Benign Melanocytes Research Articles

Vitamin A metabolism and mRNA expression of retinoid-binding protein and receptor genes in human epidermal melanocytes and melanoma cells.

Retinoids inhibit proliferation of melanocytes and melanoma cells and affect disorders of hypo- and hyperpigmentation. Such effects might involve retinoid-binding proteins, retinoid metabolites and nuclear retinoid receptors for transcriptional activation. We detected messenger RNA transcripts for the cellular retinol- and retinoic acid-binding proteins (CRBP, CRABP I and II) in cultured epidermal melanocytes. In the melanoma cell lines the major transcript was CRABP II. Nuclear retinoic acid (RA) receptor transcripts and the 9-cis-retinoic acid receptor transcript were detected in all cells. The endogenous concentrations of retinol (ROH) and its metabolite 3,4-didehydroretinol (ddROH) in melanocytes were five times those in melanoma cells. When cells were incubated with [3H]ROH the main metabolites in the melanocytes were [3H]ddROH (4%) and [3H]RA (0.4%). Formation of [3H]RA was only detected in one melanoma cell line. Both melanocytes and melanoma cells produced an unidentified metabolite when incubated with [3H]ROH and [3H]RA. Dissimilarities in the metabolism and endogenous concentration of retinoids between benign and malignant melanocytes might play a key role in differentiation and growth regulation.

Expression of metastasis suppressor gene product, nm23 protein, is not inversely correlated with the tumour progression in human malignant melanomas.

An inverse correlation between the nm23 RNA level and tumour progression of melanocytes has been reported. To elucidate whether the expression of nm23 gene product in malignant melanoma is also inversely correlated with metastatic potential, conventional prognostic parameters or the tumour suppressor protein p53, immunohisto-chemical studies using a monoclonal antibody against nm23-H1 protein were performed on 138 benign and malignant melanocytic tumours. The expression of nm23 protein was compared with that of p53 protein and conventional clinicopathological prognostic factors. The nm23 protein level in benign melanocytes and metastatic melanoma cells was also studied by Western blot analysis. No significant difference regarding the protein was observed between naevi and melanomas, either at histological or protein levels. The expression correlated with local recurrence within 1 year after surgery, level of invasion and tumour thickness, but no parallels were observed between the nm23 and p53 proteins, suggesting that gene is regulated by independent mechanisms, although located on the same chromosome. There was no inverse correlation between the nm23 protein and melanoma metastasis which suggested that the nm23 protein does not appear to be lost during melanoma metastasis.

Nucleolar organizer regions and image analysis nuclear morphometry of small cell (nevoid) melanoma

Small cell (nevoid) melanomas may provide difficulties in diagnosis as their constituent cell type resembles a benign nevoid melanocyte. In the present study, 10 small cell melanomas were analyzed for the silver staining of their nucleolar organizing regions (AgNORs), and their nuclear area and perimeter were measured by computerized digital image analysis and compared with 10 superficial spreading melanomas lacking small cell differentiation and 10 dermal nevi. The average number of AgNORs per nucleus was 5.83 (SD +/- 1.69) for small cell melanomas and was significantly different when compared with 8.49 (SD +/- 1.58) for superficial spreading melanomas (p < 0.05) and 2.71 (SD +/- 0.50) for dermal nevi (p < 0.05). Digital image analysis confirmed that the nuclear perimeter and nuclear area of cells in nevoid melanomas did not significantly differ from those of ordinary dermal nevi (p > 0.05), but both group were significantly different from superficial spreading melanomas lacking a small cell morphology (p < 0.05). Counting AgNOR numbers may be useful in evaluating small cell (nevoid) melanomas and provides a technique for differentiating their constituent cell from ordinary nevus cells. Nuclear morphometry determined by digital image analysis may help better define the nuclear size in small cell melanomas.

Protein patterns of benign and malignant human melanocytes show consistent changes in gene expression.

For human malignant melanoma, no pattern of oncogene activation has yet been identified which consistently occurs in the malignant cells. In order to better understand the transformation process, we studied the overall gene expression at the protein level in human melanoma cells in vitro by two-dimensional gel electrophoresis. For that, four established cell lines, MEWO, M5, SKMEL13, and IGR39, were used and compared with newly established cultures of normal human melanocytes. Considerable variations in the protein patterns of the different melanoma cell lines were found, whereas the patterns of normal human melanocytes correlated fairly well with each other. With respect to the expression of single proteins, we identified four major proteins which were consistently found in cultured melanocytes and stringently repressed in the four melanoma cell lines examined. On the other hand, induction of new proteins in the different melanoma cell lines was found to be less stringent and also less uniform. We propose that malignant transformation of melanocytes may be more associated with the suppression of melanocytic proteins rather than with new expression of melanoma specific proteins.

