Download the significance of serum s100, mia and ldh in cutaneous malignant

THE SIGNIFICANCE OF SERUM S100, MIA AND LDH
IN CUTANEOUS MALIGNANT MELANOMA
ANGELA SANDRU1*, SILVIU VOINEA1, MADALINA BOLOVAN2, SABIN CINCA2,
CRISTIAN BORDEA1, ALEXANDRU BLIDARU1
1
IInd Clinic of Oncologic Surgery, Oncologic Institute Bucharest, 252 Fundeni Street,
Bucharest, Romania
2
Carcinogenesis and Molecular Biology Department, Oncologic Institute Bucharest,
252 Fundeni Street, Bucharest, Romania
(Received 2 April, 2011)
Malignant melanoma is a disease with a continuously increasing incidence and an unfavorable
outcome in stage IV. It is a tumor with intense metabolic activity that produces and releases in the
blood stream enzymes, cytokines and growth factors. Although several proteins were suggested as
serum markers in malignant melanoma, until now none has proven itself sensitive enough to be
currently used in treatment monitoring and patient follow-up.
The target of this paper is to synthesize the information from the literature referring to three of
the most commonly used serum markers in malignant melanoma. With the exception of LDH, whose
role is well established, MIA and S100B are still the subject of various studies.
Keywords: malignant melanoma, tumors markers, LDH, MIA, S100B
Malignant melanoma is a surprising disease, with a clinical evolution that
cannot be patterned. It is hard to imagine that, although correctly excised, a tumor
with a thickness of less than 1 mm cannot be cured. Nevertheless, 5–15% of these
patients develop metastases (1, 2) and eventually die. On the other hand, a large
number of thick, ulcerated melanomas never relapse (3).
Because the evolution of malignant melanomas it is hard to predict, mostly in
stages I and II, efforts are being made in order to identify markers that can correlate
with disease progression and its response to treatment.
Tumor markers are molecules produced either by the tumor cells or by the
normal ones, as response to cancerous invasion (4). Many of the tumor markers are
intracellular or extracellular proteins released into the body’s fluids. The ideal
tumor marker should be: specific to a precise cancer type, undetectable in healthy
subjects or in subjects with benign pathology and sensitive enough to detect small,
incipient tumors.
*
Corresponding author (E-mail: [email protected])
ROM. J. BIOCHEM., 48, 1, 75–88 (2011)
76
Angela Sandru et al.
2
Unfortunately, none of the presently known markers has either a specificity
or sensibility of 100% (3). These inconvenients come from the fact that, on the one
hand, the majority of the proteins are also produced in small quantities in many
normal cells, and on the other hand, some are released in the circulation during the
course of some benign diseases. If in a given population, we investigate 13 tumor
markers, we find that 49% of the participants develop at least one positive test (5).
Despite these restrictions, tumor markers represent one of the main tools that can
be used for:
• screening and early diagnosis (PSA, AFP);
• guiding the diagnosis: in the case of a patient with disseminating disease, it
is helpful in determining the starting point (calcitonin in medullary thyroid
cancer, vanillylmandelic acid for pheochromocytoma);
• suggesting the disease prognosis (LDH in melanoma);
• monitoring the treatment response;
• early identification of relapse.
Serum tumor markers are not routinely used in malignant melanoma (7),
excepting LDH which is used in AJCC staging system 2009. In this neoplasia, the
prognosis is established taking into account the histology-Breslow score and
ulceration, and the clinical setting – the number of the regional involved lymph
nodes and the presence of metastases. But none of the conventional clinicopathological parameters was able to reliably identify those patients who are likely
to relapse. Therefore, new biomarkers that predict the clinical outcome are urgently
needed.
Similar to other forms of cancer, melanoma is accompanied by some alteration
of normal protein activity or concentration. From the long list of biologic serum
markers proposed for MM (S100B, MIA – Melanoma inhibitory activity, LDH –
Lactic dehydrogenase, TA90 – tumor associated antigen 90, 5SCD – 5Scysteinyldopa,
NSE – Neuron specific enolase, CRP – C Reactive Protein, etc.), only few have been
rigorously investigated in retrospective or prospective studies. This paper reviews the
most significant and best characterized serum markers in malignant melanoma –
S100, MIA and LDH – as well as their indications and limits.
