Cinzia Pinzi

Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions

Melanoma cells in culture express a variety of growth factors and cytokines and some of their autocrine and paracrine roles have been investigated. However, less information is available on the potential dynamic changes in expression of these molecules on cells during melanoma development and progression in situ. Using immunohistochemistry, we tested 40 nevi and primary and metastatic melanoma lesions for the expression of 10 growth factors and cytokines and the respective receptors representing 10 cell surface molecules. Nevi and thin (< 1 mm) primary melanomas showed little expression of ligands except weak reactivity of tumor necrosis factor‐α (TNF‐α), transforming growth factor‐β (TGF‐β), interleukin‐8 (IL‐8) and reactivity of TGF‐βR and c‐kit. Marked up‐regulation of growth factors, cytokines and receptor expression was observed in thick (> 1 mm) primary melanomas, which were stained with polyclonal or monoclonal antibodies (MAbs) for IL‐1α, IL‐1β, IL‐6, IL‐8, TNF‐α, TGF‐β, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and stem cell factor (SCF), but not IL‐2. Metastases showed similar expression patterns except that SCF was absent. Co‐expression of ligand and receptor was observed for TGF‐β, GM‐CSF and IL‐6, suggesting an autocrine role for these ligands. TNF‐α appears to be a marker of benign lesions; IL‐6 and IL‐8 expression is associated with biologically early malignancy; TGF‐β, GM‐CSF and IL‐1α are highly expressed in biologically late lesions; and TNF‐β is an apparent marker of metastatic dissemination. Our results indicate that melanoma cells utilize cascades of growth factors and cytokines for their progression. Int. J. Cancer (Pred. Oncol.) 84:160–168, 1999.

In situ expression of transforming growth factor beta is associated with melanoma progression and correlates with Ki67, HLA-DR and beta 3 integrin expression.

Transforming growth factor-beta (TGF beta), which is secreted by cultured melanoma cells constitutively, inhibits the proliferation of normal melanocytes and of most melanoma cells in vitro, but some melanoma cells from advanced stages of the disease develop resistance to TGF beta-dependent growth inhibition, without developing any change in TGF beta cell surface binding. In vitro TGF beta also downregulates the expression of HLA-DR molecules on melanoma cells, and upregulates the expression of the beta 3 integrin subunit on some cell lines. Immunohistochemical analysis of 53 melanocytic lesions (12 naevi, 30 primary melanomas and 11 metastases) revealed a trend of increasing expression of TGF beta and TGF beta receptor type III with tumour progression, and a significantly higher expression of both TGF beta (P < 0.0001) and the receptor (P < 0.05) in metastatic and thick (> 1 mm) primary melanomas compared with thin (< 1 mm) primary melanomas. The expression of TGF beta correlated with expression of a marker of proliferation, Ki67, and with HLA-DR and beta 3 integrin subunit expression. Coexpression of the four molecules was observed in all metastases and in most thick primary melanomas. These findings argue against an inhibitory effect of TGF beta on cell proliferation or HLA-DR antigen expression in melanoma, and suggest the upregulation of the beta 3 subunit. TGF beta protein appears to be a biological marker of melanoma progression in situ.

Fibrosis in regressing melanoma versus nonfibrosis in halo nevus upon melanocyte disappearance: Could it be related to a different cytokine microenvironment?

Background:  It is not clear why melanocyte disappearance occurs without fibrotic evolution in halo nevus and with fibrotic evolution in regressing melanoma.

Skin angiogenesis : Biologic bases for pathological processes

Angiogenesis is a complex biologic process characterized by the development of new blood vessels from existing vasculature. It is essential in reproduction, development, and wound repair.1 Under these conditions, angiogenesis is highly regulated (ie, turned on for short periods and then completely inhibited). In contrast, persistent unregulated angiogenesis can drive many diseases, such as growth of primary tumors and metastases, chronic arthropathies, and diabetic retinopathy. Common to all forms of angiogenesis is a general pattern of response by the capillary endothelial cell. Capillary blood vessels consist of endothelial cells and pericytes: these two cell types carry all genetic information to form tubes, branches, and whole capillary networks. Specific stimulatory molecules can initiate the process and specific inhibitory molecules can stop it. These molecules with opposing functions appear to be continuously acting in concert to maintain a quiescent microvasculature in which endothelial cell turnover is slow. Endothelial cells, however, can undergo rapid proliferation (few days’ turnover) during active angiogenesis (eg, in wound healing). The proteins involved in angiogenesis have been discovered in the past decades and their properties are well known, but their interactions with each other are not yet completely clarified. In addition, other entities such as nonvascular cells can modulate angiogenic response. This point may be crucial within a specific microenvironment, such as the skin, where resident cells—in particular, mast cells, macrophages, and fibroblasts—may exert modulation of the process. New blood vessel occurrence in the skin may be observed in several physiological and pathological circumstances, such as wound healing, psoriasis, hemangiomas, and benign and malignant cutaneous neoplasia. Morphological and Functional Bases of Angiogenesis: Vasculature in the Embryo

Red nodule on the breast

A 63-year-old woman living in the countryside referred to our department with a 2-month history of a red nodule localized on the right breast. Histological examination, immunohistochemical analyses and serologic evaluation conducted with ELISA and Western blot were performed. Clinical diagnosis of borrelial lymphocytoma was not possible solely on the clinical presentation of a classical nodular form without lymphoadenopathy. An absence of a referred prior tick bite and a previous or concomitant erythema migrans at clinical presentation rendered a more challenging diagnosis. The fact that the patient lived in the countryside, the appearance of the breast nodule in September, and serologic, histologic, and immunohistochemical analysis facilitated the diagnosis of borrelial lymphocytoma. We report this case to highlight the importance of an investigation of Lyme borreliosis when a patient living in the countryside presents with a red nodule of the nipple and areola.