Mouse Mast Cell Protease 4 Protects Against Ultraviolet-B Induced Skin Tumourigenesis

Please Note: Not all symbols were able to be reproduced, refer to the attached PDF. Excessive exposure to ultraviolet (UV)-B radiation (290-320 nm), a component of sunlight, is considered the major etiological factor in skin cancer, causing detrimental alterations in the patterns of tissue remodelling processes, inflammation, angiogenesis and lymphangiogenesis. An accumulation of mast cells (MCs) in the peri-tumoural stroma is typically a hallmark feature; this has given rise to the important question of whether MCs at the peri-lesional interface function to provide a permissive tumourigenic environment or to guard against rapid neoplastic progression. Recently, we discovered that MCs can negatively regulate inflammatory responses caused by chronic low-dose UVB irradiation of the skin (levels which cause skin damage and not induce tumours), via a pathway involving the immunomodulatory agent vitamin D3 and MC-derived interleukin (MC-IL)-10. Our current studies highlight that mouse mast cell protease 4 (mMCP4), the functional homologue of human MC chymase, is an important MC-specific mediator that can provide an additional protective mechanism against detrimental UVB-induced skin pathology. By implementing chronic high doses and excessive exposures of UVB that cause skin tumourigenesis, we demonstrate that MC-deficient c-kit mutant KitW/W-v mice engrafted with bone marrow-derived cultured mast cells (BMCMCs) from mMCP4-/- mice yield higher rates of UVB-induced ear ulceration and in situ SCCs than wild-type BMCMC-engrafted KitW/W-v mice. Interestingly, in response to extensive chronic UVB irradiation, not only mMCP4-/- BMCMC→KitW/W-v mice, but also our non-pigmented Tyrc-2j–mMCP4-/- mice, exhibit extensive lymphatic vessel dilation in their UVB-exposed ears compared to the experimental wild-type counterparts, thereby suggesting a potential role of mMCP4 and its substrates in governing protection against pathological lymph vessel dysfunction at critical stages during skin tumourigenesis. Moreover, microarray studies demonstrated that the loss of mMCP4 causes global changes in mRNA expression in multiple pathways especially upregulation of genes involved in cell migration and in the extracellular matrix (ECM) Taken together, our data provides an important mechanistic insight into the beneficial function of dermal MCs and mMCP4 at distinct checkpoints in a setting of UVB irradiation driven epidermal neoplasia.Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 201