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Biomarkers play an important role in the diagnosis and prognostic classification of various cancers and can be useful in monitoring the patient's clinical course of disease and response to therapy. Generally, biomarkers are proteins and their expressions are associated with malignant disease. In the majority of cases, the marker molecules are expressed by the tumour cells themselves or by the tumour microenvironment cells. Thus, most biomarkers can primarily be found in malignant tissues, but after active secretion or passive release at tumour destruction, they become detectable in body fluids such as blood. Besides morphological and histopathological biomarkers (anatomic site, type of the primary tumour, tumour size, invasion depth, vascular invasion and ulceration), an increasing variety of serological markers have been identified, providing the possibility of a more detailed diagnostic and prognostic subgrouping of tumour entities, up to and even changing existing classification systems. The goal of this review is to provide an overview of old and more recent serological biomarkers in malignant melanoma. We will first focus on confirmed and nonconfirmed serum tumour markers, followed by proteomic profiling, an innovative approach to identify new and better serological biomarkers in melanoma, and ending with the predictive factors for treatments in this pathology.

The exact role of the soluble form of epidermal growth factor receptor (sEGF-R) in melanoma disease remains to be determined. We focused this study on the detection of circulating levels of sEGF-R in metastatic malignant melanoma patients and on the possible relationship between sEGF-R and clinicobiological parameters including circulating interleukin-6 (IL-6) and survival. sEGF-R and IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay in serum from 75 metastatic malignant melanoma patients and 30 healthy controls. In our patients, median sEGF-R level was significantly elevated (P0.0001) compared with that of healthy controls (173.4 vs. 91.9 fm/ml). Age or sex was not associated with sEGF-R levels. Regarding tumor burden, in contrary to the detected IL-6 levels, we found that median sEGF-R levels were significantly (P = 0.045) lower in patients with high tumor burden (163 fm/ml) than in those with low tumor burden (193.8 fm/ml). An inverse correlation between IL-6 levels and sEGF-R was observed (r =-0.33; P = 0.040). No relationship between sEGF-R and time to progression or overall survival was observed while circulating IL-6 was found as a predictive factor of survival. Our results showed that sEGF-R level was elevated in metastatic malignant melanoma patients but not related to time to progression or survival and demonstrated an inverse correlation between sEGF-R and IL-6 levels. These findings imply a better understanding of EGF-R and IL-6 cross-talk function in melanoma.

Biological response parameters during biochemotherapy, including chemotherapy with immune modulating agents, have been studied extensively. Of these parameters, interleukin-6 (IL-6) has been implicated in advanced stage disease and tumour recurrence. However, there is limited information available about the significance of IL-6 in metastatic malignant melanoma (MMM). In this study, we evaluated the possible relationship between serum IL-6 level and overall survival. This retrospective study included 125 patients with MMM. Pretreatment serum IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay (ELISA) test. Kaplan-Meier survival curves were constructed and compared using the log-rank test. Cox proportional analysis was performed to assess the predictors of overall survival, which was calculated from the beginning of biochemotherapy until death. In order to establish the possible relationship between IL-6 level and overall survival, patients were divided into two groups according to a cut-off of 5 pg/ml, corresponding to the first quartile obtained by descriptive statistics of the pretreatment IL-6 level in all patients. Thirty-five patients were in the low IL-6 group and 76 patients were in the high IL-6 group. Based on this stratification, overall survival was shown to be affected by IL-6 serum level: it was higher (24.6 months) in the low IL-6 group when compared with the high IL-6 group (9.7 months) (P=0.0006). Furthermore, Cox multivariate analysis including standard melanoma prognostic factors showed that IL-6, as a variable, lactate dehydrogenase (LDH) and tumour burden were significant prognostic factors for overall survival. On the basis of this evidence, the pretreatment serum IL-6 level is a predictive factor of overall survival in MMM.