Characterization of an antigen expressed by benign melanocytes which is downregulated in malignant melanoma

Characterization of an antigen expressed by benign melanocytes which is downregulated in malignant melanoma

Significance, Specificity, and Ultrastructural Localization of HMB-45 Antigen in Pigmented Ocular Tumors

To evaluate the expression of the monoclonal HMB-45 antibody in melanocytic and nonmelanocytic ocular tumors and seek "activated" cellular subpopulations in an attempt to distinguish between benign and malignant melanocytes, to compare HMB-45 and S100 activity, and to determine the specificity of this tumor marker for melanocytic ocular lesions. Immunohistologic investigations were performed with paraffin-embedded tissue of 10 acquired conjunctival melanoses, 19 conjunctival nevi, 34 conjunctival melanomas, 69 uveal melanomas, 20 basal cell carcinomas of the lid, 20 cystic dermoids, 15 hemangiomas of the lid, 20 conjunctival papillomas, 20 squamous cell carcinomas, 20 pterygia, 11 sebaceous gland carcinomas, 10 retinoblastomas, and 5 choroidal metastatic carcinomas. The avidin-biotin peroxidase technique and monoclonal HMB-45 antibody were used. The distribution of S100 protein was studied in the melanocytic tumors for comparison. To localize the HMB-45 antigen, lowicryl-embedded tissue of uveal melanomas was investigated immunoelectron microscopically. More than 95% of the conjunctival and choroidal melanomas expressed the HMB-45 antigen, while S100 was found in all melanomas of the conjunctiva and in 91% of the uveal melanomas. In benign melanocytic lesions of the conjunctiva (nevi and melanocytes), especially the intraepithelial and junctional components stained with HMB-45, and at the site of tumor invasion, infiltrating cells showed increased HMB-45 reactivity. On the whole, HMB-45 antigen was less evenly distributed in the melanocytic tumors investigated than S100 antigen. All nonmelanocytic ocular tumors revealed no HMB-45 expression. Retinal pigment epithelium and tumor-free choroid were negative for HMB-45. The HMB-45 antigen was immunoelectron microscopically found in melanosomes at stages II and III. HMB-45 immunohistology helps in distinguishing melanocytic from nonmelanocytic ocular tumors and often clarifies the front of tumor invasion. The stronger HMB-45 reactivity probably reflects melanocytic activation, but a sharp line between benign and malignant melanocytes cannot be drawn.

Melanocytes in the anal canal epithelium

We studied the presence of melanocytes in the various epithelial zones of the anal canal, using a recently introduced melanocyte-specific antibody (HMB-45) together with antibody to S-100 protein. In normal and canals and in haemorrhoids, melanocytes, defined as intraepithelial HMB-45/S-100 positive cells, were frequently demonstrated in the anal squamous zone, only sporadically in the anal transitional zone, and not at all in the colorectal zone. In the epithelium surrounding, but clearly separated from, resected primary anal malignant melanomas, increased numbers of benign melanocytes were demonstrated in the squamous zone and transitional zone, but also in the colorectal zone. We interpret this finding as a tumour-induced proliferation of benign melanocytes normally present, but in very small numbers or in some way 'masked', in the epithelium of the upper anal canal. The demonstration of melanocytes in all three zones of the anal canal substantially supports the observation that malignant melanoma of the anal canal may originate not only below but also above the dentate line.

Primary Orbital Melanoma Associated With Orbital Melanocytosis

We report a case of primary orbital melanoma in a 17-year-old girl. The patient presented with painless proptosis during the first trimester of pregnancy. Computed tomography demonstrated a well-circumscribed mass located infra-temporally in the right orbit. The tumor was bluish-black, grossly encapsulated, and associated with orbital blue nevi. Histologic examination of the mass revealed a pigmented spindle-cell neoplasm. On electron microscopy, the presence of premelanosomes and the absence of basal lamina supported the diagnosis of melanoma. Malignant transformation of a preexisting nevus is postulated since perineural foci of benign dendritic melanocytes were seen within the melanoma. There has been no recurrence or metastasis in a 2-year follow-up. Of 30 primary orbital melanomas reviewed, 12 (40%) were associated with periorbital pigmentary disorders, such as oculodermal melanocytosis, blue nevus, and ocular melanocytosis. Our case is unique since the pigmentary lesions were limited to the orbital tissues.

Presence of cytoadhesins (IIb-IIIa-like glycoproteins) on human metastatic melanomas but not on benign melanocytes.