S100B
S100B was the first molecular marker to be used in the immunohistochemical
diagnosis of pigmented skin lesions and is still the most sensitive one. S100B is
part of the S100 protein family, having at least 21 different members (11).
S100B protein was isolated by Moore, in 1965, from the bovine brain (9) and
got its name due to its solubility in 100% saturated ammonium sulphate solution at
neutral pH. The S100 proteins are dimers made of two subunits, α and β, in all
possible combinations (αα, αβ, ββ). α subunit is coded by 13 different genes
located on the long arm of chromosome 1 (1q21), while β subunit is coded by one
gene on the long arm of chromosome 21 (21q22.3) (5, 12).
3
S100, MIA, LDH in malignant melanoma
77
Protein S100B is secreted by a large number of cells of neuroectodermal and
mesodermal origin, each dimer being specific to certain types of tissues:
• the ββ dimer is mainly made by the astrocytes but also by Schwann and
Langerhans cells (13);
• the αα dimer has a wide distribution in: skin (S100A7), keratinocytes,
skeletal muscles (S100A13), heart(S100A13, S100A10), kidneys (S100A13),
pancreas, ovary, lung (S100A10);
• the αβ dimer is found in melanocytes, glial cells, chondrocytes.
The S100B protein family represents the most numerous group from the
calcium binding proteins. This property is given by their structure, which contains
the EF-hand, made out of the helix-loop-helix sequence, which binds the calcium
selectively and with great affinity (14). Each protein contains two of these sequences,
at the N and C ends, and it can bind four calcium ions. It also has four binding sites
for copper and six for zinc, which also influence the ability to bind calcium (15, 16).
Within the cell, S100B is found both in the nucleus and cytoplasm, exhibiting
intra- and extracellular functions (12). The action mechanism is not fully
elucidated, but it is accepted that they are involved in several processes through the
activation of some enzymes and the modulation of the interaction between several
proteins:
• inhibits the assembly of microtubules via sequestration of tubulin, thus
maintaining the integrity of the cytoskeleton (13);
• regulates the progression of the cell cycle and cell differentiation;
• inhibits p53 protein phosphorylation by the C proteinkinase, thus
compromising the tumor suppressor activity of the P53 gene (17,19);
• in nanomolar concentration, in vitro, stimulates neurite outgrowth in
cerebral cortex neurons and increases neuronal life (13);
• in micromolar concentrations, in vitro, stimulates apoptosis and determines
the raise of β-amyloid precursor protein in neuronal cultures (18);
• stimulates the inflammatory response.
The over expression of S100B was initially described in neurodegenerative
diseases: Alzheimer’s disease, epilepsy, lateral amyotrophic sclerosis, the Down
syndrome. Consequently, it was demonstrated that increased blood levels appear in
traumatic brain lesions, hemorrhagic or ischemic, the values of S100B being
proportional with the lesion dimension and patient evolution (13).
In tumor samples, S100B is identified by immunohistochemistry with the
help of monoclonal antibodies. It has a high sensibility for melanic lesions, but, has
not a good specificity. In skin, the protein may be seen in melanocytes, Langerhans
cells, Schwann cells, the acini and ducts of sweat glands, sensorial corpuscles and,
of course in the tumors derived from these structures: melanomas, schwannomas,
liposarcomas, histiocytic tumors, clear cell sarcomas (20). S100B is also expressed
in large quantities in gliomas, neurofibromas, malignant tumors of the nerve
sheath, chondrosarcomas.
78
Angela Sandru et al.
4
In blood, S100B may be determined using two assays, immunoradiometric or
immunoluminometric, both having as a starting point the same method: the use of
two different monoclonal antibodies directed against two distinctive epitopes of the
β subunit of S100B. Because the β subunit is the target, this reaction allows to
identify both the αβ dimers released from melanocytes and the ββ dimers released
from the CNS (19). Given these conditions, it is possible for a patient with
malignant melanoma to exhibit a raised S100B value as result of a stroke.
