Cathepsin S (CATS) is a cysteine protease, well known for its role in MHC class II-mediated antigen presentation and extracellular matrix degradation. Disturbance of the expression or metabolism of this protease is a concomitant feature of several diseases. Given this importance we studied the localization and regulation of CATS expression in normal and pathological human ⁄ mouse skin. In normal human skin CATSimmunostaining is mainly present in the dermis and is localized in macrophages, Langerhans, T-and endothelial cells, but absent in keratinocytes. In all analyzed pathological skin biopsies, i.e. atopic dermatitis, actinic keratosis and psoriasis, CATS staining is strongly increased in the dermis. But only in psoriasis, CATSimmunostaining is also detectable in keratinocytes. We show that cocultivation with T-cells as well as treatment with cytokines can trigger expression and secretion of CATS, which is involved in MHC II processing in keratinocytes. Our data provide first evidence that CATS expression (i) is selectively induced in psoriatic keratinocytes, (ii) is triggered by T-cells and (iii) might be involved in keratinocytic MHC class II expression, the processing of the MHC class II-associated invariant chain and remodeling of the extracellular matrix. This paper expands our knowledge on the important role of keratinocytes in dermatological disease.
ADAMs are members of the zinc metalloproteinase superfamily characterized by the presence of disintegrin and metalloprotease domains. In human melanoma, ADAM-9 is expressed in focalized areas of the tumor-stroma border in both melanoma and stromal cells. However, the role of ADAM-9 in melanoma progression remains elusive. To analyze the role of stromal-derived ADAM-9 for the growth and survival of melanoma cells, we have used in vitro coculture systems of melanoma cells and ADAM-9(-/-) fibroblasts. Coculture of melanoma cells in the presence of ADAM-9(-/-) fibroblasts led to increased melanoma cell proliferation and reduced apoptosis as compared with control cocultures. We identified TIMP-1 and sTNFRI as the two relevant factors expressed in increased amounts in culture supernatants from ADAM-9(-/-) fibroblasts. TIMP-1 was associated with induced melanoma cell proliferation, whereas soluble TNFR1 mediated the reduced cellular apoptosis in vitro. In vivo, injection of murine melanoma cells into the flank of ADAM-9(-/-) animals resulted in the development of significantly larger tumors than in wild-type animals as a result of increased proliferation and decreased apoptosis of melanoma cells. Taken together, stromal expression of ADAM-9 during melanoma development modulates the expression of TIMP-1 and sTNFR1, which in turn affect tumor cell proliferation and apoptosis.
ADAM-9 is a metalloproteinase expressed in peritumoral areas by invading melanoma cells and by adjacent peritumoral stromal cells; however, its function in stromal and melanoma cells is not fully understood. To address this question in vivo in a spontaneous melanoma model, we deleted ADAM-9 in mice carrying the hepatocyte growth factor (Hgf) transgene and knock-in mutation Cdk4, demonstrated to spontaneously develop melanoma. Spontaneous melanoma arose less frequently in ADAM-9-deleted mice than in controls. Similarly reduced tumor numbers (although with faster growth kinetics) were detected upon induction of melanoma with 7,12-dimethylbenz[a]anthracene (DMBA). However, more lesions were induced at early time points in the absence of ADAM-9. Increased initial and decreased late tumor numbers were paralleled by altered tumor cell proliferation, but not apoptosis or inflammation. Importantly, significantly reduced lung metastases were detected upon ADAM-9 deletion. Using in vitro assays to address this effect mechanistically, we detected reduced adhesion and transmigration of ADAM-9-silenced melanoma cells to/through the endothelium. This implies that ADAM-9 functionally and cell autonomously mediates extravasation of melanoma cells. In vitro and in vivo we demonstrated that the basement membrane (BM) component laminin β3-chain is a direct substrate of ADAM-9, thus contributing to destabilization and disruption of the BM barrier during invasion. In in vitro invasion assays using human melanoma cells and skin equivalents, depletion of ADAM-9 resulted in decreased invasion of the BM, which remained almost completely intact, as shown by continuous staining for laminin β3-chain. Importantly, supplying soluble ADAM-9 to the system reversed this effect. Taken together, our data show that melanoma derived ADAM-9 autonomously contributes to melanoma progression by modulating cell adhesion to the endothelium and altering BM integrity by proteolytically processing the laminin-β3 chain. This newly described process and ADAM-9 itself may represent potential targets for anti-tumor therapies.
Proteins of the a disintegrin and metalloprotease (ADAM) family are transmembrane proteins involved in ectodomain shedding and in cellular interactions. In skin, ADAM-15 is detected in the epidermis and dermal vascular structures by immunolocalization. Expression is also detected in isolated fibroblast, keratinocytes and endothelial cells in culture. Despite high expression of ADAM-15 throughout the wound repair process, wound healing experiments in vivo revealed a dispensable role of ADAM-15 for the healing process. No alterations in wound closure, re-epithelialization, contraction, scar formation and angiogenesis were detected in animals carrying ADAM-15-/- deletion. When analysing melanoma development by grafting melanoma cells into the flank of ADAM-15-/-, no significant alteration in tumor growth was detected. However, at later stages, melanomas in the ADAM-15-/- animals were smaller than those grown in WT animals. At all time points, no significant differences in vascularization of the peritumoral stroma and tumors were detected. Interestingly, we could detect a reduced number of metastasized lungs and lymph nodes in ADAM-15-/- animals as compared to control littermate mice. In conclusion, our study indicated that ADAM-15 is dispensable for cutaneous wound healing and B16F1 melanoma growth, but significantly contributes to metastasis formation.
CD137 is expressed on diverse immune cell populations, including activated T cells and natural killer (NK) cells. The interaction between CD137 and its ligand CD137L expressed on activated antigen-presenting cells enhanced T cell or NK cell activity strongly. Anti-CD137 agonistic antibody is reported to have strong antitumor effects through increasing tumorspecific cytotoxic T cells. However, studies on CD137 and CD137L concerning T-cell lymphoma, whose tumor cells can express CD137, have been limited. In this study, we tried to elucidate the role of CD137 and CD137L in cutaneous T-cell lymphoma (CTCL). Flow cytometric analysis showed that CTCL cell lines (MyLa, SeAx, Hut78, and HH cells), CD4 + CD7 -T cells in blood from Sezary syndrome patients, and a murine lymphoma cell line (EL-4 cells) expressed CD137L as well as CD137 on the cell surface. In addition, CD137 and CD137L expression on CTCL tumor cells in the skin were also confirmed by immunohistochemistry. Furthermore, CD137 and CD137L mRNA expression levels were elevated in CTCL lesional skin. Serum soluble CD137L levels were increased in advanced CTCL patients, compared to healthy controls. We next investigated the involvement of CD137-CD137L interactions in CTCL progression using CTCL cell lines. A neutralizing antibody for CD137L or CD137 inhibited proliferation and cell survival of CTCL cell lines. On the other hand, recombinant CD137-Fc protein promoted tumor proliferation. Moreover, CD137L neutralizing antibody attenuated phosphorylation of ERK1/2, Akt, p38 MAPK, and JNK in CTCL cell lines. Blocking CD137L also induced the downregulation of antiapoptotic protein Bcl-2 and phospho-BAD. Thus, our findings prompt a novel therapeutic approach to treat CTCL based on the discovery that CD137-CD137L interactions play a critical role in CTCL development.
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