ViewpointCD40 and epithelial cells: across the great divide
Section snippets
CD40 production and function in normal epithelial cells
Within stratified squamous epithelium, self-renewing stem cells residing in the basal layer give rise to terminally differentiating cells that undergo major biochemical and morphological changes as they migrate upward, finally dying and being shed from the surface as squames. This process of epithelial differentiation appears to be a specialized form of apoptosis[5]. Consistent with this is the restricted expression of the anti-apoptotic Bcl2 protein to basal epithelial cells, with loss of
CD40 on carcinomas
A comprehensive immunohistochemical analysis of the expression of CD40 in carcinoma cells remains to be performed, although several studies show that CD40 is present on carcinomas arising at different anatomical sites. The majority of carcinomas of the nasopharynx[20], bladder[21], ovary and liver express CD40 (Fig. 1b), whereas only a proportion of breast and colorectal carcinomas are CD40+ (L.S. Young et al., unpublished). More differentiated squamous cell carcinomas of the skin show low
CD40 signalling and viral mimicry
The widespread expression of CD40 by carcinomas raises the question of whether this receptor is involved in the aetiology of these malignancies. In this regard, it is interesting that many of the effects of CD40 ligation on epithelial cells and B cells are mimicked by the expression of latent membrane protein 1 (LMP1), an Epstein–Barr virus (EBV)-encoded membrane protein, which is essential for EBV-induced B-cell transformation in vitro[25]. LMP1 is expressed in EBV-associated tumours of both
CD40 function is context dependent
There is confusion about the ability of CD40 ligation or LMP1 expression either to confer a survival/growth advantage or to inhibit cell growth. These differential effects might be dependent on the nature of the stimulus—transient, such as CD40 ligation, or persistent, as in the stable expression of LMP1 in EBV-associated tumours—and on the cellular context. Thus, whereas CD40 ligation in resting B cells results in survival and growth, the response to CD40 ligation in B-cell lymphoma cell lines
CD40L and epithelial cells
What is the source of CD40L at epithelial cell sites? It could be delivered by activated T cells, particularly during inflammatory responses. Of interest is the demonstration that γδ T cells, which interact preferentially with epithelium, can express functional CD40L in vitro[35]. Thus, activated T cells expressing CD40L might be important in triggering the epithelial cell CD40 pathway in inflammatory skin diseases and might protect from the potential oncogenic effects of chronic inflammation,
Conclusions and therapeutic implications
The current data support a role for the CD40 pathway in regulating the growth and differentiation of epithelial cells. The relative contributions of CD40-activated NF-κB and AP-1 transcription factors to these effects remain to be determined. A possible role for CD40 in carcinogenesis is suggested by the ability of the oncogenic EBV-encoded LMP1 protein to function as a constitutively activated CD40. In addition, an LMP1–CD40 chimaera comprising the N-terminus and transmembrane domains of LMP1
Acknowledgements
Work performed in our laboratory is supported by the Medical Research Council, UK and the Cancer Research Campaign, UK.
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