Scratching the Surface in Cancer
Published online at Lab Times.
Tissue damage is one of the many risk factors for cancer. For instance, patients suffering from epidermolysis bullosa, a chronic skin-blistering condition, are highly vulnerable to skin cancers. New research at King’s College London sheds light on the mechanism underlying tumor progression in skin abrasions and how antibiotics may serve as a surprising solution.
Barely a month into 2015 and cancer therapeutics may already be looking at a tough year ahead. First, scientists at Johns Hopkins University, USA, called it a ‘game of chance‘ when they suggested that cancer is not so much the outcome of genetic or environmental risk factors as it is of random, deleterious mutations in our DNA. Now, biologists led by Fiona Watt at King’s College London, UK, demonstrate that even skin bacteria in surface wounds can be notorious for initiating skin cancer. These studies suggest that we have barely scratched the surface in understanding cancer and beg for redesigning treatment regimens based on the novel pieces of information.
As early as 1855, the father of modern pathology Rudolf Virchow predicted that cancers can arise from a patch of chronically irritated cells. Today, a barrage of studies have shown an increased risk of cancer in patients with chronic inflammations such as those of the stomach or bowel-lining, or skin-blistering conditions such as epidermolysis bullosa.
Damaged tissue and tumors have many similarities – they both develop blood clots, show a local burst of immune response and a surge in growth-promoting molecular pathways, viz. MAP-kinase signaling, which lay the groundwork for new tissue and blood vessels at these sites. Fiona Watt and colleagues previously showed that when repair pathways go overboard, they tip a fragile balance that turns healing wounds into benign tumors. In their recent paper, the group used transgenic mice with elevated MAP-kinase signaling (InvEE mice) to study the mechanism of wound-induced tumors.
Skin lesions in InvEE mice are highly susceptible to tumor formation. Inflammatory cells flock to the sites of abrasions and ramp up body’s defense response by secreting proteins called cytokines. Some of these cells also express surface proteins called toll-like receptors (TLRs). TLRs not only mediate the immune response but are also known to be part of tumor-initiating molecular pathways. This makes them appealing candidates in wound-induced tumors. In a series of experiments, the Watt lab tested the effects of deleting different TLRs on tumor formation at the site of the lesions. They found that removal of specifically TLR5 reduced tumorigenesis in wounded InvEE mice, suggesting that TLR5 is a major player in wound-induced tumors.
But what attracts TLR5-positive cells to the wound site in the first place? “When the skin barrier is breached, bacteria will penetrate the skin and we were able to demonstrate that sensing of bacteria by immune cells at wound sites can promote tumor formation”, says Esther Hoste, lead author of the paper. It is known that TLR5 is a receptor for the bacterial protein flagellin, so their hunch was that skin bacteria invites TLR5-positive immune cells to the wounds and are responsible for the tumors at these sites. Indeed, mice treated with a broad-spectrum antibiotic enrofloxacin that depleted their skin of bacterial load, were less susceptible to wound-induced tumors, whereas, local application of flagellin to InvEE wounds exacerbated tumor formation. “We could show that treatment with antibiotics reduces the risk of skin tumor formation, while addition of bacterial products could induce tumor formation”, she says.
The Watt lab’s findings may provide a rather simple solution to a persisting problem of wound-induced skin cancers in patients with chronic ulcers and skin-blistering diseases. Theirs is the first report of bacteria as a causal agent in skin cancers. Esther sums up, “Our findings raise the possibility that the incidence of skin tumors in people suffering from chronic inflammation of the skin, such as ulcers or sores, and skin-blistering diseases could be reduced by systemic antibiotics treatment and the use of more specific targeting strategies in wound-induced malignancies might present an interesting clinical avenue”.
Photo “Staph aureus” courtesy Esther Simpson via Creative Commons