Wound healing and cancer metastasis share common early signalling pathways that have led to the hypothesis that tumours are “wounds that do not heal”, a phrase first coined by Virchow in the 19th century. Now it is recognised that a common starting point for both is an epithelial-to-mesenchymal transition (EMT) of cell phenotype, allowing a stationary, differentiated cell to become migratory or invasive. EMT is required during embryogenesis, for re-epithelialisation during wound healing and is also a hallmark of cancer metastasis. EMT and the reciprocal mesenchymal to epithelial transition (MET) are also key processes involved in stem cell differentiation.
The purpose of EMT is to reprogram epithelial cells into motility. This occurs via loss of cell-adhesion and tight junctions, while simultaneously developing mesenchymal machinery e.g. formation of intermediate filaments, filopodia, and lamellopodia. This cellular reprogramming is initiated by diverse extracellular signals; yet the signalling pathways that regulate re-epithelialisation during wound healing and EMT leading to metastasis in cancer are remarkably similar.
Ageing is associated with impaired wound healing, problematic chronic wounds and cancer, e.g. squamous cell carcinoma. Hormonal changes occur with age, but the best example of programmed aging is demonstrated by menopause in the human female. Estrogen receptors (ER) are highly expressed in human skin and estrogen insufficiency in postmenopausal women leads to a diminished defense against oxidative stress, resulting in atrophic skin changes, acceleration of skin aging and a higher incidence of non-healing chronic wounds. Although some studies have shown estrogen receptors alpha and beta (ERa and ERβ) regulate EMT in prostate and breast cancer, there are no studies of human skin. In breast cancer ERβ inhibits EMT and invasion, and in prostate carcinoma, a key function of ERβ is to maintain an epithelial phenotype and repress mesenchymal characteristics. Hypoxia is now emerging as one of the most relevant conditions triggering EMT and hypoxia - induced EMT diminishes ERβ expression, which is sufficient to promote EMT in the prostate. In ovarian cancer oestrogen promotes EMT through ERa, suggesting the increased risk of cancer in women on hormone replacement therapy may be modulation of EMT via ERa.
Human epidermal keratinocytes predominately express ERβ with little or no ER, The anti-aging effects of oestrogen on human skin have been attributed to antioxidant mechanisms modulated via ERβ. However the expression of ERb in human skin is significantly decreased in the epidermis of those above 70 years of age, which may contribute to the loss of the protective effect of oestrogen in human skin with aging. EMT is now taking central stage as the convergence point between cancer, inflammation and degenerative fibrotic diseases and normal physiological processes including development and wound healing. Identifying the molecular and functional parallels between wound healing and the developing tumour stroma and distinguishing where the two processes diverge will have important applications beyond skin biology.
Aims of Project
• Determine the role of ERβ in EMT or MET in human epidermal keratinocytes during wound healing • Establish how changes associated with aging e.g. hormones, inflammation, hypoxia impair ERβ signalling pathways • Distinguish the concordant biological functions and pathways important in regeneration and repair modulated by ERβ from the discordant pathways that differentiate cancer from wounds • Investigate the efficacy of selective oestrogen receptor modulators (SERMS), e.g. tamoxifen and raloxifene as selective ERβ agonists, in order to reduce the safety concerns associated with oestrogen therapy via ERa