UV-Induced Triggering of a Biomechanical Initiation Switch Within Collagen Promotes Development of a Melanoma-Permissive Microenvironment in the Skin.

摘要

The overall objective of our proposal was to test whether UV irradiation facilitates the exposure of the HU177 cryptic epitopes which may represent a "solid state biomechanical initiation switch" that promotes inflammation, skin damage and the creation of a melanoma permissive niche. We have successfully completed the majority of the experiments outlined in our original proposal. Overall, our studies indicate that the UV - irradiation of triple helical collagen in vitro, in the absence of proteolytic enzymes can induced changes in the structure of collagen that results in the exposure of the HU177 cryptic collagen epitope. UV - mediated triggering of the HU177 biomechanical collagen switch depended on the precise dose and wavebands of UV irradiation used and the type and preparation of ECM proteins evaluated. Importantly, UV - irradiation of full thickness skin resulted in exposure of the HU177 epitope, which was associated with elevated levels of inflammatory infiltrates including neutrophils, macrophages and mast cells. Pre - treatment of mice with anti - HU177 epitope antibody inhibited UV - induced mast cell accumulation and decreased UV - induced melanoma tumor growth in vivo. These data are consistent with the ability of UV - irradiation induced exposure of the HU177 cryptic collagen epitope in creating an inflammatory and tumor permissive microenvironment in the skin. Taken together, our data are consistent with the possibility that strategies might be developed that could selectively target the HU177 collagen epitope and be used prior to long term sun exposure to limit inflammation, and skin damage resulting from solar irradiation.