Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The occasional occurrence of primary extra-cutaneous malignant melanomas (MM) has led to the hypothesis that melanocytes derived from the neural crest may be arrested in their migration and may undergo an in situ malignant transformation. However, aggregates of nevus cells have only rarely been identified by histological examination in a few organs other than skin and eye. Tyrosinase is a melanin biosynthetic enzyme that is considered one of the most specific markers of melanocytic differentiation. We have attempted to detect cells committed to the melanocytic lineage, in human tissues, by means of tyrosinase gene expression. Total RNA was extracted from normal and neoplastic tissues and analyzed using a highly sensitive reverse transcription PCR assay with primers specific for the tyrosinase gene. Peripheral blood mononuclear cells (PBMC) from healthy subjects were used as negative controls. Tyrosinase transcripts were identified in a wide range of normal organs such as skin, lymph nodes, antrum, colon, kidney, lung, testis, ovary, breast, and peripheral nerve. Tyrosinase RNA was also detected in neoplastic samples including benign cutaneous nevi, lymph nodes involved by MM, breast carcinoma, liposarcoma, malignant lymphoma, and schwannoma. PBMC from patients with metastatic MM were also positive, while no positivity was detected in blood specimens from patients with other cancers. Therefore, it appears likely that cells expressing the tyrosinase gene are present in a wide range of human tissues. Although these cells still have to be accurately identified, one could propose that they might correspond to either fully differentiated melanocytes, melanocytic precursors, or Schwann cells bearing potentialities of melanocytic differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Tyrosinase gene expression in human tissues. 751 6

In recent years, it has become evident that T cells can recognize peptides of melanocytic lineage antigens such as gp100, MART-1, and tyrosinase at the tumor cell surface and can subsequently destroy these cells. It is thus feasible to develop immunotherapeutic approaches based on the melanocytic marker profiles of melanoma cells. One of the predictors of the success rate of such a treatment is the extent of positive (target) tumor cells within the lesions of the patient. First, we investigated the presence of these three proteins in 18 human melanoma cell lines using RT-PCR and immunohistochemistry. In 11 cell lines, mRNA and protein of all three markers could be detected; in one cell line, only two markers were present, and six melanoma cell lines showed no evidence for these markers. Secondly, we stained frozen sections of 105 human melanocytic lesions, 13 common nevocellular nevi, 13 atypical nevi, 13 early primary melanomas (Breslow < 1.5 mm), 25 advanced primary melanomas (aPM; Breslow > or =1.5 mm), and 41 melanoma metastases (MM) with antibodies against glycoprotein 100, melanoma antigen recognized by T cells, and tyrosinase. In addition, we used the 3,4-dihydroxy-L-phenylalanine reaction to detect tyrosinase enzyme activity as a confirmation of the tyrosinase immunohistochemical results in a subset of the lesions. In the benign lesions, glycoprotein 100 was more prominently expressed in epidermal melanocytes, whereas melanoma antigen recognized by T cells was encountered in all or nearly all dermal melanocytes in all nevocellular nevi and atypical nevus lesions. Tyrosinase was found in a lower percentage of melanocytes, both in the epidermis and in the dermis within these lesions. With regard to heterogeneity of staining within the malignant lesions, we found that 54% (early primary melanomas), 48% (aPMs), and 56% (MM) of the lesions stained within the same staining category for all three proteins studied. Approximately 17% of the aPM and MM lesions did not show positive tumor cells for any of the three proteins. We conclude that a subgroup of patients with high expression should be selected for immunotherapeutic treatment approaches based on the presence of these proteins.
 ...
PMID:Heterogeneous expression of immunotherapy candidate proteins gp100, MART-1, and tyrosinase in human melanoma cell lines and in human melanocytic lesions. 924 53

Monoclonal antibody T311 specifically detects tyrosinase protein expression. Tyrosinase-derived peptides are recognized by CD8+ T-cells and applied in immunotherapy. We examined formalin-fixed paraffin-embedded tissue of 50 melanoma (primary n=31, metastatic n=19) and 41 control cases (junctional, dermal, compound, Spitz, Reed, balloon-cell nevi) by immunochemistry using the alkaline phosphatase-anti-alkaline phosphatase method after antigen retrieval. Staining with mAb T311 showed a sensitivity of 94% for melanoma with a very high specificity for melanocytic cells. Immunopositivity (94% of melanomas overall) correlated inversely with clinical stage: clinical stage I and stage II showed 100%, stage III and stage IV 86% immunoreactivity each. Staining changed from an exclusively homogeneous pattern in early stages to a more heterogeneous pattern in later stages. Melanocytic control tissue like nevi of different subtypes all showed weak to moderate, homogeneous immunoreactivity with polarity towards the epidermis. RT-PCR ELISA analysis of short-term melanoma cell cultures displayed mRNA expression in only half of the originally immunopositive tumors only, suggesting rapid mRNA expression loss in culture. mAb T311 allows detection of melanoma-associated tyrosinase protein expression and thus profiling of melanomas using routine archival tissue suited for immunotherapy approaches involving tyrosinase derived epitopes.
 ...
PMID:Tyrosinase immunoreactivity in formalin-fixed, paraffin-embedded primary and metastatic melanoma: frequency and distribution. 960 39

