Integrin signaling and expression in squamous cell carcinoma

Integrins are cell surface molecules consisting of alpha and beta heterodimers that serve as adhesion molecules and receptors for extracellular matrix proteins. We became interested in this class of molecule when we discovered that the A9 tumor-associated antigen expressed by squamous cell carcinomas (SCC) had identity with the alpha 6 beta 4 integrin. alpha 6 beta 4 was also identified as a tumor antigen in pancreatic carcinoma and murine lung carcinomas by other investigators, demonstrating that this molecule is strongly expressed in many tumor cells when compared to normal cells from the same tissues. Following the identification of these antigens as an integrin, efforts have focused on understanding the role of the alpha 6 beta 4 integrin in cancer development and progression. The normal function of the alpha 6 beta 4 integrin involves cell adhesion to extracellular matrix and an anchoring response that is not yet fully characterized. alpha 6 beta 4 is a receptor for laminin 5 and it is a component of the hemidesmosome, the anchoring structure in normal stratified epithelium. Aberrant phosphorylation, overexpression of alpha 6 beta 4, loss of alpha 6 beta 4 expression, failure to polarize hemidesmosomal components, and dominant negative mutations of alpha 6 beta 4 are implicated in blocking the normal signaling pathway through this receptor. We hypothesize that this integrin is part of a multi-molecular signaling cascade that is disrupted in most tumors, and that this disruption may occur by a variety of mechanisms. This paper reviews the evidence germane to the hypothesis.