Expression and putative function of lymphocyte endothelial epithelial-cell adhesion molecule in human testis.

The testis is an immunologically privileged site where germ cell antigens are protected from autoimmune attack and foreign tissue grafts may survive for extended periods. However, the testicular environment does not preclude inflammatory reactions and tissue-specific recruitment of T lymphocytes appears to be a crucial component of the inflammation cascade. Here, we demonstrate expression of lymphocyte endothelial epithelial-cell adhesion molecule (LEEP-CAM), a putative receptor mediating lymphocyte adhesion to endothelia and some epithelia, in human testis. In all specimens examined, expression of LEEP-CAM could be observed on endothelial cells of testicular blood vessels, including those within the lamina propria of seminiferous tubules. Sections of histologically normal testis showed strong LEEP-CAM expression within the seminiferous epithelium localised to Sertoli cells, whereas immunoreactivity was almost absent in tubules with severely impaired spermatogenesis. In a modified Stamper-Woodruff adhesion assay, binding of activated lymphocytes to normal testicular tissue was reduced by 61% after incubation with anti-LEEP-CAM mAb as compared with controls (P < 0.00001). In conclusion, intratubular LEEP-CAM expression is correlated with normal spermatogenesis and Sertoli cell function. In this context, it may contribute to adhesive cell-cell interactions. Moreover, the constitutive expression in human testis could play a role for localisation of T cells during testicular inflammation.

Targeted expression of bcl-2 to murine basal epidermal keratinocytes results in paradoxical retardation of ultraviolet- and chemical-induced tumorigenesis.

The antiapoptotic protein bcl-2 is found up-regulated in a number of malignant and premalignant skin conditions of keratinocyte origin, but in normal skin, it is expressed at low levels only in interfollicular epidermis. To investigate whether unregulated bcl-2 expression could affect the incidence of epidermal tumors, we have generated a mouse line that over-expresses human bcl-2 in the basal layer of epidermis under the control of the human keratin 14 promoter. These mice were subjected to both UVB photocarcinogenesis and classical two-stage chemical carcinogenesis. Although transgenic bcl-2 in these mice reduces the formation of sunburn cells after short-term UVB irradiation, chronically UVB irradiated K14/bcl-2 mice were protected against tumor development, because transgenic mice developed tumors much later and at a significantly lower frequency than controls. Immunohistochemical analyses of the UVB-induced tumors revealed no significant differences in the degree of inflammatory cell infiltrates. When either K14/bcl-2 mice or F(1) progeny of matings with mice expressing an activated Ha-ras oncogene (K14/bcl-2/ras) were treated with 9,10-dimethyl-1,2-benzanthracene/phorbol 12-myristate 13-acetate, the latency of first papilloma appearance was the same in transgenic mice and controls, but further papillomas developed more slowly in the mutant mice. Moreover, the K14/bcl-2/ras mice developed far fewer albeit larger tumors/mouse than did the ras/+ controls. The rate of conversion to malignant carcinomas, the carcinoma grade, and the frequency of lymph node metastases were not significantly different between mutants and controls. We conclude that, despite its antiapoptotic function, bcl-2, overexpressed in basal epidermal keratinocytes, exerts a paradoxical retardation on the development of skin tumors induced by chemical carcinogens and particularly by UVB.

Basal-cell adhesion molecule (B-CAM) is induced in epithelial skin tumors and inflammatory epidermis, and is expressed at cell-cell and cell-substrate contact sites.

Basal-cell adhesion molecule (B-CAM) is a 90 kDa cell surface glycoprotein of the immunoglobulin superfamily that functions as a laminin-binding receptor. B-CAM is upregulated following malignant transformation of some cell types in vivo and in vitro, thus being a candidate molecule involved in tumor progression. As cutaneous distribution and function of B-CAM are largely unknown, we have studied its expression and regulation in normal and diseased human skin. In normal skin, B-CAM was expressed by endothelial cells of dermal blood vessels. In contrast, B-CAM was strongly upregulated within the tumor tissue of both malignant and benign epithelial skin tumors, including basal cell carcinomas, squamous cell carcinomas, keratoacanthomas, and common warts. Transformation-associated upregulation was confirmed in vitro, but normal keratinocytes also expressed B-CAM under culture conditions. Interestingly, the basal epidermal layer of normal-appearing skin surrounding the tumors also expressed B-CAM, and B-CAM were induced on the basal and apicolateral surfaces of basal keratinocytes in inflammatory skin disorders suggesting transformation-independent mechanisms of epidermal induction of the B-CAM. Immunoelectron microscopy studies of cultured transformed keratinocytes revealed that B-CAM was expressed at cell-cell and cell-substrate contact sites. Halting proliferation of transformed keratinocytes through cytostatic drugs resulted in decreased B-CAM synthesis. Likewise, inducing terminal differentiation in keratinocyte cultures by increasing the Ca(2+) concentration in the medium decreased B-CAM expression. In contrast, both ultraviolet A and B irradiation of cultured human keratinocytes resulted in significantly increased expression of the B-CAM. Overall, it appears that B-CAM expression in human skin is associated with activated states of keratinocytes, and that B-CAM may be involved in cell-cell adhesion or migration, in addition to its known function as a laminin receptor. J Invest Dermatol 115:1047-1053 2000