How Does Inflammation Cause Skin Cancers?

How Does Inflammation Cause Skin Cancers?
Observations and controlled animal studies suggest that chronic inflammation induces SCCs; we may now know a bit more about how.

Chemokines are cytokines that attract lymphocytes. In skin, the CC class of chemokines may be especially important. Antigen-experienced T cells express CC-type receptors (CCRs); indeed, CCR4 mediates homing of cutaneous T cells. A novel chemokine receptor, D6, soaks up these CC chemokines and, in normal circumstances, helps shut off inflammation by making the chemokines unavailable.

Now, a group of researchers reports that D6-deficient mice show greatly increased susceptibility to developing papillomas induced by the inflammation-producing carcinogen phorbol ester. In contrast, transgenic mice with lots of D6 are resistant to tumor formation. Without D6 receptors, CC chemokine ligand-3 (CCL3) continues to attract aberrantly (in excess, and for a longer time) CD3+ T cells and dermal mast cells.

Comment: Infiltration of CD3+ T cells and dermal mast cells has previously been associated with development of skin cancer. The resultant excess in cytokines and cells leads to epidermal hyperproliferation and ras-driven tumor formation. The chronic presence of T cells and mast cells and persisting inflammation also increase the tendency for squamous cell carcinomas to invade and metastasize.

Chronic inflammation in human oral mucosa — from tobacco carcinogens, human papillomavirus, or chronic allergic stomatitis — may cause chronic overproduction of CC chemokines. Perhaps these abundant CC chemokines saturate all D6 receptors, allowing the overflow to bind to active CCRs and induce cancers. Many SCCs of the oral mucosa are driven by ras mutations, so ras-driven proliferation of squamous cells by chemokines has potential clinical relevance, including for possible interventions. Most SCCs in skin are based on mutations of p53 rather than ras. We don’t know yet if excessive tissue chemokine levels foster gain-of-function mutations of p53.

— Mark V. Dahl, MD