The first data on the significance of serum values of S100B protein in
malignant melanoma were published in 1995 (21). From then on, multiple
prospective studies emphasized the importance of this tumor marker in MM. It can
be used to:
(i) Appreciate the extent of the disease, knowing that serum values increase
in parallel with the clinical stage (22) – It is commonly accepted that S100B values
are proportional with the tumor load of the body. In a study on 126 patients, at a
cut off of 0.15 µg/l, Guo et al. (21) noticed that S100B sensibility changed with the
progression of the disease; in stages I and II, the overvalues were observed in only
1.3% of cases, in stage III in 8.7%, and in stage IV, 73.9% of patients presented
high S100 levels. In another study, that established a 0.09 µg/l cut off, a sensibility
of 75% was reached in identifying cases with metastasis (23). S100B values
depend on the location of the metastases, with maximum values in cerebral and
hepatic metastases (24).
(ii) Evaluate the treatment response – Evaluating treatment response can be
done through a wide range of paraclinical investigations (echo, CT scan, MRI,
PET-CT). It seems that similar results may be obtained through the monitoring of
pre- and post-therapy S100B serum values (25), which would represent an
important benefit, given the lower costs and the possibility to repeat them any time.
Treatment response is indicated by the decrease of serum values, while a raise in
concentration suggests tumor progression. Smit et al. even claim that a quick
normalization of the S100B during polichemotherapy or immunotherapy is
accompanied by a longer survival (28). On the contrary, an increase in S100B
during systemic treatment attests failure and strongly suggests that the treatment
plan should be changed (25).
(iii) Predict the disease free survival and the overall survival – The ability of
S100B to suggest evolution in patients with malignant melanoma was the subject
of many papers. In a study on 412 patients with malignant melanoma, Hauschild
et al. demonstrated that the estimated overall survival was significantly higher
(p<0.01) in subjects with S100B<0.2 µg/l, comparing with those having
S100B>0.2 µg/l, regardless of the clinical stage (26). The same conclusion was
reached in a study where S100B’s threshold was 0.15 µg/l (27). Patients with
metastatic MM, with normal values of S100B, live longer than those who have a
S100B higher than the upper normal limit (28): the median survival was 14 months
for S100B<0.16 µg/l and 6.6 months for S100B>0.16 µg/l (28). A large prospective
5
S100, MIA, LDH in malignant melanoma
79
study on 1007 patients with MM in stages I–III showed that S100B was a more
sensitive survival predictor, stronger than the clinical stage (22): 30% of patients
with S100B<0.10 µg/l were alive after five years, comparing to only 6% of those
with S100B>0.10 µg/l (22). However, for stage I it is considered that S100B has a
lower prognostic significance, here being undermined by the thickness of the tumor
and the presence of ulceration.
(iv) Post-therapy follow-up period – Although commonly debated on, no
protocol on post therapy follow-up was established in malignant melanoma. In
Germany, it is recommended that patients with thin melanomas should be
evaluated every six months, and those with thick and intermediary melanoma,
every three months. At each check up, except for the clinical exam, one has to
determine S100B and also to do an echo of the regional lymph nodes (29).
There are opinions stating that S100B sensibility in identifying metastases is
higher than that of other conventional methods (30, 31) The serum protein
concentration exceeded the threshold limit of 0.2 µg/l established in this study,
with 5–23 weeks before the appearance of other clinical and paraclinical signs of
disease (30). Martensen et al. consider that for a stage III melanoma, increased
values of S100B after lymph node dissection represent an independent prognostic
factor (22). It has been suggested even that S100B monitoring pre- and postlymphadenectomy could be used as a quality control marker for dissection (31).
It has to be noticed that it is difficult to compare the results obtained by
different authors because there are many variables: methods to determine S100,
reference values (threshold limits), melanoma stage system, features of different
patient groups.
In a meta-analysis of 116 articles concerning S100B, published until January
2008, Mocellin et al. concluded that S100B could have an important role in
establishing the therapy plan and patient follow-up for stages I-III malignant
melanoma (32). Then, why has it not been implemented in routine practice so far?
Because studies stating the exact opposite opinion also exists:
• in a prospective analysis of 266 patients in stages I-III malignant
melanoma, Curry et al. noticed that S100B has a minimum value in
identifying patients who would develop relapse (33);
• Egberts et al. measured the S100B level before and after sentinel node
biopsy in 259 patients with stages I-II malignant melanoma, reporting a
reference limit of 0.12 µg/l. They found no correlation between serum
S100B concentration, on the one hand, and histopathology of the sentinel
node, overall survival and disease free survival, on the other hand (34);
• increased values of S100B may also be found in other circumstances:
healthy patients 4%, septic patients 20% (35);
• no general normal threshold was accepted, although a kit manufacturer
recommended 0.12 µg/l (LIA – mat Sangtec –100).
