The bright and the dark sides of activin in wound healing and cancer
Maria Antsiferova
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Sabine Werner
)
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Department of Biology, Institute of Molecular Health Sciences
,
ETH Honggerberg, HPL E12, 8093, Zurich
,
Switzerland
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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
cancerinduced 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
e tumours that overexpress activin. Here, we summarize the previously described roles of activin in wound healing and scar formation and
cn discuss functional studies that revealed different functions of activin in the pathogenesis of cancer. The relevance of these findings for
ie clinical applications will be highlighted.
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ll Key words: Activin, Cancer, Tumour microenvironment, Wound healing
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an Introduction contacts and start expressing mesenchymal markers such as
ru In 1863, Rudolf Virchow had already recognized that chronic vimentin. Furthermore, matrix metalloproteinases and other
Jo irritation and inflammatory hyperplasia are predispositions for proteolytic enzymes that are produced by epithelial and stromal
cancer development (Virchow, 1863). A century later, Alexander cells are involved in the breakdown of extracellular matrix, which
Haddow suggested that tumour production is a possible is essential for the migration of the cells at the wound edge, and
overhealing (Haddow, 1974). Finally, Harold Dvorak postulated also for increased cancer cell motility and invasion (reviewed by
that tumors are wounds that do not heal (Dvorak, 1986). These Arnoux et al., 2005).
observations suggested that common cellular and molecular Besides the similar behaviour of epithelial cells during wound
mechanisms are active in wounds and in cancer, and this concept healing and cancerogenesis, many similarities have also been
has been strongly supported during subsequent years by various found in the stroma of healing wounds and carcinomas. These
experimental studies. include similarities in the cellular composition and also in the
A hallmark of wounds and of carcinomas (cancer of epithelial deposited extracellular matrix. Examples of the matrix alterations
cells) is the enhanced proliferation and migration of epithelial that are seen in wounds and in tumours are differences in collagen
cells. In healing wounds, this allows efficient re-epithelialization remodeling compared with that in normal tissues, and upregulation
of the injured body site and it is terminated when the wound is fully of various extracellular matrix molecules, such as tenascin-C and
covered by a new epidermis. In a carcinoma, however, this process an embryonic splice variant of fibronectin. Furthermore,
is not self-limiting and results in unlimited tumour growth and fibrinogen is released from injured vessels upon wounding or
eventually metastasis (reviewed by Schafer and Werner, 2008). from chronically hyperpermeable vessels in tumours (reviewed by
During cutaneous wound repair, keratinocytes at the wound edge Werner and Grose, 2003; Egeblad et al., 2010). It is subsequently
lose their cellcell contacts, rearrange their actin cytoskeleton and cleaved by thrombin to form fibrin, which polymerizes to form a
express various proteases to degrade the basement membrane and clot. This matrix provides a favourable substrate that promotes cell
interstitial connective tissue. These events are reminiscent of the migration and proliferation (Dvorak, 1986).
epithelialmesenchymal transition (EMT) that occurs during Inflammation is a central event in wound repair that protects
development and is also frequently seen in advanced-stage the host from infection, as inflammatory cells release reactive
carcinomas. However, in skin wounds EMT is only partial and oxygen species and proteases to defend bacteria. Furthermore,
reversible keratinocytes retain some intercellular contacts and inflammatory cells are potent sources of various growth factors
continue to express epidermal keratins (reviewed by Schafer a (...truncated)