Interleukin-1beta converting enzymes (ICEs/caspases) are involved in programmed cell death (apoptosis). This study sought to quantify the caspase-1 level in metastatic malignant melanoma patients and to try to establish a correlation between the level of caspase-1 and different parameters related to this pathology. In addition, we evaluated the possible relationship between the clinical response to biochemotherapy and the caspase-1 level. The serum caspase-1 level was determined in 81 metastatic malignant melanoma patients and 50 normal volunteers using enzyme-linked immunosorbent assay (ELISA). Patients received cisplatin, recombinant interleukin-2 (Proleukin) and alpha-interferon (Roferon A) in two induction cycles, and assessment of clinical response was performed according to World Health Organization (WHO) criteria. The median caspase-1 level in melanoma patients was significantly higher (P = 0.0035) than in control samples. Interestingly, a positive correlation between caspase-1 level and the tumour burden was shown (rs = 0.629, P = 0.009). When the clinical response was taken into consideration, the level of caspase-1 was significantly higher in biochemorefractory patients compared with responding ones (P = 0.04). After treatment, the caspase-1 level remained very high in biochemorefractory patients, while in responding ones no change was observed. Furthermore, a positive correlation between the clinical response and the caspase-1 level was established (rs = 0.404, P = 0.024). In conclusion, we observed an elevated caspase-1 level in metastatic malignant melanoma patients. In addition, the correlations obtained between the caspase-1 level and both the tumour burden and the clinical response to the treatment support the concept that disrupted apoptosis pathways might be involved in the progressive disease of advanced melanoma and/or may confer resistance to treatment.

Trends in the incidence of melanoma show that it is one of the fastest growing cancers throughout the world [1]. At the same time, despite huge advancements in medicine, the death rate because of melanoma has remained static showing the lack of progress in the treatment of this pathology [2]. Chemotherapy, biological agents, or combinations of both had little impact on patient survival [3]. However, decades of research at the basic and clinical levels led to significant advances in understanding genetic changes in melanoma resulting in availability of promising new experimental agents [4].

The transmembrane receptor Fas/APO-1, together with its protein-binding partner (Fas ligand), is a key regulator of programmed cell death and induces apoptosis when it binds Fas ligand (FasL) or soluble Fas ligand (sFasL). However, soluble Fas (sFas) blocks apoptosis by inhibiting binding between Fas and FasL or sFasL. At present, the status of sFas and sFasL in metastatic malignant melanoma remains unknown. This study sought to evaluate the relationship between plasma levels of sFas and/or sFasL and clinical response in 45 metastatic malignant melanoma patients treated by biochemotherapy. sFas and sFasL were measured by specific enzyme-linked immunosorbent assay (ELISA) tests in the sera from patients and 34 healthy donors. Overall, sFas and sFasL levels in patients were significantly higher (P < 0.0001) than in healthy donors. Before the biochemotherapy treatment the sFas level was about the same in biochemorefractory (n = 26) as in responder patients (n = 19). In contrast, the sFasL level was very high only in biochemorefractory patients. At the end of the treatment, in biochemorefractory patients the sFas level was extremely significantly increased (P < 0.0001) and a significant decrease in the plasma levels of sFasL was observed (P = 0.0002). In responder patients, no change in sFas and sFasL was detected. In conclusion, elevated levels of sFas and sFasL might be associated with poor prognosis in advanced melanoma; their possible role in the regulation of apoptosis in influencing the response to biochemotherapy should be further explored.

During recent years it has become clear that the production of most cytokines could play an important role in malignancies. We previously demonstrated that a high endogenous interleukin-6 (IL-6) level is significantly correlated with a high tumour burden and resistance to biochemotherapy in metastatic malignant melanoma patients. However, little is known about the origin of IL-6 and the pattern of IL-6 receptor (IL-6R) expression. In this report, we studied the expression of IL-6R and intracellular IL-6 using flow cytometry in tumour cells provided by fine-needle aspiration of lymph nodes and palpable metastatic lesions from 14 patients refractory to biochemotherapy and six responder patients. Moreover, we established the relationship between these parameters and the serum IL-6 level. Our results demonstrated that, following treatment, the percentage of HMB45-positive (HMB45+) cells expressing functional IL-6R, intracellular IL-6 or both IL-6R and IL-6 significantly decreased in patients refractory to biochemotherapy. In contrast, in responder patients the percentage of HMB45+ cells expressing IL-6R increased and those expressing IL-6 remained stable. Regarding the serum IL-6 level, an 11-fold increase was observed in the patients refractory to biochemotherapy, but only a 1.8-fold increase in the responder patients. In conclusion, in metastatic malignant melanoma patients with a poor prognosis, the endogenous production of IL-6 is concomitant with a decrease in functional IL-6R and intracellular IL-6 expression, suggesting the involvement of an IL-6/IL-6R complex.