E- and P-cadherin expression in tumor tissues and soluble E-cadherin levels in sera of patients with skin cancer

doi:10.1016/0923-1811(95)00493-9

Journal of Dermatological Science

Volume 13, Issue 1, October 1996, Pages 30-36

https://doi.org/10.1016/0923-1811(95)00493-9 Get rights and content

Abstract

The expression pattern of epithelial (E)- and placental (P)-calcium-dependent cell-cell adhesion molecules was examined immunohistochemically in various skin tumors. E- and P-cadherin expression was preserved in nodular and superficial types of basal cell carcinoma (BCC). In well-differentiated squamous cell carcinoma (SCC), E-cadherin on the cell surface of the tumor was reduced but expression of P-cadherin was preserved more frequently at the peripheral sites of the tumor than in the central sites of the tumor. Paget's cells and melanoma cells did not express E- or P-cadherins in the nest of the epidermis. Immunoreactive E-cadherin levels in sera were significantly elevated in patients with invasive Paget's disease, metastatic malignant melanoma and severe types of psoriasis and atopic dermatitis when compared with those of normal controls. Reduced or loss of cadherin in localized tumor cells may be correlated with the proliferation, and the level of soluble E-cadherin in circulation may be a marker in the extent of damaged skin by tumor and/or inflammation.

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Acute eczema is an inflammatory skin disease characterized by the formation of small intraepidermal blisters, reduction of the adhesion molecule E-cadherin from the keratinocyte surface, and impaired keratinocyte cohesion. Here, we reveal that the disintegrin and metalloprotease ADAM10 is critically involved in regulating E-cadherin cell-surface expression in cultured primary human keratinocytes and in diseased human skin. Proinflammatory cytokines, transforming growth factor-β, and lipopolysaccharide led to increased release of soluble E-cadherin by activating mitogen-activated protein kinase signaling in cultured keratinocytes. Moreover, these stimuli decreased the amount of pro-ADAM10 and increased the level of the active protease, leading to loss of E-cadherin from the cell surface and decreased keratinocyte cohesion. In situ examination and immunoblot analyses of E-cadherin and ADAM10 expression in lesional skin of eczema revealed that the reduction of E-cadherin expression in areas of blister formation closely correlated with increased level of ADAM10 expression and elevated E-cadherin shedding. Our data suggest that ADAM10-mediated E-cadherin proteolysis leads to the impaired cohesion of keratinocytes observed in eczematous dermatitis and provide previously unreported insights into the understanding of the molecular mechanisms involved in inflammatory diseases with loss in epithelial integrity.
T-cadherin negatively regulates the proliferation of cutaneous squamous carcinoma cells
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In the epidermis, E- and P-cadherin are the major components of intercellular adherence junctions (Nose and Takeichi, 1986), and are involved in morphogenesis and maintaining the structure of skin (Hirai et al, 1989). It is reported that the expressions of E- and P-cadherin are reduced in SCC, melanoma, and Paget's disease and reduction of cadherin expression is considered to be related to the detachment of carcinoma cells from the tumor mass (Shirahama et al, 1996; Furukawa, 1997). The contribution of T-cadherin to keratinocyte cell–cell adhesion, however, is not yet known.Vestal and Ranscht (1992) showed, using T-cadherin cDNA-transfected CHO cells, that T-cadherin induced calcium-dependent, homophilic adhesion, like E- or P-cadherin.
T-cadherin is a unique member of the cadherin superfamily that lacks the transmembrane and cytoplasmic domains, and is instead linked to the cell membrane via a glycosyl-phosphatidylinositol anchor. We previously reported that T-cadherin was specifically expressed on the basal keratinocytes of the epidermis, and the expression of T-cadherin was significantly reduced in invasive cutaneous squamous cell carcinoma (SCC) and in the lesional skin of psoriasis vulgaris. In this study, to obtain an insight into the role of T-cadherin in keratinocytes, we used transfection methods and examined the effect of overexpression or knockdown of T-cadherin in immortalized keratinocyte cell lines derived from SCC. T-cadherin overexpressed cells showed clearly reduced cell proliferation, but the influence of cell–cell adhesiveness and cell mobility was not detected. Using a tetracycline-regulated expression system, we also confirmed that the suppression of cell proliferation was dependent on the expression level of T-cadherin. Cell cycle analysis demonstrated that over expression of T-cadherin induced a delay in the G₂/M phase. Our findings suggest that T-cadherin acts as an endogenous negative regulator of keratinocyte proliferation and its inactivation is the cause for keratinocyte hyperproliferation in SCC or in psoriasis vulgaris.
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Research paperE- and P-cadherin expression in tumor tissues and soluble E-cadherin levels in sera of patients with skin cancer

Abstract

The cadherin: cell-cell adhesion molecules controlling animal morphogenesis

Development

Cadherins: a molecular family important in selective cell-cell adhesion

Annu Rev Biochem

Cadherin cell adhesion receptors as a morphogenic regulator

Science

Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas

Cancer Res

A novel cadherin cell adhesion molecule: its expression patterns associated with implantation and organogenesis of mouse embryos

J Cell Biol

Expression pattern of E- and P-cadherin in mouse embryos and uteri during the peri-implantation period

Dev Growth Differ

E-cadherin expression in squamous cell carcinomas of head and neck: inverse correlation with tumor dedifferentiation and lymph node metastasis

Cancer Res

E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells

J Cell Biol

Expression of E- and P-cadherin in gastric carcinoma

Cancer Res

Expression of P-cadherin in gastric carcinoma and its reduction in tumor progression

Int J Cancer

Expression of cadherin cell adhesion molecules during human skin development: morphogenesis of epidermis, hair follicles and sweat ducts

Arch Dermatol Res

Cadherins in cutaneous biology

J Dermatol

Cadherin intercellular adhesion molecule in hepatocellular carcinoma: loss of E-cadherin expression in an undifferentiated carcinoma

Cancer Lett

Epithelial (E-) and placental (P-) cadherin cell adhesion molecule expression in breast carcinoma

J Pathol

Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer

Cancer Res

Research paper
E- and P-cadherin expression in tumor tissues and soluble E-cadherin levels in sera of patients with skin cancer