Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

Abstract

Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. In the last decades, it was shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and is combined with a poor prognosis. In this prospective study, we examined the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Between 1993 and 2004, 3386 patients with primary cutaneous melanoma were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. In all, 1270 patients could be followed up for further statistical analysis (Fisher's exact test, Mantel -Haenszel w 2 test, Kaplan -Meier curves). The MT data of disease-free interval and overall survival were compared univariately and multivariately in Cox regression analysis. Immunohistochemical overexpression of MT in tumour cells of patients with primary melanoma (310 of 1270; 24.4%) was associated with a higher risk for progression (117 of 167; 70.1%) and reduced survival (80 of 110; 72.7%) of the disease (Po0.0001). Similarly, Kaplan -Meier curves gave highly significant disadvantages for the MT-positive group. Univariate analysis (relative risk 7.4; 95% confidence interval (CI) 5.2 -10.2; Po0.0001 for progression; relative risk 7.1; 95% CI 4.7 -10.9; Po0.0001 for survival), as well as multivariate analysis with other prognostic markers resulted in MT overexpression as a highly significant and independent factor for prognosis in primary melanoma.

Melanoma Prognosis: A REMARK-Based Systematic Review and Bioinformatic Analysis of Immunohistochemical and Gene Microarray Studies

“…In other cases [GRP78 (26), cyclin B1 (32), CDK1 (32), nm23 (33,34), and topoisomerase II (32)], the opposite was observed; gene transcript levels differ while no significant outcome-related effect was observed at the protein level. For the remaining 16 molecules [BCL2 (32,38), survivin (18,32) (28,44), and SPP1/osteopontin (29,45,46)], concordance could not be assessed due to between-study differences making a direct comparison untenable. In addition, there were 4 molecules for which disparate findings were observed between different measures of clinical outcome.…”

Gene expression identifies heterogeneity of metastatic propensity in high‐grade soft tissue sarcomas

“…45 A possible role of metallothioneins in metastasis of oral cancers and melanoma has also been suggested. 41,42 This approach does not distinguish between genes expressed by the sarcoma cells or host stromal or inflammatory cells. Several different groups of genes expressed by tumor cells may have predictive value in a disease, and gene expression profiles of nontumor cells may as well, possibly reflecting a host response to the tumor.…”

“…They have been reported to be overexpressed in a variety of cancers, and also bind cytotoxic agents via their thiol groups. Metallothionein expression has also been correlated with cell proliferation and invasion in breast cancer, [40][41][42][43][44] and has also been associated with poor survival in colorectal cancer. 45 A possible role of metallothioneins in metastasis of oral cancers and melanoma has also been suggested.…”

“…Metallothioneins have been implicated in the process of metastasis, although the mechanism is unclear. [40][41][42] Metallothioneins are cysteine-rich proteins that bind a variety of metal ions. They have been reported to be overexpressed in a variety of cancers, and also bind cytotoxic agents via their thiol groups.…”

UV or Not UV: Metals Are The Answer

“…The latter event could occur in one of two major ways: increased uptake of available heavy metals due to a polymorphism in one of the many metallothioneins that regulate heavy metal uptake or by exposure to high environmental levels of metals that overwhelm normal metallothionein regulation of metals (see below). Although no direct measurements of metallothioneins and their association with melanoma risk have yet been reported, several studies document that metallothionein expression in primary melanomas is a strong prognostic factor for survival, even in thin melanomas (15). This should not be too surprising as large amounts of Cu 2+ become available as the tight compartmentalization of melanin synthesis (which is governed by the copper dependent enzyme tyrosinase) in the melanosome (a solid matrix type of synthesis) becomes progressively disrupted during melanomagenesis (16), and one feature of melanosome biology that is largely ignored is that this organelle can be duplicated (without nuclear genetic input) and passed on to the next generation of cells.…”