80
Angela Sandru et al.
6
Taking into account the diverse opinions, we can conclude that S100B has a
higher significance in evolved forms of melanoma, but for stages I-II we have to be
cautious, and new data should be needed.
MIA
Melanoma inhibitory activity (MIA) was purified in 1989 (36, 37) and cloned
in 1994 (38, 39). Its discovery is linked to the search for autocrine growth factors
in malignant melanoma.
Initially, it was considered that MIA has a tumor suppressor activity, hence
the name (38, 39). In vitro, MIA alters the morphology of melanoma cells and
inhibits thymidine incorporation in the DNA (41, 42). Adding MIA to melanoma
cell lines determines cells rounding with the loss of intercellular links and growth
inhibition. Consequent studies showed that in vivo, MIA’s function is opposite to
the above mentioned one, its active secretion by the melanoma cells promoting
invasion and metastasis (40).
MIA is a small protein coded by a gene on the long arm of chromosome 19
(19q13.27–13.33), made out of four exons (42). Through its translation, a precursor
of 131 amino acids is formed and later through its cleavage, the mature protein is
generated. Mature MIA consists of 107 amino acids and has a molecular weight of
11 kDa (36, 37). The first 24 aminoacids (signal peptide) from the precursor
control MIA’s transport in the extracellular compartment (42, 39). At this level,
MIA interacts with fibronectin, a glycoprotein from the extracellular matrix with a
major role in intercellular adhesion, differentiation, raise and cell migration (46).
Fibronectin contains multiple binding sites for integrins, membrane receptors that
mediate cell attachment to surrounding tissues, but also to other structures, such as
collagen, fibrin, heparan sulfate, and proteoglycans (47).
Data from the literature suggest MIA’s mechanism of action: four MIA
molecules bind to specific sites of a fibronectin molecule, thus impeding integrin
coupling with fibronectin (48). MIA sterically interferes with the fibronectin
binding to α4β1 and α5β1 integrins, with subsequent inactivation of their function
(49). All these MIA properties in vivo may explain its inhibitory activity in vitro:
the protein impedes the attachment of melanoma cells to the culture dishes.
In vivo, MIA is synthesized both by normal tissue and malignant tumors, and
it can also be detected in some other pathological states. In healthy tissue, MIA
expression is limited to chondrocytes (40, 43). Its synthesis is initiated at the
beginning of chondrogenesis, intrauterine, and continues during cartilage
development and also during fractures’ healing (40). Some authors suggest that at
this level MIA functions as a chemotactic factor for mesenchymal stem cells (40),
thus favoring the chondrogenic phenotype and inhibiting the osteogenic one.
In vitro, in chondrocyte cell cultures, MIA expression is inhibited by retinoic
acid adding, which explains why it was also called CD-RAP (cartilage derived
retinoic acid-sensitive protein) (44).
7
S100, MIA, LDH in malignant melanoma
81
During chondrogenesis, MIA serum values increase significantly. In a study
published in 2004, Bosserhoff et al. stated that pregnant women after week 38, and
children and teenagers under 17 have MIA serum values above median (45).
MIA may be identified in several tumor types through immunohistochemistry, Western-blot or RT-PCR, but with higher specificity for malignant
melanoma and chondrosarcomas. It is also expressed, in variable quantities, in
certain advanced stage adenocarcinomas: breast, gastric, pancreatic, colic, ovarian
cancer (35, 50–54). MIA is not expressed in either normal skin or benign
melanocytes (38, 39). It is revealed in small to moderate levels in the majority of
benign nevi and in very large quantities in malignant melanomas, in the primary
tumor and in secondary deposits as well (54). In malignant melanoma, the
induction of MIA synthesis seems to be an early event in carcinogenesis, taking
into account that all in situ tumors express MIA (40).
The active secretion of MIA by malignant melanocytes allows them to
interrupt the connections with the extracellular matrix. In malignant melanoma, the
number of contacts between tumor cells and fibronectin, laminin and tenascin
drops with 30–50% comparing to normal cells (55). The detachment of malignant
melanocytes from the extracellular matrix and the basal membrane increases their
motility, thus favoring local invasion and metastases.
