Suprabasal alpha 5 beta1 integrin expression stimulates formation of epidermal squamous cell carcinomas without disrupting TGFbeta signaling or inducing spindle cell tumors.
During epidermal chemical carcinogenesis benign papillomas convert to squamous cell carcinomas, some of which undergo epithelial-mesenchymal conversion to highly malignant spindle cell tumors. TGFbeta inhibits early stages of carcinogenesis but promotes the spindle cell phenotype in later stages. One hallmark of spindle cell tumors is upregulation of the alpha 5 beta 1 integrin fibronectin receptor. To examine the significance of altered alpha 5 beta1 integrin expression, we induced tumors in transgenic mice expressing alpha 5 beta1 in the suprabasal epidermal layers. Invalpha 5 beta1 mice developed threefold more papillomas and squamous cell carcinomas than wild-type (Wt) littermates; however, no spindle cell tumors or increased metastases were observed. Suprabasal expression of the alpha 6 beta 4 integrin increases squamous cell carcinoma formation and decreases TGFbeta sensitivity while alpha 3 beta1 may have the opposite effect. In contrast, nuclear phosphoSmad2 labeling in Invalpha 5 beta1 epidermis and tumors was indistinguishable from Wt, and suprabasal alpha 5 beta1 did not block TGFbeta-induced Smad2/3 translocation or growth inhibition in cultured keratinocytes. We conclude that upregulation of alpha 5 beta1 does not predispose the epidermis to undergo conversion to spindle cell tumors and that the mechanism by which alpha 5 beta1 influences susceptibility to carcinogenesis is independent of perturbed TGFbeta signaling.
Owens
David M
DM
Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
Broad
Simon
S
Yan
Xiaohong
X
Benitah
Salvador A
SA
Watt
Fiona M
FM
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; D039081:Integrin alpha5beta1; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta