Elsevier

Clinical Biochemistry

Volume 37, Issue 7, July 2004, Pages 512-518
Clinical Biochemistry

Review
S100 proteins as cancer biomarkers with focus on S100B in malignant melanoma

https://doi.org/10.1016/j.clinbiochem.2004.05.012Get rights and content

Abstract

Although histochemical staining of the S100 protein family has been used for many years in the diagnosis of malignant melanoma, recent studies suggest one of the proteins comprising the S100 family, S100B, has particular utility in many aspects of the clinical management of malignant melanoma. This protein has been shown to be of use in staging malignant melanoma, in establishing prognosis, in evaluating treatment success and in predicting relapse. S100B is an independent prognostic factor and pretreatment circulating S100B concentrations predict duration of survival in melanoma patients. Survival is significantly longer in melanoma patients with normal S100B levels compared to those with elevated levels. Circulating S100B levels very sensitively detect metastatic growth of malignant melanoma, particularly in stage IV disease where S100B is certainly superior to other laboratory parameters. S100B concentrations reflect tumor mass. Serum S100B levels predict efficacy of treatment. Decreasing S100B concentrations reflect response to therapy while increasing S100B concentrations indicate tumor progression. Circulating S100B has a role to play in the decision to switch treatment regimens.

Section snippets

Background

More than 20 years ago, it was demonstrated that melanoma cells are able to secrete a soluble form of S100 protein [1] and later it was demonstrated that S100 proteins were also present in tumors like glioma and neuroblastoma in addition to malignant melanoma [2], [3]. The aim of this review is to discuss the present status of serum S100 proteins as markers in cancer, with particular emphasis on serum S100B protein as a marker of malignant melanoma.

Biochemical properties

S100 proteins belong to the S100/calmodulin/parvalbumin/troponin C superfamily whose members are characterized by the presence of a pair of EF-hand (i.e. helix-loop-helix structure) calcium-binding motifs [4], [5], [6]. The binding of calcium induces conformational changes in the S100 protein, exposing more hydrophobic areas, and this may facilitate the interaction of S100 proteins with secondary effector molecules. S100 proteins are generally thought to be calcium sensor proteins that modulate

Function of S100 proteins

S100 proteins have been shown to have both intracellular and extracellular functions. The extracellular function of S100B is mediated by binding to the cell surface receptor for glycation end product (RAGE) and is presently under investigation [16], [17].

S100 proteins are involved in a large number of cellular activities, most of which require calcium-dependent binding of target proteins. Intracellularly, S100B is involved in signal transduction via the inhibition of protein phosphorylation,

Association of S100 proteins with cancer

A wide range of human diseases including cancer and diseases of the skin and cardiovascular system have been attributed to a deregulation of S100 genes expression [14]. The levels of expression of individual S100 proteins vary considerably in different tumors and with respect to the progression of malignancy [5], [14].

Elevated intratumoral levels of S100B have been detected in malignant melanoma and to a lesser extent in thyroid carcinoma and renal cell carcinoma [23]. The strength of S100B

S100 markers in tissue

Immunohistochemical procedures have greatly increased the capability to properly classify tumors. S100 proteins are widely distributed in the peripheral and central nervous systems [41]. S100 proteins are expressed in astrocytes, oligodendrocytes, Schwann cells, adrenal medulla and a variety of other cells including chondrocytes adipocytes and melanocytes [4], [42], [43].

Despite the great progress made in the diagnosis of malignant melanoma, conventional histology continues to represent the

Serum S100B immunoassays

Commercially available serum S100B immunoassays are listed in Table 2. Of these S100B assays, the Sangtec®100 immunoassay (measuring S100B protein) is the most widely used in malignant melanoma. The assay was tested for cross-reactivity between S100B and other members of the S100 protein family of similar structure (particularly S100A1, S100A4 and S100A6), using different human recombinant S100 proteins [50]. No cross-reactivity with the other S100 proteins could be demonstrated.

Clinical use of serum S100B in malignant melanoma

Great efforts have been made during recent years to quantify melanoma associated compounds in the blood [51]. Several different markers have been examined including melanoma associated antigens, cytokines, metalloproteinases, angiogenesis factors, adhesion molecules, cell growth factors, immunoregulatory molecules and metabolites of melanin synthesis [28], [52]. Of all these compounds, S100B is at the moment the most widely applied biomarker in malignant melanoma patients. Especially in

Diagnosis and staging of malignant melanoma

Since malignant melanoma is a skin tumor that is easily visible on the body surface, no tumor markers are required for screening purposes. With advancing tumor stage, the proportion of melanoma patients who have circulating S100B levels in excess of the upper reference limit increases. This may be interpreted as an indication of micro- or macro-metastases [53]. Serum S100B is of great clinical significance in melanoma patients at all stages of the tumor.