Another possible MIA’s mechanism of action is the inhibition of the cellular
mediated immune antitumor response. As the immune system cells express α4β1
integrins, it was stated that MIA blocks the receptors on the leukocyte surface. In vitro
experiments showed that MIA inhibits peripheral blood mononuclear proliferation and
decreases the cytotoxic activity of lymphokine-activated killer cell (LAK) in a dose
dependent process (39, 40). These data suggest that MIA may contribute to the
immunosuppression, which is frequently seen in melanomas. MIA might also favor
melanoma progression by inducing the expression of other tumor associated genes (40).
Taking into account that MIA is a protein made by malignant melanocytes in
amounts correlated to tumor progression, it was investigated whether MIA serum
values may represent a useful marker in the follow-up of patients with malignant
melanoma.
In one of the first studies published by Bosserhoff et al. in 1997, serum MIA
was detected using an ELISA test. The upper normal limit was established at
6.5 ng/ml by measuring MIA in the blood of 72 healthy donors. The determined
values overcame the limit established in 13% of patients with stage I malignant
melanoma, 23% in stage II, 81% in stage III and 97% in stage IV (35, 56).
These promising results encourage the initiation of other trials. Further
studies raised the cut-off value in order to increase specificity and sensibility. Thus,
considering pathological MIA serum values greater than 8.5 ng/ml, Faries et al.
obtained a specificity of 100% in identifying relapse in stage III malignant
melanoma, with a sensibility of only 46% (57). Relapse occurred in all patients
with positive MIA in the next two years (57). Most authors believe that values
higher than 14 ng/ml are pathologic. With this threshold, the specificity of
82
Angela Sandru et al.
8
metastases detection varies between 96.8% (24) and 98.9% (58), with a sensibility
between 50% (58) and 70% (24).
The serum concentration of MIA is directly proportional to the tumor mass,
and this is why it may be used as a marker of the treatment response (56, 59). The
surgical removal of metastasis or the answer to chemotherapy is accompanied by
normalization of MIA values (58, 59). The persistence of high values, despite of
the systemic treatment, suggests an unfavorable prognosis (62).
Some enthusiastic researchers affirm that MIA measurement may replace
other staging methods (59) and could represent the ideal test for screening of the
sentinel node (60). Post-surgery follow-up of patients in stages I and II can be
made by determining MIA, which has a positive predictive value big enough to
suggest occult metastases, clinically undetectable (66).
Before fully accepting this new marker, one must take into account several
elements:
• MIA is positive in 17% of patients with malignant epithelial tumors;
• rheumatic diseases accompanied by joint destruction present raised values
of MIA (even above 100 ng/ml): rheumatoid arthritis, psoriatic arthritis
(61). MIA is probably being actively freed from chondrocytes during
cartilage destruction;
• during chondrogenesis, MIA serum concentration is increased. This is the
reason why it is not indicated in the follow-up of patients with less than
17 years old and of pregnant women having more than 38 weeks of
pregnancy (45);
• in stages I and II of disease, MIA specificity is less than 67% (63);
• there are few studies which deny MIA usefulness in the follow-up of
patients with malignant melanoma (64, 65), but they are performed on a
small number of subjects.
LACTIC DEHYDROGENASE
LDH is an enzyme found in all body cells in different forms and proportions.
There are four different classes, two of which are dependent on cytochrome c, and
the other two are NAD dependent (nicotinamid adenin dinucleotid). In this review,
we refer only to the LDH NAD(P) dependent form, which exists as five isozymes.
Each isozyme is a tetramer composed of a combination of two different subunits:
M and H. Their physical, catalytic and immunological properties differ, depending
on the monomer type they consist of (67).
LDH2 (3HM) is produced by the reticuloendothelial system and it is usually
the predominant form in serum. Elevated levels of LDH accompany any disease
characterized by cell destruction (11): hemolysis, myocardial infarction-LDH1(4H),
acute pancreatitis, hepatic cytolysis-LDH5(4M), meningitis, encephalitis. It is often
used as a marker of tissue breakdown. Serum concentrations above the upper
9
S100, MIA, LDH in malignant melanoma
83
admitted threshold were also documented in different cancer forms: Hodgkin
lymphoma and non-Hodgkin lymphoma, multiple myeloma, lung cancer, prostate
cancer, ovarian and testicular dysgerminomas. Elevated serum LDH levels reflect
tumour cell turnover and tumour burden (19).
