Journal of Cell Science The bright and the dark sides of activin in wound healing and cancer Maria Antsiferova* and Sabine Werner* Department of Biology, Institute of Molecular Health Sciences, ETH Honggerberg, HPL E12, 8093, Zurich, Switzerland *Authors for correspondence (maria.antsiferova@cell.biol.ethz.ch; sabine.werner@cell.biol.ethz.ch) Journal of Cell Science 125, 1–9 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.094789 Summary Activin was initially described as a protein that stimulates release of follicle stimulating hormone from the pituitary, and it is well known for its important roles in different reproductive functions. In recent years, this multifunctional factor has attracted the attention of researchers in other fields, as new functions of activin in angiogenesis, inflammation, immunity, fibrosis and cancer have been discovered. Studies from our laboratory have identified activin as a crucial regulator of wound healing and skin carcinogenesis. On the one hand, it strongly accelerates the healing process of skin wounds but, on the other hand, it enhances scar formation and the susceptibility to skin tumorigenesis. Finally, results from several laboratories have revealed that activin enhances tumour formation and/ or progression in some other organs, in particular through its effect on the tumour microenvironment, and that it also promotes cancer- induced bone disruption and muscle wasting. These findings provide the basis for the use of activin or its downstream targets for the improvement of impaired wound healing, and of activin antagonists for the prevention and treatment of fibrosis and of malignant tumours that overexpress activin. Here, we summarize the previously described roles of activin in wound healing and scar formation and discuss functional studies that revealed different functions of activin in the pathogenesis of cancer. The relevance of these findings for clinical applications will be highlighted. Key words: Activin, Cancer, Tumour microenvironment, Wound healing Introduction In 1863, Rudolf Virchow had already recognized that ‘‘chronic irritation and inflammatory hyperplasia are predispositions for cancer development’’ (Virchow, 1863). A century later, Alexander Haddow suggested that ‘‘tumour production is a possible overhealing’’ (Haddow, 1974). Finally, Harold Dvorak postulated that ‘‘tumors are wounds that do not heal’’ (Dvorak, 1986). These observations suggested that common cellular and molecular mechanisms are active in wounds and in cancer, and this concept has been strongly supported during subsequent years by various experimental studies. A hallmark of wounds and of carcinomas (cancer of epithelial cells) is the enhanced proliferation and migration of epithelial cells. In healing wounds, this allows efficient re-epithelialization of the injured body site and it is terminated when the wound is fully covered by a new epidermis. In a carcinoma, however, this process is not self-limiting and results in unlimited tumour growth and eventually metastasis (reviewed by Scha ¨fer and Werner, 2008). During cutaneous wound repair, keratinocytes at the wound edge lose their cell–cell contacts, rearrange their actin cytoskeleton and express various proteases to degrade the basement membrane and interstitial connective tissue. These events are reminiscent of the epithelial–mesenchymal transition (EMT) that occurs during development and is also frequently seen in advanced-stage carcinomas. However, in skin wounds EMT is only partial and reversible – keratinocytes retain some intercellular contacts and continue to express epidermal keratins (reviewed by Scha ¨fer and Werner, 2008). By contrast, cancer cells that undergo EMT often acquire a fibroblast-like morphology; they lose their cell–cell contacts and start expressing mesenchymal markers such as vimentin. Furthermore, matrix metalloproteinases and other proteolytic enzymes that are produced by epithelial and stromal cells are involved in the breakdown of extracellular matrix, which is essential for the migration of the cells at the wound edge, and also for increased cancer cell motility and invasion (reviewed by Arnoux et al., 2005). Besides the similar behaviour of epithelial cells during wound healing and cancerogenesis, many similarities have also been found in the stroma of healing wounds and carcinomas. These include similarities in the cellular composition and also in the deposited extracellular matrix. Examples of the matrix alterations that are seen in wounds and in tumours are differences in collagen remodeling compared with that in normal tissues, and upregulation of various extracellular matrix molecules, such as tenascin-C and an embryonic splice variant of fibronectin. Furthermore, fibrinogen is released from injured vessels upon wounding or from chronically hyperpermeable vessels in tumours (reviewed by Werner and Grose, 2003; Egeblad et al., 2010). It is subsequently cleaved by thrombin to form fibrin, which polymerizes to form a clot. This matrix provides a favourable substrate that promotes cell migration and proliferation (Dvorak, 1986). Inflammation is a central event in wound repair that protects the host from infection, as inflammatory cells release reactive oxygen species and proteases to defend bacteria. Furthermore, inflammatory cells are potent sources of various growth factors and cytokines that are required for new tissue formation (reviewed by Werner and Grose, 2003). In cancer, inflammation is essential for the generation of anti-tumour immunity and elimination of ARTICLE SERIES: Cell Biology and Disease Commentary 1 JCS online publication date 18 September 2012