Oral Presentation 27th Lorne Cancer Conference 2015

Mast cell protease 4 protects against chronic ultraviolet B-induced skin tumourigenesis. (#18)

Houng H Taing 1 2 , Natasha Kolesnikoff 2 , Emma Gordon 2 , Kelly Betterman 2 , Kwok-Ho Yip 2 , Gunnar Pejler 3 , Stephen J Galli 4 , Michael Samuel 2 , Natasha Harvey 2 , Michele A Grimbaldeston 2
  1. University of Adelaide, Adelaide, SA, Australia
  2. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
  3. Swedish Univeristy of Agricultural Sciences, Uppsala, Sweden
  4. Standford Univeristy School of Medicine, Stanford, USA

Excessive exposure to ultraviolet-B (UVB) radiation (290-320 nm), a component of sunlight, is considered the major etiologic factor in skin cancer, causing detrimental alterations in the patterns of tissue remodelling processes, inflammation and angio- / lymphangio-genesis. An accumulation of mast cells (MCs) in the peri-tumour 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 do not induce tumours), via a pathway involving the immunomodulatory agent Vitamin D3 and MC-derived 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 skin neoplasia than wild-type BMCMC-engrafted KitW/W-v mice. Interestingly, in response to extensive chronic UVB irradiation, not only mMCP4-/-BMCMC-engrafted KitW/W-v mice, but also our non-pigmented B6-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. Taken together, our data provides an important mechanistic insight into the beneficial function of dermal MCs at distinct checkpoints in a setting of UVB irradiation driven epidermal neoplasia.