LDH is not useful in screening and diagnosis of malignant melanoma, as it is
not specific for it. Nevertheless, its efficacy was shown in monitoring patients in
advanced stages. TNM staging of malignant melanoma from 2002 introduced a
new M category – M1c, which corresponds to any distant metastatic lesion
accompanied by the raise of serum LDH. This initiative was motivated by the fact
that in all published studies, after a multivariate analysis, the increase of serum
LDH in stage IV patients was associated with an unfavourable prognosis (68).
The M1c subcategory was maintained in 2009 staging system (69). By
analyzing patients with distant metastasis from the AJCC melanoma staging
database in 2008, it was noticed that their evolution was strongly linked to serum
LDH. Thus, stage IV patients with normal LDH had an overall survival rate of 65%
at 1 year and 40% at 2 years, respectively. On the other hand, patients with LDH
above the upper normal limit at the time of staging had 1 year overall survival of
only 32% and a 2 year overall survival of 18% (69).
Various studies compare the characteristics of the three markers discussed in
this paper and try to identify their role in each stage of the disease. The first one
was published in 1999 by Deichmann et al. and it followed 71 stage IV malignant
melanoma patients (70), aiming to determine the markers ability to discriminate
between progressive and stable disease.
Table 1
Correlations between S100, MIA and LDH in stage IV MM
S100
MIA
LDH
Cut off (%)
0,12 µg/l
6,5 ng/ml
240 U/l
Sensibility (%)
91
88
79
Specificity (%)
76
73
92
Adapted after (70)
The study showed that all three markers were able to predict disease
evolution, but MIA and S100B brought just as much information as LDH in
metastatic disease (70).
The situation is different for localized melanoma. Garbe et al. surveyed
296 clinically disease free patients with stages II and III malignant melanoma for
19 months. During the follow-up, 41 of them developed metastatic disease (71).
Table 2 shows the ability of the three markers to detect metastatic disease – both
MIA and S100B have a higher accuracy than LDH in the diagnosis of newly
occurring metastasis; therefore, they may be useful in the follow-up of disease-free
stage II and III melanoma patients (71).
84
Angela Sandru et al.
10
Table 2
Correlations between S100B, MIA, LDH in stage II-III MM
Cut off
S100B
MIA
LDH
0,12 µg/l
10,49 ng/ml
240 U/l
Sensibility
(%)
29
22
2
Specificity
(%)
93
97
90
Positive predictive value
(%)
84
86
77
Adapted after (71)
CONCLUSIONS
There is no international agreement regarding the number and type of serum
markers required in the follow-up of patients with malignant melanoma. From the
multitude of proposed markers, LDH, S100B and MIA seem to be the most
trustworthy.
S100B and MIA may be used in the screening of patients with stage II and III
in order to identify occult metastases (71). Elevation of S100B in stages II and III
melanoma patients might detect a haematogenic or lymphatic dissemination with
several months before the onset of overt disease (72). For this reason, Bouwhuis et
al. recommend serial determinations of S100B serum levels (73). Both S100B and
MIA correlate with DFS and OS of melanoma patients, but simultaneous use of the
two markers increases sensibility and maintains specificity (24).
The sensibility of S100B and MIA is high enough to predict the treatment
response, which is not valid for LDH.
LDH is not recommended in routine monitoring of patients with stages I-III
malignant melanoma, because it does not have the ability to detect occult
metastases. On the other hand, it is compulsory to measure LDH in patients with
metastatic melanoma in order to have a correct staging (stage IV M1c). In stage IV,
LDH increase represents the most powerful prognostic determinant of diminished
survival (74).
We believe that the evaluation of these three serum markers in combination
with the established prognostic parameters (Breslow thickness, limphnode status)
might provide a better stratification of patients in new adjuvant therapeutic trials.
For the future, the development of new predictive markers that can monitor
response to therapy in patients who are clinically disease-free would substantially
improve treatment and disease management.
REFERENCES
1.
2.