Glycoproteins IIb and IIIa, a heterodimer complex, play a vital role in blood platelet aggregation and are members of a wide family of membrane receptors known as integrins or cytoadhesins. Cellular interaction to extracellular matrix (ECM) adhesive proteins is mediated by integrins. Certain tumor cells are known to interact with ECM and blood platelets in the process of metastasis. However, it is not known if tumor cells, compared with their normal counterparts, acquire IIb-IIIa-like receptors to help them in their metastatic spread. In this study, monoclonal antibodies directed against the IIb-IIIa platelet glycoprotein complex were used on frozen biopsies of normal and various tumor tissues to detect the presence of these integrins. These studies demonstrate the presence of IIb-IIIa-like glycoproteins on the cells of metastatic malignant melanoma but not on benign melanocytes and rarely on other tumors. The presence of integrins on melanomas may help explain their propensity for frequent metastasis.

Depigmentation: Its significance in patients with melanoma

Malignant melanoma is the leading cause of death from tumors of the skin, and its incidence is rising at an alarming rate.1,2 The American Cancer Society estimated that melanomas account for 1–2% of all cancer deaths.3 The prognosis for a malignant melanoma is directly related to the thickness of the tumor as measured by the Breslow or Clark technique.4 Although the incidence of melanoma has increased, fortunately there also has been an improved survival rate. Patients with clinical stage 1 disease (no clinical evidence of tumor in regional lymph nodes) and a tumor depth of less than 0.75 mm have a 95–100% 5-year survival rate5 if the malignancy is properly excised. The improvement in cure rates or longer survivals probably results from earlier diagnosis made possible by public awareness campaigns, rather than from advances in medical or surgical therapy.62,73 Those patients with a deep tumor and/or advanced disease (stage 2, regional lymph node metastases; stage 3, distal metastases) have a dismal prognosis. Treatment of patients with metastatic melanoma is disappointing. Surgical ablation of tumor in regional lymph nodes (clinical stage 2) gives a 20% 5-year survival rate, but even these patients cannot be assured of a cure. Melanomas can recur as long as 20 years after excision.There have been numerous isolated reports of depigmentation occurring in association with cutaneous or ocular melanomas.8–18 This is a rather paradoxical association. Melanoma is an uncontrolled proliferation of malignant melanocytes. In contrast, depigmentation is an abnormal destruction of benign melanocytes. That the two phenomena occur together has attracted attention in recent years.20–23 It has been suggested that patients with metastatic disease who develop a vitiligo-like depigmentation survive for longer periods than might ordinarily be expected. This observation led to speculation that induction of vitiligo might be considered after resection of the primary melanoma to prevent metastases and to enhance survival.24In this chapter, the literature on the subject of melanoma and depigmentation is reviewed. Also, the question of whether their joint occurrence influences the longevity of survival is examined. Various examples of similar observed phenomena within the animal kingdom are reviewed. Lastly, some attempt is made to explain the pathogenesis of this interesting phenomenon.

De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis.

The 89-kDa cell surface glycoprotein, P3.58, is detectable on advanced human melanomas in situ but not on benign melanocytes or early melanomas. cDNA cloning of P3.58 from melanoma cells was accomplished by screening a lambda zap expression vector library with monoclonal antibodies produced against the denatured antigen. Nucleotide sequencing of the clones revealed that P3.58 is identical to the intercellular-adhesion molecule 1. No qualitative differences in P3.58 mRNA species could be seen between melanoma cells and hematopoietic cells and no differences in gene organization were observed between peripheral blood leukocytes and melanoma cells. Inspection of the deduced amino acid sequence of P3.58 indicated the presence of the consensus sequence characteristic for complement-binding proteins. The acquisition of this cell-adhesion molecule during the process of tumor progression is speculated to contribute to the development of metastasis in melanoma.

Regulation of a cell surface protease by inhibitors in vivo exhibited by benign and malignant melanocytes

Regulation of a cell surface protease by inhibitors <i>in vivo</i> exhibited by benign and malignant melanocytes

Characterization of Four Antigens Distinguishin Benign and Malignant Human Melanocytes

Characterization of Four Antigens Distinguishin Benign and Malignant Human Melanocytes

Characterization of cell surface antigens distinguishing benign and malignant human melanocytes

Characterization of cell surface antigens distinguishing benign and malignant human melanocytes

Melanocyte colonization of oral squamous cell carcinoma

This is a report of squamous carcinomas of the oral mucosa which have been colonized by benign melanocytes. In some tumors, melanocytes undergo hyperplasia and are found not only within the in situ portions of tumors but also in the infiltrative portion. Literature is cited which indicates that benign melanocytes may also colonize intravascular tumor emboli and metastatic foci.