Peripheral Blood Tyrosinase Messenger RNA Detection and Survival in Malignant Melanoma

Kunter, Uta; Buer, Jan; Probst, M.; Duensing, Stefan; Dallmann, Iris; Grosse, Jens; Kirchner, Hartmut; SCHLUEPEN, E.M.; Volkenandt, Matthias; Ganser, Arnold; Atzpodien, Jens

doi:10.1093/jnci/88.9.590

Cited by 136 publications

(99 citation statements)

References 18 publications

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“…There is no agreement in the literature as to the percentage of positive tyrosinase determinations in stage III patients, with a wide range of values up to 60%, according to the different studies (Brossart et al, 1993;Kunter et al, 1996;Pittman et al, 1996;Glaser et al, 1997;Farthman et al, 1998;Proebstle et al, 2000;Reinhold et al, 2001). Our results showed a positive tyrosinase expression in 49% of patients.…”

Section: Discussioncontrasting

confidence: 73%

Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: a clinical follow-up study of 110 patients

et al. 2003

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The aim of this study is to define the relationship between the tyrosinase expression in the peripheral blood and the clinical course of the disease in stage III disease-free melanoma patients after radical lymph node dissection. RT -PCR techniques were used to identify tyrosinase mRNA in 110 patients; a total of 542 blood samples were investigated. In all, 54 patients (49%) showed at least one positive result; 13 patients (11.8%) showed baseline positive results: six became negative thereafter, whereas seven showed follow-up positive results until disease progression occurred. One or more positive determinations were found during follow-up in 41 patients with negative baseline tyrosinase. No correlation was found between baseline results and the relapse rate or disease-free survival (DFS), whereas a significant correlation was found between positive tyrosinase results and disease recurrence during follow-up. In fact, 72.9% of positive patients relapsed, but only 19.3% of negative cases did so. The median interval between the positive results and the clinical demonstration of the relapse was 1.9 months (range 1 -6.6). Disease-free survival multivariate analysis selected, as independent variables, Breslow thickness (P ¼ 0.05), lymph node involvement according to the AJCC classification (P ¼ 0.05) and tyrosinase expression (P ¼ 0.0001). In conclusion, RT -PCR tyrosinase mRNA expression is a reliable and reproducible marker associated with a high risk of melanoma progression and we encourage its clinical use in routine follow-up.

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Section: Discussioncontrasting

confidence: 73%

Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: a clinical follow-up study of 110 patients

et al. 2003

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“…Several other preclinical parameters have been reported to correlate with disease progression in melanoma, including cytogenetic abnormalities, DNA ploidy and S-phase fraction, the expression of metastasis associated gene products, elevated serum levels of soluble adhesion molecules and the detection of circulating melanoma cells in peripheral blood using reverse transcription-polymerase chain reaction (RT-PCR) for tyrosinase messenger RNA (Trent et al, 1990;Smith et al, 1991;Xerri et al, 1994;Karlsson et al, 1996;Kunter et al, 1996). These parameters could reflect increase in the total tumour mass, recurrence of the disease or the presence of occult melanoma.…”

Section: Resultsmentioning

confidence: 99%

Elevated serum levels of S100 and survival in metastatic malignant melanoma

Buer

Probst²,

Franzke³

et al. 1997

Br J Cancer

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Summary Current reports suggest serum S100 as a prognostic marker for disease progression in advanced malignant melanoma. In this study, we assessed serum levels of S100 and multiple clinical factors in relation to overall survival in 99 patients with metastatic malignant melanoma seen at our institution between May 1990 and April 1996. For statistical analysis, we used both univariate and multivariate Cox proportional-hazards models. Elevated serum levels of S100 correlated with poor outcome in metastatic malignant melanoma (P < 0.0001), univariate analysis). Upon multivariate analysis, however, S100 added no information to known clinical prognostic parameters.