Ranieri JM, Wagner JD, Wenck S, Johnson CS, Coleman JJ 3rd, The prognostic importance of
sentinel lymph node biopsy in thin melanoma, Ann. Surg. Oncol., 13, 927–932 (2006).
Kalady MF, White RR, Johnson JL, Tyler DS, Seigler HF, Thin Melanomas. Predictive Lethal
Characteristics From a 30-Year Clinical Experience, Ann. Surg., 238, 528–537 (2003).
11
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
S100, MIA, LDH in malignant melanoma
85
Carlson JA, Ross JS, Slominski A, Linette G, Mysliborski J, Hill J, Mihm M Jr., Molecular
diagnostics in melanoma, J. Am. Acad. Dermatol., 52, 743–775 (2005).
Sokoll LJ, Chan DW, Biomarkers for Cancer Diagnostics, in: Abeloff's Clinical Oncology, 4th
ed, Abeloff M, Armitage J, Niederhuber J, Kastan M, McKenna WG, eds, Churchill Livingstone,
Philadelphia, 2008, pp 147–160.
Brochez L, Naeyaert JM, Serological markers for melanoma, Br. J. Dermatol., 143, 256–268
(2000).
http://www.hkacs.org.hk/uploadimages/download/00802/35.Use_of_Tumour_Markers.pdf
(accessed Jan 2011).
Hauschild A, Glaser R, Christophers E, Quantification of melanoma-associated molecules in
plasma/serum of melanoma patients, Recent Results Cancer Res., 158, 169–177 (2001).
Ohsie SJ, Sarantopoulos GP, Cochran AJ, Binder SW, Immunohistochemical characteristics of
melanoma, J. Cutan. Pathol., 35, 433–444 (2008).
Moore BW, A soluble protein characteristic of the nervous system, Biochem. Biophys. Res.
Commun., 19, 739–744 (1965).
Gogas H, Eggermont AM, Hauschild A, Hersey P, Mohr P, Schadendorf D, Spatz A, Dummer
R, Biomarkers in melanoma, Ann. Oncol., 20, 8–13 (2009).
http://en.wikipedia.org/wiki/S–100_protein (accessed Jan 2011).
http://atlasgeneticsoncology.org//Genes/S100BID42195ch21q22.html (accessed Jan 2011).
Rothermundt M, Peters M, Prehn JHM, Arolt V, S100B in Brain Damage and Neurodegeneration,
Microsc. Res. Tech., 60, 614–632 (2003).
Heizmann CW, Ca2+-binding S100 proteins in the central nervous system, Neurochem. Res., 24,
1097–1100 (1999).
Zimmer DB, Cornwall EH, Landar A, Song W, The S100 protein family: history, function, and
expression, Brain Res. Bull., 37, 417–429 (1995).
Heizmann CW, Cox JA, New perspectives on S100 proteins. A multi-functional Ca2+, Zn2+- and
Cu2+-binding protein family, Biometals, 11, 383–397 (1998).
Jäckel A, Deichmann M, Waldmann V, Bock M, Näher H, S–100 beta protein in serum, a tumor
marker in malignant melanoma-current state of knowledge and clinical experience, Der
Hautarzt, 50, 250–256 (1999).
Li Y, Wang J, Sheng JG, Liu L, Barger SW, Jones RA, et al, S100B increases levels of
β-amyloid precursor protein and its encoding mRNA in rat neuronal cultures, J. Neurochem.,
71,1421–1428 (1998).
Jennings L, Murphy GM, Predicting Outcome in Melanoma: Where are we now?, Br. J. Dermatol.,
161, 496–503 (2009).
Cochran AJ, Wen DR, S–100 protein as a marker for melanocytic and other tumours,
Pathology, 17, 340–345 (1985).
Guo HB, Stoffel-Wagner B, Bierwirth T, Mezger J, Klingmüller D, Clinical significance of
serum S100 in metastatic malignant melanoma, Eur. J. Cancer, 31A, 1898–1902 (1995).
Mårtenson ED, Hansson LO, Nilsson B, von Schoultz E, Månsson Brahme E, Ringborg U,
Hansson J, Serum S–100B Protein as a Prognostic Marker in Malignant Cutaneous Melanoma,
J. Clin. Oncol., 19, 824–831 (2001).
Tas F, Yasasever V, Duranyildiz D, Camlica H, Ustuner Z, Aydiner A, Topuz E, Clinical value
of protein S100 and melanoma-inhibitory activity (MIA) in malignant melanoma, Am. J. Clin.
