Activin: The Active (or missing) ingredient in Skin Cancer and Wound Healing?

Enjoy this summary of a publication from the most recent issue of Nature Communication by Antsiferova and colleagues.

The protein that makes wounds heal quicker is called Activin. However, if an excess of it is present, it promotes the formation and growth of dangerous skin tumours. This has just been shown by ETH Zurich researchers led by Sabine Werner.
Rudolf Virchow was a good observer. In 1863 he wrote that chronic damage to skin and previous injuries promote the formation of malignant tumours. He backed up this statement with numerous personal observations. This year a research team led by Professor of Cell Biology Sabine Werner has confirmed what Virchow suspected, and has done so at the molecular level, which was not possible for him at that time.
In a paper just published in Nature Communications the researchers demonstrate for the first time the existence of a molecular driver which, on the one hand, plays an important role in wound healing, but on the other hand, also promotes skin cancer. Citing the researcher Harold Dvorak, who postulated it in 1986, the ETH Zurich professor says “Tumours are wounds that do not heal. A cancer uses the same mechanisms that a wound also needs in order to heal, but becomes dependent on them and never switches them off.” She says this is recognisable by the pattern of gene activity in tumours.
Activin as a “suspect”
Based on her previous results on wound healing, Sabine Werner suspected that the growth and differentiation factor Activin might also play an important role in the formation of tumours. A high concentration of this protein is needed to speed up wound healing. If it is inactive or less abundant, wounds heal much slower and, in fact, with a better cosmetic appearance, because in its absence there is much less formation of the unwanted and non-functional connective tissue that is a characteristic feature of scars.
In the new paper, she and her post-doctoral co-worker Maria Antsiferova now show that Activin actually promotes the formation of skin tumours. In their model using transgenic mice overexpressing Activin in keratinocytes, the major cell type of the epidermis, the researchers were able to illustrate that increased amounts of Activin promote the formation of tumours. When they subjected transgenic and non-transgenic control animals to a particular procedure that induces the formation of skin tumours, the transgenic animals developed many more tumours in a shorter time. The incidence also increased: compared to their “normal” littermates, a larger percentage of the transgenic animals developed tumours.
Activin reprograms immune cells
However, Activin is not directly responsible for the malignant transformation of keratinocytes. The protein uses a roundabout route by reprogramming various immune cells. For example, it suppresses the division of the so-called gamma-delta-T-cells of the epidermis, which are able to recognise tumour cells and to kill them. As a result, these cells are depleted from the epidermis and the tumour is no longer attacked. Activin also induces what are known as regulatory T-cells, which inhibit the immune system’s attack on the tumour. The principal experimenter Maria Antsiferova says “In our paper we can show which cells are affected by Activin.” On the other hand, the researchers do not yet know, which Activin-regulated genes in the targeted immune cells are responsible for the observed effects. “That will be the next aspect we will study.”
To understand the importance of Activin in the development of skin cancer, the ETH Zurich researchers studied not only the mouse model. From the Dermatology Clinics of the Universities of Lausanne and Zurich, with which Sabine Werner collaborates closely, she received expert support in determining the malignancy of the tumours found in the mice, and also human skin cancer tissues to determine the level of Activin in the latter. They obtained the same result as in the mouse model: Activin was also present at an elevated concentration in the human skin cancer samples, especially in malignant squamous cell carcinomas.
Sabine Werner now plans to investigate whether an excessive level of Activin is also present in the precursor stages of skin tumours that occur frequently in skin exposed to sunlight. The ETH Zurich researchers also want to find out whether the same immune cells that are involved in the Activin-induced formation of tumours in mice are also important for the development of skin cancer in humans and if this correlates with Activin expression levels.
Activin inhibition feasible
Obviously, the researchers are also looking for a strategy to inhibit activin action. Although that could impair wound healing, Werner thinks the risk is justifiable. The ETH Zurich professor says “Many cancer therapies suppress the immune system and wound healing, so from that point of view it would nevertheless be a feasible method.” Therefore, the next step would be to use antagonists that specifically inhibit Activin, which are already being produced by pharmaceutical companies for other purposes.
However, Activin is not the villain in every case. Not every skin tumour overexpresses this factor. Werner says “Each tumour must be considered specifically, to see how much of Activin it expresses, which leads us to personalised medicine: every patient must be treated individually.”
Literature reference:  Antsiferova M, Huber M, Meyer M, Piwko-Czuchra A, Ramadan T, MacLeod AS, Havran WL, Dummer R, Hohl D & Werner S: Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response. Nature Communications, Volume: 2, Article number: 576, doi:10.1038/ncomms1585

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