ABSTRACT
BACKGROUND: In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40-60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon alpha (IFN-alpha)-mediated growth suppression in vitro. MATERIALS AND METHODS: To determine whether IFN-alpha, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-alpha. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-alpha treatment. RESULTS: The results of the investigations provided evidence that, as a result of systemic IFN-alpha treatment, Stat1 and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated. CONCLUSIONS: Unlike primary and metastatic melanomas, melanoma precursor lesions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to melanoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-alpha treatment may represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanoma.
Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Interferon-alpha/therapeutic use , Melanoma/metabolism , Melanoma/therapy , Precancerous Conditions/metabolism , Precancerous Conditions/therapy , Skin Neoplasms/metabolism , Skin Neoplasms/therapy , Trans-Activators/antagonists & inhibitors , Aged , DNA, Neoplasm/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Down-Regulation , Humans , Immunohistochemistry , In Vitro Techniques , Interferon alpha-2 , Melanoma/genetics , Phosphorylation , Precancerous Conditions/genetics , Recombinant Proteins , STAT1 Transcription Factor , STAT3 Transcription Factor , Skin Neoplasms/genetics , Trans-Activators/genetics , Trans-Activators/metabolismABSTRACT
Atypical (dysplastic) nevi are melanocytic lesions, which are precursors of melanoma as well as markers of increased melanoma risk. Although these lesions exhibit distinct clinical and histological features, their molecular features are largely unknown. To determine whether atypical, compared to benign nevi, from patients with a clinical history of malignant melanoma reveal molecular changes, we analyzed these lesions for the expression of two growth factors (basic fibroblast growth factor and transforming growth factor alpha), their receptors (fibroblast growth factor receptor-1 and epidermal growth factor receptor), and two cell adhesion molecules (MUC18 and alpha v beta 3 integrin), all of which are expressed in primary and metastatic melanomas. The results demonstrated a statistically significant correlation (P = 0.02) between increasing degrees of histological atypia and expression of epidermal growth factor receptor in the epidermal keratinocytes of atypical melanocytic lesions. Furthermore, both atypical and benign nevi revealed considerably high levels of overall gene activity in their dermal melanocytic and epidermal keratinocytic compartments. In contrast, the epidermal-dermal junction wherein melanoma evolves showed little gene activity, suggesting that molecular events occurring adjacent to this junction may be important for melanocytic transformation.
Subject(s)
Antigens, CD , Dysplastic Nevus Syndrome/pathology , Melanoma/pathology , Neural Cell Adhesion Molecules , Skin Neoplasms/pathology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , CD146 Antigen , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Dysplastic Nevus Syndrome/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/metabolism , Gene Expression Regulation, Neoplastic/physiology , Humans , Immunohistochemistry , In Situ Hybridization , Melanoma/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , RNA, Messenger/analysis , Receptors, Fibroblast Growth Factor/genetics , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Vitronectin/genetics , Receptors, Vitronectin/metabolism , Skin Neoplasms/metabolism , Transforming Growth Factor alpha/genetics , Transforming Growth Factor alpha/metabolismABSTRACT
Statistically 3 out of 4 patients with diabetes mellitus die from the secondary effects of the disease. Approximately 30%-40% of patients with end stage renal disease (ESRD) have diabetes. Simultaneous kidney/islet cell transplantation offers an innovative approach to the treatment of these chronic and disabling illnesses. Nursing care priorities are directed at maintaining central venous access and normoglycemia. Prescribed nursing care protocols require specialized postoperative assessments, interventions, and intensive patient education. These protocols have been developed in order to foster islet cell graft revascularization and ultimately to eliminate exogenous insulin requirements and regression of secondary complications of diabetes.
