Cell activation via CD44 occurs in advanced stages of squamous cell carcinogenesis

Abstract

Squamous cell carcinoma (SCC) derives from dysplastic or metaplastic stratified epithelia. The process of squamous cell carcinogenesis has been investigated for the potential role of the adhesion molecule CD44, whose standard form (CD44s) and isoforms generated by alternative splicing of variant exons are known to display altered expression during tumorigenesis in other systems. We have utilized an in vitro correlate of squamous cell carcinogenesis, in which progression stages from normal squamous epithelium to dysplastic lesions and to SCC are represented by primary cultures of normal keratinocytes, by human papilloma virus-immortalized keratinocytes (UP) and by HPVimmortalized/v-Ha-ras transfected tumorigenic keratinocytes (UPR). We investigated expression of CD44 and of variant isoforms, from mRNA to intracellular and surface protein levels, and found no relationship between expression of CD44 and stages of squamous cell carcinogenesis. However, when the function of CD44 was analyzed as Ca(2+) mobilization ability upon monoclonal antibody binding and crosslinking, signal transduction via CD44 was found only for the neoplastic stage (UPR cells). Ca(2+) mobilization was completely independent of density of surface CD44. We have performed similar analyses in an in vitro model of SCC in which four squamous tumor cell lines and UPR cells were sorted according to increasing resistance to external cytotoxic stimuli, i.e. starving conditions, treatment with the retinoid N-(4-hydroxyphenyl)retinamide and cytolytic activity of effector lymphokine-activated killer cells. No relationship between expression of CD44 and level of cell resistance against external cell death-inducing stimuli was found, while CD44-mediated Ca(2+) mobilization ability was restricted to the highly resistant tumor cell lines. Our results indicate that the role(s) of CD44 in squamous cell proliferative disorders can be evinced from the functional features of the molecule, rather than from its phenotypic repertoire.

Prognostic significance of CD44s expression in resected non-small cell lung cancer

“…Additionally, the functional role of CD44 has revealed different features of the molecule in the two histological subtypes. In SCC, only cells of the neoplastic stage can transduce subcellular signals via CD44 [26], whereas CD44s down-regulation in the NSCLC cell line H322, derived from a primary bronchioalveolar carcinoma of the lung, may confer a protective advantage by allowing escape from tumoricidal effector cells, including activated macrophages of the host, thus promoting tumorigenesis [27]. …”

CD44v10 interaction with Rho‐kinase (ROK) activates inositol 1,4,5‐triphosphate (IP3) receptor‐mediated Ca2+ signaling during hyaluronan (HA)‐induced endothelial cell migration

“…A number of laboratories, including our own, have demonstrated that the binding of HA to CD44-expressing cells promotes intracellular Ca 2ϩ mobilization, which is a pre-requisite for the onset of a variety of biological activities [Bourguignon et al, 1993Galluzo et al, 1995;Bruno et al, 2000;Partida-Sanchez et al, 2000]. Although the cellular and molecular mechanisms involved in HA/CD44-mediated Ca 2ϩ signaling are currently not well understood, one of the likely pathways involves the phosphatidylinositol cascade that leads to Ca 2ϩ release from intracellular stores [Berridge, 1993;Yoshida and Imai, 1997].…”

Molecular markers of metastasis in squamous carcinomas

“…This is well known for p53 protein, where over expression usually indicates mutation. The same phenomenon is being increasingly recognized for other markers; for example, CD44 protein is expressed on the cell surface of squamous carcinoma cells in vitro , but the presence of the protein is independent of its function in signal transduction, which is essential for tumourigenesis11.…”