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Scientists Discover How Healthy Epithelial Cells Naturally Eliminate “Precancerous” Ones

A recombinant protein enhances the elimination of precancerous cells and suppresses the formation of tumours and precancerous lesions, potentially applicable as a therapeutic candidate for cancer prevention.

Epithelial cells make up the continuous, protective layer that lines the outer surfaces of our organs and blood vessels, and the inner surfaces of cavities in many internal organs. They perform a variety of functions including but not limited to absorbing water and food in the digestive canal, secreting enzymes, hormones, mucus, and sweat, and protecting the tissues underneath from desiccation, pathogens, radiation, and toxins. They also contribute to the immune surveillance system.

In recent years, scientists have found that the human body possesses defence mechanisms run by non-immune epithelial cells that can recognise and extrude neighbouring precancerous cells from the epithelium in a process known as cell competition. Accordingly, this immune-like surveillance mechanism has attracted significant attention due to its potential for identifying and developing immune-like therapeutic targets to treat, or better yet, prevent cancer. However, researchers have not been able to identify the types of ligand-receptor interactions that are involved in the process of precancerous cell recognition by normal epithelial cells.

Seeking answers to this unresolved question, scientists at Waseda University embarked on an investigation that led them to uncover the mechanisms by which healthy epithelial cells detect and eventually eliminate precancerous ones. Their findings revealed that normal epithelial cells push out precancerous cells from the epithelial cell layer, effectively preventing cancer development.

“During the process of cell competition, normal epithelial cells can be primed by contact with precancerous cells. However, it was previously unclear how neighbouring normal epithelial cells recognise precancerous cells to eliminate them,” explained Professor Takeshi Maruyama, an Associate Professor at the Waseda Institute for Advanced Study at Waseda University, who led the research group on the premise of their study.

In the study, Maruyama and colleagues discovered that a plasma membrane protein called Canis suboptimal alteration recognising protein (Canis AltR) acts as a recognising protein for cell competition in healthy canine epithelial cells. In humans, Canis AltR is most similar to the leukocyte immunoglobulin-like receptor B3 (LILRB3).

Upon closer examination, the scientists found that AltR/LILRB3 interacts with major histocompatibility complex class I (MHC class I) that is expressed on precancerous epithelial cells. This interaction activates AltR/LILRB3, which triggers an intracellular pathway called SHP2–ROCK2 (Src homology-2 domain-containing protein tyrosine phosphatase-2–Rho-associated protein kinase 2). This pathway leads to the “accumulation of cytoskeletal components” in normal epithelial cells at the boundary with precancerous cells. This creates a mechanical force to extrude precancerous cells out of the epithelium to remove them from the body. Interestingly, this molecular mechanism takes place independently of a natural killer or CD8+ cell-mediated immune activity.

Having uncovered a new immune-like mechanism to suppress tumorigenesis, the researchers are optimistic that the findings of their study can offer important implications for cancer treatment in clinical settings, bringing us closer to developing more effective therapeutics and perhaps conquering cancer.

“The recombinant MHC-I-α3 protein used in this study enhances the elimination of precancerous cells and suppresses the formation of tumours and precancerous lesions. We hope that this biomolecule would contribute to a therapeutic candidate for cancer prevention by the elimination of precancerous cells,” said Maruyama. [APBN]

Source: Ayukawa et al. (2021). Epithelial cells remove precancerous cells by cell competition via MHC class I–LILRB3 interaction. Nature Immunology, 22, 1391–1402.