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Successful blockade

05.05.2014

Using a new active substance, scientists from the University Hospital of Würzburg have managed to stop the growth of skin cancer cells. Further tests are now required to see whether this inhibitor can be used in treatment and whether it also has a growth-inhibiting effect on the tumor cells of other types of cancer.

Not only can viruses trigger annoying and unpleasant infections, such as influenza or measles, they are also responsible for a number of human cancers. One example is Merkel cell carcinoma – a rare but highly aggressive form of skin cancer. Around six years ago, scientists found evidence here that a virus is present in roughly 80 percent of all carcinomas – the so-called Merkel cell polyomavirus.

How viruses cause cancer

The exact mechanism used by the virus to make cells divide and multiply unchecked is not yet known. What is clear, however, is that special proteins encoded by the virus genome, which are known in scientific jargon as T antigens, play a pivotal role. Studies on related tumor viruses have revealed that T antigens are able to inactivate the so-called retinoblastoma protein inside cells; this protein is responsible for preventing uncontrolled cell proliferation.

Therefore, the interaction between the T antigen and the retinoblastoma protein provides a suitable target for potential treatment. Whether this will have the desired result has now been researched by scientists from the Department of Dermatology, Venereology and Allergology at the University Hospital of Würzburg. The results of their study have just been published in the scientific journal PLOS One.

Attack on intermediary protein

“To enable the T antigen to interact with the retinoblastoma protein, it needs a mediator of sorts in the form of a particular protein, the so-called heat shock protein HSP70,” says Christian Adam, a Research Associate at the Department of Dermatology, Venereology and Allergology and lead author of the study. Adam and his colleagues therefore blocked HSP70 with a chemical inhibitor and examined the consequences. The results were very promising.

“Our first step was to investigate which of the total of 17 variants in the members of the HSP70 family are present inside the cells,” explains Adam. To this end, a number of Merkel cell cancer lines were analyzed, as well as other cancer cells for comparison. One variant stood out with a clear majority: the HSC70 isoform. “What we know about this isoform is that a high concentration in cancer cells goes hand in hand with a poor prognosis for the patient,” remarks Adam. Or, to put it another way, HSC70 is apparently good for tumor growth.

The scientists then examined what happens when HSC70 is blocked using the special inhibitor developed by a partner in the USA. Again, the result was clear: “Of the seven cell lines we worked with, five died after treatment,” says Adam. This success was evident not only in the cell culture, but also in animal experiments. This is a result which, in Adam’s words, allows “a certain amount of hope.”

A surprising result

However, one thing that slightly complicates the issue is the fact that the cells responded regardless of whether or not they were infected with viruses. “We tested the influence of the HSC70 inhibitor both on cells carrying viruses and on cells without a viral infection,” says Adam. In both groups, some lines responded extremely sensitively to the treatment, and others not at all.

This is a result that can be interpreted in various ways. As one possibility, it suggests that an HSC70 inhibitor would be a potential drug for various different types of tumor in which the protein is present in increased concentrations inside the cells, regardless of whether or not a virus has triggered the tumor growth or some other cause is responsible for it.

Further investigations are needed

The other explanation is as follows: “Just because it has not been possible so far to prove the presence of viruses in all Merkel cell cancer lines, this does not mean that no viruses were involved in their creation,” says Adam. It might just as well be that the detection methods were not sensitive enough to locate the virus genome. Or that the cells expelled the viruses again after they had caused them to multiply unchecked.

Many questions, therefore, which will need to be answered before a new drug for the fight against cancer is launched on the market. Until then, “many more studies and tests will be necessary,” comments Adam. Though the results so far are promising.

Merkel cell carcinoma

Merkel cell carcinomas, compared to other malignant tumors of the skin, are relatively rare. Every year, two to three in a million light-skinned people develop it. However, this number has been rising dramatically in recent years. This type of cancer predominantly affects older people; it is also more prevalent in people with a weakened immune system, such as patients after an organ transplant or AIDS sufferers. This is why the researchers looked for a virus that might be involved in this disease and also finally found it. Ultraviolet light is another risk factor.

Why no viruses can be found in about 20 percent of Merkel cell carcinomas is unclear. One explanation for this is that Merkel cell carcinoma actually involves two or more closely related cancers, of which only one is infected with Merkel cell polyomaviruses.

The HSP70 Modulator MAL3-101 Inhibits Merkel Cell Carcinoma. Christian Adam, Anne Baeurle, Jeffrey L. Brodsky, Peter Wipf, David Schrama, Jürgen Christian Becker, Roland Houben. PLoS ONE 9(4): e92041. doi:10.1371/journal.pone.0092041

Contact

Christian Adam, Adam_C@ukw.de

Gunnar Bartsch | idw - Informationsdienst Wissenschaft
Further information:
http://www.uni-wuerzburg.de

Further reports about: Dermatology HSC70 Venereology carcinoma carcinomas explanation retinoblastoma viruses

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