The diagnostic sensitivity of serum S100B

Prognosis in malignant melanoma

The most significant prognostic markers in malignant melanoma are tumor thickness and lymph node status. However, S100B has also proved to be strongly related to prognosis of malignant melanoma [64] and to predict survival [46], [61], [63]. von Schoultz et al. [46] analyzed 643 patients with all clinical stages of malignant melanoma and demonstrated the relative hazard of death increased 5-fold when circulating S100B exceeded 0.6 μg/l. These serum S100B survival data were confirmed by Kärnell

Monitoring treatment in malignant melanoma

Monitoring therapy is the primary indication for the use of tumor markers since the changes of tumor marker levels in the blood should ideally allow conclusions to be drawn about changes in tumor mass. The serological determination of S100B protein in melanoma patients has provided data on its efficacy in monitoring treatment [47], [57], [63], [67]. Unsuccessful treatment can be detected early if there is a marked rise in S100B level. It also stands to reason that melanoma patients with high

Follow-up of malignant melanoma

Limited data are currently available regarding when during the process of micro- or macro-metastasis serum protein S100B level begin to rise. An elevated S100B serum level in a patient who have been diagnosed with malignant melanoma and is considered to be cured by the surgical intervention is an ominous sign and indicates melanoma recurrence [72], [73]. In a report by Henze et al. [62], the serum levels for S100B paralleled the course of disease in every patient investigated. However,

References (74)

  • D.B. Zimmer et al.

    The S 100 protein family: history, function, and expression

    Brain Res. Bull.

    (1995)
  • D. Kligman et al.

    The S 100 protein family

    Trends Biochem. Sci.

    (1988)
  • S. Ueda et al.

    Serotonergic sprouting into transplanted C-6 gliomas is blocked by S-100 beta antisense gene

    Brain Res. Mol. Brain Res.

    (1995)
  • R. Wicki et al.

    Repression of the candidate tumor suppressor gene S 100A2 in breast cancer is mediated by site-specific hypermethylation

    Cell Calcium

    (1997)
  • C. Rosty et al.

    Overexpression of S 100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation

    Am. J. Pathol.

    (2002)
  • K. Bjornland et al.

    Expression of matrix metalloproteinases and the metastasis-associated gene S 100A4 in human neuroblastoma and primitive neuroectodermal tumor cells

    J. Pedriatr. Surg.

    (2001)
  • S. Gongoll et al.

    Prognostic significance of calcium-binding protein S 100A4 in colorectal cancer

    Gastroenterology

    (2002)
  • H.B. Guo et al.

    Clinical significance of serum S 100 in metastatic malignant melanoma

    Eur. J. Cancer

    (1995)
  • A. Marks et al.

    S 100 protein expression in human melanoma cells, comparison of levels of expression among different cell lines and individual cells in different phases of the cell cycle

    Exp. Cell Res.

    (1990)
  • P. Kaskel et al.

    S-100 protein in peripheral blood: a marker for melanoma metastases: a prospective 2-center study of 570 patients with melanoma

    J. Am. Acad. Dermatol.

    (1999)
  • C.L. Huang et al.

    Laboratory tests and imaging studies in patients with cutaneous malignant melanoma

    J. Am. Acad. Dermatol.

    (1998)
  • R. Gaynor et al.

    Herschman HR, S 100 protein is present in cultured human malignant melanomas

    Nature

    (1980)
  • H. Kawasaki et al.

    Classification and evolution of EF-hand proteins

    Biometals

    (1998)
  • D.B. Zimmer

    Examination of the calcium-modulated protein S 100 alpha and its target proteins in adult and developing skeletal muscle

    Cell Motil. Cytoskeleton

    (1991)
  • C.W. Heizmann et al.

    New perspectives on S 100 proteins: a multi-functional Ca(2+)-Zn(2+)- and Cu(2+)-binding protein family

    Biometals

    (1998)
  • K. Haglid et al.

    An immunological study of human brain tumors concerning the brain specific protein S-100 and 14.3.2

    Acta Neuropathol. (Berl.)

    (1973)
  • T. Isobe et al.

    The amino-acid sequence of the alpha subunit in bovine brain S-100a protein

    Eur. J. Biochem.

    (1981)
  • C.W. Heizmann et al.

    S 100 proteins: structure, functions and pathology

    Front Biosci.

    (2002)
  • J. Hu et al.

    S 100beta induces neuronal cell death through nitric oxide release from astrocytes

    J. Neurochem.

    (1997)
  • G. Ghanem et al.

    On the release and half-life of S 100B protein in the peripheral blood of melanoma patients

    Int. J. Cancer

    (2001)
  • R. Molina et al.

    S-100 protein serum levels in patients with benign and malignant diseases: false-positive results related to liver and renal function

    Tumour Biol.

    (2002)
  • P.T. Wilder et al.

    S-100B (beta beta) inhibits the protein kinase C-dependent phosphorylation of a peptide derived from p53 in a Ca2+-dependent manner

    Protein Sci.

    (1998)
  • E.C. Ilg et al.

    Expression pattern of S 100 calcium-binding proteins in human tumors

    Int. J. Cancer

    (1996)
  • Y. Yonemura et al.

    Inverse expression of S 100A4 and E-cadherin is associated with metastatic potential in gastric cancer

    Clin. Cancer Res.

    (2000)
  • X.J. Guo et al.

    Identification of a serum-inducible messenger RNA (5B10) as the mouse homologue of calcyclin: tissue distribution and expression in metastatic, ras-transformed NIH 3T3 cells

    Cell Growth Differ.

    (1990)
  • S. Trocha et al.

    Tumour markers in melanoma

  • G.S. Misotten et al.

    Prognostic value of S-100beta serum concentration in patients with uveal melanoma

    Arch. Ophthalmol.

    (2003)

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