatic transport.
In the kidneys, podoplanin is present on podocytes, which are specialized cells that wrap around the capillaries within the glomerulus. These podocytes are part of the kidney’s filtration system, and podoplanin’s presence helps prevent proteins from leaking into the urine. The protein is also found on type I alveolar cells in the lungs. These cells cover most of the lung surface and are involved in the development of the alveoli, where gas exchange takes place.
Podoplanin’s Role in Cancer Progression
Cancer cells can express podoplanin on their surface, a process that contributes to tumor progression and spread. This abnormal expression allows cancer cells to become more mobile and invade surrounding tissues. Forcing podoplanin expression in cancer cells leads to changes in their shape, including the formation of filopodia-like protrusions, which are finger-like extensions that aid cell movement. This increased mobility is linked to the remodeling of the cell’s internal scaffolding, known as the actin cytoskeleton.
Podoplanin also contributes to metastasis by interacting with platelets in the bloodstream. Tumor cells expressing podoplanin can bind to a receptor called C-type lectin-like receptor 2 (CLEC-2) on platelets, leading to platelet aggregation. This aggregation forms a “cloak” or microthrombus around the circulating cancer cells, which can shield them from immune system attacks. The platelet-tumor cell aggregates also help cancer cells adhere to blood vessel walls in distant locations, facilitating the formation of new tumors.
Involvement in Lymphedema and Kidney Disease
Podoplanin’s normal functions are directly linked to the development of certain diseases when its activity is impaired. In the lymphatic system, if podoplanin function is impaired, it can lead to improper fluid drainage. This dysfunction results in congenital lymphedema, a chronic swelling caused by the accumulation of lymphatic fluid. Mice lacking podoplanin have shown significant defects in lymphatic vessel formation and function, including disorganized and blood-filled lymphatic vessels.
In the kidneys, podoplanin is expressed on podocytes, which are integral to the glomerular filtration barrier. Damage to these podocytes is a feature of various kidney diseases, and a reduction in podoplanin expression on these cells has been observed in some proteinuric conditions. This decrease in podoplanin can lead to impaired filtration, allowing proteins to leak into the urine, a condition known as proteinuria. The loss of podoplanin expression can even precede visible changes in the podocytes’ structure, suggesting its involvement in the early stages of kidney injury.
Clinical Use as a Biomarker and Therapeutic Target
Knowledge of podoplanin’s expression patterns has practical applications in medical diagnosis and treatments. As a biomarker, doctors can detect podoplanin in tissue samples using techniques like immunohistochemistry. This helps identify specific cell types, such as lymphatic endothelial cells, and distinguish them from blood vessel endothelial cells. Podoplanin immunostaining is also useful in diagnosing certain cancers, including mesotheliomas, some germ cell tumors like seminomas, and specific brain tumors.
Because podoplanin is often expressed on the surface of aggressive cancer cells and aids in their spread, it is being explored as a target for therapies. Researchers are developing various strategies, including monoclonal antibodies, designed to block podoplanin’s function. These therapies aim to inhibit cancer cell migration, invasion, and platelet aggregation, thereby preventing metastasis. This research holds promise for developing targeted treatments that could reduce tumor growth and spread in patients with podoplanin-expressing cancers.