Squamous cell carcinoma (SCC) is a form of nonmelanoma skin cancer, which is the most common type of human malignancy with over 1 million new cases in the USA each year.

In the July 2 issue of the Journal of Clinical Investigation, two separate studies by research teams at Glasgow University and Baylor College of Medicine uncover 2 previously unidentified regulators of SCC development, providing insights into the development of this potentially lethal disease.

Mutations in the p53 tumor suppressor gene have been implicated in tumor formation: some give rise to a loss-of-function whereas the majority of mutations result in a gain-of-function. In the first of these two studies, Dennis Roop, Carlos Caulin, and colleagues from Baylor College of Medicine, set out to determine whether gain-of-function or loss-of-function mutations in p53 are more critical for SCC development.

The authors show that certain p53 mutations occurring in human SCCs demonstrate gain-of-function properties that accelerate the frequency and progression of malignant SCC. Future studies will hopefully discover ways to target these mutations for therapeutic purposes.

A link between skin inflammation and SCC formation was first reported in the 19th century. In the second of these 2 new JCI studies, Robert Nibbs, Gerard Graham, and colleagues from Glasgow University show that the chemokine receptor D6 acts to sequester inflammatory molecules known as chemokines and as such is essential to suppressing the development of skin cancer. They show that D6-deficient mice are acutely sensitive to SCC formation and that D6 expression is induced in cells in close proximity to invasive SCC cells from human oral SCCs. In the absence of D6, skin inflammation sensitizes skin cells to tumor formation.

In an accompanying commentary on these two studies, David Owens from Columbia University in New York comments that “if a heightened inflammatory state in the skin can influence p53 gain-of-function status, this may have important implications for the prognosis of SCCs”.

Source: An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations