Members of the ADAMTS family of
proteases degrade
proteoglycans and thereby have the potential to alter tissue architecture and regulate cellular functions. Aggrecanases are the main
enzymes responsible for
aggrecan degradation, due to their specific cleavage pattern. In this study, the expression status, the macromolecular organization and localization of ADAMTS-1, ADAMTS-4/
aggrecanase-1 and ADAMTS-5/
aggrecanase-2 in human normal larynx and
laryngeal squamous cell carcinoma (LSCC) were investigated. On
mRNA level, the results showed that ADAMTS-4 was the highest expressed
enzyme in normal larynx, whereas ADAMTS-5 was the main
aggrecanase in LSCC presenting a stage-related increase up to stage III (8-fold higher expression compared to normal), and thereafter decreased in stage IV. Accordingly, immunohistochemical analysis showed that ADAMTS-5, but not ADAMTS-4, was highly expressed by
carcinoma cells. Sequential extraction revealed an altered distribution and organization of multiple molecular forms (latent, activated and fragmented forms) of the
enzymes within the cancerous and their corresponding macroscopically normal laryngeal tissues, compared to the normal ones. Importantly, these analyses indicated that critical macromolecular changes occurred from the earliest LSCC stages not only in malignant parts of the tissue but also in areas that were not in proximity to
carcinoma cells and appeared otherwise normal. Overall, the results of the present study show that ADAMTS-5/
aggrecanase-2 is the main
aggrecanase present in laryngeal
carcinoma suggesting a critical role for the
enzyme in
aggrecan degradation and laryngeal tissue destruction during
tumor progression.