Although aberrant
integrin expression has been documented in many epithelial
tumors, little is known about how
integrins influence neoplastic progression. To examine this issue, transgenic mice in which the alpha2beta1 or
alpha3beta1 integrin was expressed in the suprabasal epidermal layers via the
involucrin promoter were subjected to skin
carcinogenesis. Equal numbers of benign squamous
papillomas were observed in transgenic and wild-type animals. However, the frequency of conversion of
papillomas to malignant
squamous cell carcinomas was much lower in alpha3beta1 transgenic than in alpha2beta1 transgenic and wild-type mice. No differences were observed in apoptosis or in the expression of endogenous
integrins in transgenic and wild-type
papillomas. However, alpha3beta1 transgenic
papillomas displayed a diminished proliferative capacity and were more highly differentiated as judged by BrdUrd incorporation and
keratin 10 expression, respectively, than alpha2beta1 transgenic and wild-type
papillomas. Two
proteins that associate with alpha3beta1 and not alpha2beta1 are extracellular matrix
metalloproteinase inducer and CD81. Extracellular matrix
metalloproteinase inducer expression correlated inversely with the degree of differentiation in normal epidermis and in transgenic and wild-type
papillomas. Up-regulation of CD81 was observed in 100% of wild-type and 88% of alpha2beta1 transgenic
papillomas but in only 25% of alpha3beta1 transgenic
papillomas. CD81 was undetectable in untreated epidermis and strongly expressed in all transgenic and wild-type
squamous cell carcinomas. Our results demonstrate that the
alpha3beta1 integrin can suppress malignant conversion, and that the mechanism may involve CD81.