CD44 Is Exposed to the Extracellular Matrix at Invasive Sites in Basal Cell Carcinomas

Abstract

SUMMARY:We have previously shown, by light microscopy, that the level of expression of CD44 (pan-CD44, CD44v3, CD44v5, and CD44v6) in human basal cell carcinomas is related to growth pattern and invasiveness (Br J Dermatol 1099;140:17-25). We have now studied the fine distribution of these CD44 isoforms in the same tumors using immunoelectron microscopy. Despite the strong differences in the level of expression in tumor areas with different growth patterns, CD44 was consistently found almost exclusively at intercellular surfaces, with a very strong predilection for widened intercellular pouches, ie, identical to the distribution in the normal epidermis. This prevalent distribution corroborates a role for CD44 in maintaining hyaluronan-filled spaces (J Histochem Cytochem 1998;46:241-248). However, the correlation between the presence of CD44 and the presence of such pouches was not absolute, indicating that other factors are involved as well. In contrast to the prevailing literature, we also found a weak but distinct labeling of cell surfaces facing the extracellular matrix. Interestingly, this appeared significantly elevated in the thinnest, most irregular, and usually most peripheral tumor cell strands, where it was associated with tumor cell protrusions and absence of a basal lamina. Thus, the CD44 ϩ protrusions were in direct contact with the extracellular matrix and apparently represented sites of invasion. The mechanisms that may contribute to a role of CD44 at these sites include binding of extracellular matrix components (notably hyaluronan) and several biologically active factors such as hepatocyte growth factor/scatter factor and matrix metalloproteinase 9. (Lab Invest 2002, 82:313-322).

Microarray profiles of human basal cell carcinoma: Insights into tumor growth and behavior

“…Similar implications can be made about our observed downregulation of the hyaluronic acid receptor CD44. Previous studies have demonstrated that CD44 is only upregulated at invasive sites in BCCs [50], or in rare forms of metastatic BCC [51]. Ordinarily however, BCC exhibits low levels of CD44.…”

Cancer stem‐like cells in adenoid cystic carcinoma of salivary glands: relationship with morphogenesis of histological variants

“…The CD44 family has a binding capacity for ECM components, particularly hyaluronan (41). The interaction between CD44 and hyaluronan is known to be involved in tumor invasion in some malignant neoplasms (42, 43). We believe that ECM plays a role in niche construction for CSCs in AdCC.…”

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

“…First, expression of CD44 by the tumour cells can increase the interaction with endothelial cells and transmigration across an endothelial monolayer (Fujisaki et al, 1999;Mine et al, 2003;Draffin et al, 2004;Ratliff, 2005). Second, in a wide variety of systems, increased CD44 expression has been shown to correlate strongly with increased invasive potential of tumour cells Jothy, 1999, 2001;Dingemans et al, 2002;Kobayashi et al, 2002;Bourguignon et al, 2003;Xu and Yu, 2003;Kim et al, 2004;Miletti-Gonzalez et al, 2005) and in particular, increasing evidence points to an important role for CD44 in mediating directional cell migration (Alstergren et al, 2004;Avigdor et al, 2004;Zhu et al, 2004Zhu et al, , 2005Miletti-Gonzalez et al, 2005;Tzircotis et al, 2005).…”