Stop signal discovered for skin cancer

An extraordinary breakthrough in understanding what stops a common form of skin cancer from developing could make new cancer treatments and prevention available to the public in five years.  

Developing SCC on the skin. Cells are growing in an uncontrolled fashion after damaging the tumour suppressor

In research published today in the leading international cancer journal, Cancer Cell, an international team of scientists led by Professor Stephen Jane and Dr Charbel Darido of Monash University's Department of Medicine at the Alfred Hospital, has discovered a gene that helps protect the body from squamous cell cancer (SCC) of the skin. 

The Cancer Council estimates that two in three Australians will be diagnosed with skin cancer before the age of 70 with SCC being one of the most common forms. Up until now, its genetic basis has not been well understood, with surgical treatments the only option. 

Professor Jane said the team discovered that a gene with an important role in skin development in the foetus is missing in adult SCC tumour cells. Although the researchers initially focused on skin cancer, they found that the protective gene is also lost in SCC that arises in other tissues, including head and neck cancers, that are often associated with a very poor outcome for the patient. 

"Virtually every SCC tumour we looked at had almost undetectable levels of this particular gene, so its absence is a very profound driver of these cancers," Professor Jane said. 

In collaboration with Associate Professor Rick Pearson from the Peter MacCallum Cancer Centre, the Monash researchers showed that loss of this particular gene knocks out the signal to stop skin cells from growing. Without this stop signal, the cells keep increasing in number and eventually forms a cancer. 

Identifying this driver of cancer in skin and other organs provides a clear direction for developing strategies for both prevention and treatment in the relatively near future. 

"Our research indicates that drugs already in clinical trials for other cancers may actually be effective in treating SCC - they just need to be applied to skin or head and neck cancers.  

"This means that a number of the usual hurdles in getting therapies to trial have already been cleared, so patients could be reaping the benefits of this research in under five years," Professor Jane said. 

"It's a similar case with prevention. There are strategies by which we could increase the expression of this gene that will likely afford some protection from skin cancer, for example in the form of a supplement in sun-cream. The molecules that would increase this expression, are very well validated, so there would be few barriers to applying them in clinical trials." 

Source: Monash University [November 15, 2011]

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Using Viagra to combat malignant melanoma

At first it sounds like good news: The body's own immune system gets active in almost every cancer – however, not necessarily for the benefit of the patient. "We distinguish between two different types of immune response," says Professor Dr. Viktor Umansky, immunologist at DKFZ and University Medical Center Mannheim. "On the one hand, cells of the immune system specifically attack tumor cells. On the other, however, almost every tumor causes in its microenvironment a chronic inflammatory immune response which suppresses the specific antitumor immunity." 

MDSC (myeloid-derived suppressor cells) suppress the tumor-specific immune response [Credit: Dr. Alexandra Sevko, German Cancer Research Center]

In an inflammatory immune response, immune cells of a certain type migrate into the tumor environment and release characteristic immune mediators. "Our aim is to reduce the chronic inflammations and, thus, to support the immune system in actively fighting the cancer," Umansky said. 

He and his team have now studied chronic inflammation as it is caused by malignant melanoma. For their research, they used genetically-modified (transgenic) mice that spontaneously develop a type of skin cancer which is very similar to human melanoma. In the tumor environment and in metastatic lymph nodes of the animals, the investigators detected inflammatory mediators such interleukin-1-β and interferon-γ. These immune mediators attract what are called myeloid-derived suppressor cells (MDSC). These immune cells are known to inhibit the immune system's most important tumor-specific fighters, the T cells. 

What exactly happens when T cells get under the influence of MDSC? When the researchers exposed T cells obtained from the spleen of a healthy mouse to MDSC in the culture dish, the T cells stopped proliferating. Moreover, the T cells reduced the level of an important activating molecule. "This shows that tumor-specific T cells are actively suppressed by myeloid-derived suppressor cells," said Umansky, explaining their findings. 

The melanoma mice were then given sildenafil. This substance, which is better known under its trade name, Viagra®, had already been reported to improve tumor immunity in experimental animal models several times before. Of the mice that had been given the substance with their drinking water, more than twice as many were still alive after about seven weeks as of their untreated fellows. In the animals that had been treated, both the number of tumor-specific T cells and the level of activating molecules had returned to normal. This means that sildenafil successfully neutralizes the chronic inflammation in the melanoma environment and combats the immunosuppressive activity of MDSC. 

"Our research approach is special because the disease takes a very similar course in mice as melanoma does in humans," Viktor Umansky said explaining the medical relevance of his findings. "Therefore, it is very well possible that sildenafil can also inhibit the immunosuppressive effects of inflammation and thus improve antitumor immunity in people with melanoma. In this way, the drug may contribute to achieving better treatment results in malignant melanoma."  

Source: Helmholtz Association of German Research Centres [November 08, 2011]

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