Integrin A6 Cleavage in Mouse Skin Tumors

ABSTRACT

We have previously identified a structural variant of the 􀀁6 integrin (Laminin receptor) called 􀀁6p. The 􀀁6p variant is a 70 kDa form of the full-length 􀀁6 integrin (140 kDa) that remains paired with either the 􀀂1 or 􀀂4 subunit on the cell surface. 􀀁6p is produced by urokinase-type plasminogen activator (uPA), which removes the extracellular 􀀂-barrel domain while the receptor is on the cell surface. The 􀀁6p integrin was present in human prostate cancer tissue but not in normal tissue and the cleavage of the 􀀁6 integrin extracellular domain promotes tumor cell invasion and migration on laminin. The objective of the present study was to determine whether the 􀀁6p integrin is observed in other models of carcinogenesis. Our results indicate detectable low levels of 􀀁6p in normal mouse skin, and comparatively elevated levels in mouse papillomas and squamous cell carcinomas induced by DMBA, TPA and MNNG treatments. Furthermore, we have found that 􀀁6p was present at high levels in skin melanomas of transgenic mice that over express activated Ha-ras under the control of the tyrosinase promoter. Finally, subcutaneous injection into athymic nude mice of a malignant mouse keratinocyte derived cell line (6M90) that is 􀀁6p negative, results in the development of tumors that contain 􀀁6p integrin. The latter results indicate that 􀀁6p is induced in vivo suggesting that the tumor microenvironment plays a major role in the production of 􀀁6p. Taken together, these data suggest that the cell surface cleavage of the 􀀁6 integrin may be a novel mechanism of integrin regulation and might be an important step during skin tissue remodeling and during carcinogenesis.