Tyrosinase is a key enzyme in melanin biosynthesis and represents a marker of melanocytic differentiation. We previously generated T311, a murine monoclonal antibody to the tyrosinase recombinant protein. This study was performed to evaluate T311 as a diagnostic immunohistochemical reagent for use on formalin-fixed paraffin-embedded pathological material. We analyzed the specificity of the antibody on a panel of normal and neoplastic tissues, and we assessed its sensitivity in a large number of metastatic and primary malignant melanomas, nevi, three angiomyolipomas, and two vitiligo specimens. T311 revealed intense reactivity on paraffin-embedded material. Immunoreactivity was limited to cells of melanocytic differentiation and no immunostaining was present in unrelated normal tissues and tumors. Eighty-four percent of metastatic malignant melanomas were immunoreactive with T311 and showed predominantly a homogeneous expression pattern. However, in primary melanomas of the desmoplastic/spindle cell type, T311 revealed a poor immunoreactivity. Nevi showed intense staining at the junctional zone, while the dermal component revealed decreasing reactivity towards deeper areas. Only one angiomyolipoma was focally immunoreactive with T311. Vitiligo specimens were immunonegative. We conclude that T311 is a specific and sensitive marker for the detection of melanocytic lesions in formalin-fixed paraffin-embedded tissues and a useful serological reagent for diagnostic pathology.
 ...
PMID:T311--an anti-tyrosinase monoclonal antibody for the detection of melanocytic lesions in paraffin embedded tissues. 1078 67

While histological analysis represents a powerful tool for the classification of melanocytic lesions as benign or malignant, a clear-cut distinction between a nevus and a melanoma is sometimes a challenging step of the diagnostic process. The immunohistochemical detection of tyrosinase, cardinal melanogenic enzyme during melanocytic maturation, has often been helpful in formulating a differential diagnosis due to the peculiar staining pattern in nevocytes compared with melanoma cells. Tyrosinase distribution in nevi appears to overlap with the cytoarchitectural changes observable within these lesions, that result in epidermal or superficial dermal nevocytes being larger and strongly expressing melanocytic differentiation antigens, such as tyrosinase, compared with deeper dermal nevus cells. Our study aimed to evaluate the immunohistochemical expression pattern of tyrosinase in different histological types of acquired dysplastic melanocytic nevi, including junctional, compound, and intradermal nevi. Moreover, to estimate whether in nevocytes the expression of tyrosinase was associated with their differentiation state, we investigated the expression of two recognized markers of pluripotency, CD34 and nestin. In all examined nevi, our analysis revealed a remarkable immunoreactivity for tyrosinase in junctional and superficial dermal nevocytes and a decreasing gradient of staining in dermal nevocytes, up to become negative in deeper dermis. Meanwhile, junctional and dermal nevocytes were lacking in CD34 protein. Furthermore, nestin immunostaining showed an opposite distribution compared with tyrosinase, leading us to look into the tyrosinase/nestin expression pattern in melanocytic nevus as a tool to better understand the final stages of differentiation of melanocyte precursors toward their ultimate anatomical site into the epidermis.
 ...
PMID:Tyrosinase and nestin immunohistochemical expression in melanocytic nevi as a histopathologic pattern to trace melanocyte differentiation and nevogenesis. 3023 88

The purpose of this study was the clinical and histo-immunohistochemical analysis of two cases: a cutaneous pigmented facial malignant melanoma and a lumbar congenital nevus with malignant transformation. A series of clinical elements raised the suspicion of some malignant melanocytic lesions and the histopathological analysis through the paraffin embedding technique confirmed the clinical suspicion. The immunohistochemical analysis using the streptavidin-biotin-peroxydase method of the facial malignant melanoma showed: S100 protein intense and diffuse positive, Tyrosinase diffuse positive, HMB45 strong and focal positive, Cyclin D1 positive in approximately 40% and Ki-67 positive in almost 70% of the tumor cells. The malignant melanoma developed on the nevocellular nevus displayed: S100 protein intense and diffuse positive, both in the nevus cells and in the malignant melanocytes as well, Tyrosinase intense and diffuse positive in the malignant melanocytes, poor and focal positive in the nevus cells and HMB45 intense and focal positive in the malignant cells and positive in the isolated nevus cells. Cyclin D1 was positive in about 70% of the malignant cells, but negative in the nevus area and Ki-67 was found positive in relatively 30% of the malignant melanocytes, also in less than 1% of the nevus cells. The pattern and the intensity of the Tyrosinase and HMB45 immunoexpression are important in the differentiation of the nevus cells from the malignant melanocytic cells. The immunoexpression of Cyclin D1 does not correlate directly with the proliferating activity of the malignant melanocytic cells in all types of malignant melanomas.
 ...
PMID:Clinical and Pathological Analysis of Two Cases of Cutaneous Malignant Melanoma. 3053 30