James E. Fitzpatrick

Loss of Desmocollin 3 in Skin Tumor Development and Progression

Desmocollin 3 (DSC3) is a desmosomal cadherin that is required for maintaining cell adhesion in the epidermis as demonstrated by the intra‐epidermal blistering observed in Dsc3 null skin. Recently, it has been suggested that deregulated expression of DSC3 occurs in certain human tumor types. It is not clear whether DSC3 plays a role in the development or progression of cancers arising in stratified epithelia such as the epidermis. To address this issue, we generated a mouse model in which Dsc3 expression is ablated in K‐Ras oncogene‐induced skin tumors. Our results demonstrate that loss of Dsc3 leads to an increase in K‐Ras‐induced skin tumors. We hypothesize that acantholysis‐induced epidermal hyperplasia in the Dsc3 null epidermis facilitates Ras‐induced tumor development. Further, we demonstrate that spontaneous loss of DSC3 expression is a common occurrence during human and mouse skin tumor progression. This loss occurs in tumor cells invading the dermis. Interestingly, other desmosomal proteins are still expressed in tumor cells that lack DSC3, suggesting a specific function of DSC3 loss in tumor progression. While loss of DSC3 on the skin surface leads to epidermal blistering, it does not appear to induce loss of cell–cell adhesion in tumor cells invading the dermis, most likely due to a protection of these cells within the dermis from mechanical stress. We thus hypothesize that DSC3 can contribute to the progression of tumors both by cell adhesion‐dependent (skin surface) and likely by cell adhesion‐independent (invading tumor cells) mechanisms.

Desmosomal defects in acantholytic squamous cell carcinomas

Acantholytic squamous cell carcinoma (Acantholytic SCC) are epithelial tumors characterized by a loss of cell adhesion between neoplastic keratinocytes. The mechanism underlying loss of cell‐cell adhesion in these tumors is not understood.

HLA antigen expression in melanocytic lesions: Is acquisition of HLA antigen expression a biomarker of atypical (dysplastic) melanocytes?

BACKGROUNDnAlthough criteria are established for the histologic diagnosis of atypical nevi (AN), consensus about the criteria in the diagnosis of and in the definition of AN is limited. Moreover, intraobserver and interobserver differences in the application of these criteria for the diagnosis of AN have been observed.nnnOBJECTIVEnWe sought to determine the usefulness of HLA antigen expression as a biomarker of AN.nnnMETHODSnThe immunoperoxidase reaction was used to mark common nevi and AN with HLA class I heavy chain-, β2microglobulin (β2m)-, and HLA class II β chain-specific monoclonal antibodies.nnnRESULTSnHLA class I heavy chain, β2m, and HLA class II β chain were expressed in 5 (8.6%) of the 58 common nevi and in 46 (∼72%) of the 64 atypical melanocytic lesions. Among common lesions, only halo nevi expressed HLA class I heavy chain, β2m, and HLA class II β chain. The level of HLA class I heavy chain β2m and of HLA class II β chain expression correlated with the degree of cytologic atypia and architectural disorder.nnnLIMITATIONSnThe number of lesions tested and the subjective nature of the analysis of immunohistochemical staining of tissue sections are both limitations.nnnCONCLUSIONSnThe data presented suggest that HLA antigen expression is an objective biomarker that correlates well with the degree of cytologic atypia in AN and may: (1) be useful to distinguish common nevi from AN, and (2) represent a more objective measure to determine which AN should be excised.

Recent Observations on the Heterogeneity of Human Effector Memory T Cells and Novel Cytokines Implicated in Cutaneous Inflammation and Psoriasis

Psoriasis is a chronic inflammatory skin disease that affects 2.2% of Americans and is a substantial detriment on the quality of life. Psoriasis is a complex interaction between numerous immune cells and has been considered largely a T-helper type 1 (Th1) T-cell-mediated response. Although numerous cytokines, including tumor necrosis factor-αβ, interleukin 1β, and interferon-γ, have been identified with distinct roles in skin inflammation and psoriasis, proinflammatory functions of newly identified cytokines have been linked recently to the alternative T-cell subsets Th17 and Th22 that are distinct in their functions and cytokine profiles. This review summarizes the basic research, translational applications, and new therapeutic developments contributing to the understanding of the diversity of human effector CD4+ Th1, Th17, and Th22 T cells, as well as the proinflammatory cytokines associated with these subsets in psoriasis.