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“…1-4 and unpublished results). The latter was found in solid tumors, in cells in culture, and in blood-borne melanoma cells (5)(6)(7). The possibility that melanocyte-specific proteins were synthesized but later degraded was supported by the numerous reports identifying peptides derived from such melanogenic proteins as tyrosinase, TRP1͞gp75, and gp100͞Pmel 17 that serve as tumor antigens recognized by T cells of melanoma patients (see, for example, refs.…”

mentioning

confidence: 99%

Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells

Halaban

Cheng

Zhang

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

247

252

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The loss of tyrosinase, the key enzyme in melanin synthesis, has been implicated in the dedifferentiation of malignant melanocytes. The presence of tyrosinase transcripts and antigenic peptides in melanoma tumors prompted us to investigate whether the basis for the loss of the enzyme was proteolytic degradation. Toward this aim, we followed the kinetics of synthesis, degradation, processing, chaperone binding, inhibitor sensitivity, and subcellular localization of tyrosinase in normal and malignant melanocytes. We found that, in amelanotic melanoma cell lines, tyrosinase failed to reach the melanosome, the organelle for melanin synthesis, because it was retained in the endoplasmic reticulum (ER) and then degraded. Tyrosinase appeared mostly as a 70-kDa core-glycosylated, endoglycosidase H-sensitive, immature form bound to the ER chaperone calnexin and had a life-span of only 25% of normal. Maturation and transit from the ER to the Golgi compartment was facilitated by lowering the temperature of incubation to 31°C. Several proteasome inhibitors caused the accumulation of an Ϸ60-kDa tyrosinase doublet that was more prominent in malignant than in normal melanocytes and promoted, to various degrees, the maturation of tyrosinase in melanoma cells and the translocation of the enzyme to melanosomes. The appearance of ubiquitinated tyrosinase after treatment of normal melanocytes with N-acetyl-L-leucinyl-L-leucinal-L-norleucinal reinforced our notion that some tyrosinase is normally degraded by proteasomes. Proteolysis of tyrosinase by proteasomes is consistent with the production of antigenic tyrosinase peptides that are presented to the immune system by major histocompatibility complex class I molecules.Loss of pigmentation is observed in human melanomas in situ and in metastatic melanoma cells established in culture. The several studies designed to elucidate the basis for this phenotype have been focused on tyrosinase, the key enzyme of melanogenesis. In those in which both protein and mRNA levels were examined, a posttranscriptional regulation was implicated because, despite low or undetectable tyrosinase protein levels, tyrosinase mRNA was detected easily (refs. 1-4 and unpublished results). The latter was found in solid tumors, in cells in culture, and in blood-borne melanoma cells (5-7). The possibility that melanocyte-specific proteins were synthesized but later degraded was supported by the numerous reports identifying peptides derived from such melanogenic proteins as tyrosinase, TRP1͞gp75, and gp100͞Pmel 17 that serve as tumor antigens recognized by T cells of melanoma patients (see, for example, refs. 8 and 9 reviewed in ref. 10).Tyrosinase (70-80 kDa) is a type I membrane glycoprotein whose cDNA predicts a peptide of Ϸ58 kDa, a 28-amino acid cytosolic tail, and five putative N-glycosylation sites (refs. 2 and 11 and for review see refs. 12 and 13). Like other membrane glycoproteins, tyrosinase is processed in the endoplasmic reticulum (ER) by resident chaperones and enzymes (14,15). Reductions in me...

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Peripheral Blood Tyrosinase Messenger RNA Detection and Survival in Malignant Melanoma

Abstract: The results of this study demonstrate that the detection of tyrosinase mRNA in cells in the peripheral blood by RT-PCR may be a useful prognostic marker for predicting tumor progression and poor clinical outcome in patients with malignant melanoma.

Cited by 136 publications

References 18 publications

Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: a clinical follow-up study of 110 patients

Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: a clinical follow-up study of 110 patients

Elevated serum levels of S100 and survival in metastatic malignant melanoma

Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells

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