Many of us develop calluses at one point or another, but for some people calluses and corns can become severe and highly inconvenient. In some rare cases, extreme thickening of the skin is a symptom of a particular form of esophageal cancer. New research investigates the link between foot calluses and cancer of the esophagus in mice and humans.
Calluses form naturally as a result of putting too much pressure on the skin or subjecting it to excessive friction. The thickening of the top layer of the skin is the body’s way of protecting the skin underneath.
For some people, however, calluses can become so severe that the hardened skin needs to be removed with a razor. The American Podiatric Medical Association recommend that people with diabetes or circulatory problems have their feet checked because in their case, calluses can lead to more serious problems.
New research, from the Queen Mary University of London in the United Kingdom, examines the link between keratin (the protein found in the outer layers of the skin, which plays a key role in forming calluses) and a form of esophageal cancer called “tylosis.”
Tylosis affects more than 8,000 people in the U.K. It causes severe thickening of the skin in the hands and feet, and it has been associated with an esophageal cancer risk of over 95 percent. As a result, medical professionals refer to the condition as tylosis with oesophageal cancer (TOC).
In the United States, esophageal cancer ranks as the eleventh leading cause of death, as almost 16,000 people are estimated to have died from the disease in 2016.
Previous research has investigated the link between tylosis, calluses, and esophageal cancer, but this new study focuses on a particular gene found to play a crucial role in thickening the skin.
The study was published in the journal Nature Communications, and it was led by authors Thiviyani Maruthappu and Anissa Chikh.
Researchers used genetically modified mice to study the iRHOM2 gene.
A group of mice had the iRHOM2 gene removed, and these mice developed a much thinner epidermis on their paws, compared with mice that still had the gene.
Additionally, researchers found reduced expression of keratin 16 (K16) in iRHOM2-free mice.
As the authors explain, K16 is a cytoskeletal scaffolding protein that can be found in abundance at the pressure-bearing points in the footpad of mammals.
Researchers also examined K16 levels in humans with TOC, and they found a similarly heightened expression of the protein. This suggests that the iRHOM2 gene helps to regulate K16 in both humans and mice.
To the authors’ knowledge, this is the first time that iRHOM2 has been identified as a regulator of K16 in humans and mice. This is also the first study to demonstrate that iRHOM2 binds to K16, and that this interaction increases in TOC patients.
Additionally, the research shows that the iRHOM2-K16 interaction also downregulates the expression of K6 – a keratin that typically binds together with K16.
“These findings highlight a novel and fundamental role for iRHOM2 in regulating the epithelial response to mechanical stress,” write the authors.
“As K16 is highly expressed in disease states such as epithelial cancers and inflammatory dermatoses, there may be a broader significance for the role of iRHOM2 in the pathophysiology of these disorders, which remains to be explored.”