Oncol., 27, 225–228 (2004).
Auge JM, Molina R, Filella X, Bosch E, Gonzalez Cao M, Puig S, et al., S–100beta and MIA in
advanced melanoma in relation to prognostic factors, Anticancer Res., 25, 1779–1782 (2005).
Harpio R, Einarsson R, S100 proteins as cancer biomarkers with focus on S100B in malignant
melanoma, Clin. Biochem., 37, 512–518 (2004).
Hauschild A, Engel G, Brenner W, Gläser R, Mönig H, Henze E, Christophers E, S100B protein
detection in serum is a significant prognostic factor in metastatic melanoma, Oncology, 56, 338–344
(1999).
86
Angela Sandru et al.
12
27. Bolander A, Agnarsdóttir M, Wagenius G, Strömberg S, Pontén F, Ekman S, Brattström D, et
al., Serological and immunohistochemical analysis of S100 and new derivatives as markers for
prognosis in patients with malignant melanoma, Melanoma Res., 18, 412–419 (2008).
28. Smit LH, Korse CM, Hart AA, Bonfrer JM, Haanen JB, Kerst JM, et al, Normal values of serum
S–100B predict prolonged survival for stage IV melanoma patients, Eur. J. Cancer, 41, 386–392
(2005).
29. Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, et al., Evidence
and interdisciplinary consense-based German guidelines: diagnosis and surveillance of
melanoma, Melanoma Res., 17, 393–399 (2007).
30. Jury CS, McAllister EJ, MacKie RM, Rising levels of serum S100 protein precede other
evidence of disease progression in patients with malignant melanoma, Br. J. Dermatol., 143,
269–274 (2000).
31. Kruijff S, Bastiaannet E, Kobold AC, van Ginkel RJ, Suurmeijer AJ, Hoekstra HJ, S–100B
concentrations predict disease-free survival in stage III melanoma patients, Ann. Surg. Oncol.,
16, 3455–3462 (2009).
32. Mocellin S, Zavagno G, Nitti D, The prognostic value of serum S100B in patients with cutaneous
melanoma: a meta-analysis, Int. J. Cancer, 123, 2370–2376 (2008).
33. Curry BJ, Farrelly M, Hersey P, Evaluation of S–100beta assays for the prediction of recurrence
and prognosis in patients with AJCC stage I-III melanoma, Melanoma Res., 9, 557–567 (1999).
34. Egberts F, Momkvist A, Egberts JH, Kaehler KC, Hauschild A, Serum S100B and LDH are not
useful in predicting the sentinel node status in melanoma patients, Anticancer Res., 30, 1799–1805
(2010).
35. Bosserhoff AK, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R, Stolz W, Buettner R,
Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma,
Cancer Res., 57, 3149–3153 (1997).
36. Bogdahn U, Apfel R, Hahn M, Gerlach M, Behl C, Hoppe J, Martin R, Autocrine tumor cell
growth-inhibiting activities from human malignant melanoma, Cancer Res., 49, 5358–5363
(1989).
37. Apfel R, Lottspeich F, Hoppe J, Behl C, Durr G, Bogdahn U, Purification and analysis of growth
regulating proteins secreted by a human melanoma cell line, Melanoma Res., 2, 327–336 (1992).
38. Blesch A, Bosserhoff AK, Apfel R, Behl C, Hessdoerfer B, Schmitt A, et al, Cloning of a novel
malignant melanoma-derived growth regulatory protein, MIA, Cancer Res., 54, 5695–5701
(1994).
39. Bosserhoff AK, Melanoma inhibitory activity (MIA): an important molecule in melanoma
development and progression, Pigment Cell Res., 18, 411–416 (2005).
40. http://www.signaling-gateway.org/molecule/query?afcsid=A003970&type=abstract (accessed Dec 2010).
41. Weilbach FX, Bogdahn U, Poot M, Apfel R, Behl C, Drenkard D, et al., Melanoma-inhibiting
activity inhibits cell proliferation by prolongation of the S-phase and arrest of cells in the G2
compartment, Cancer Res., 50, 6981–6986 (1990).
42. Bosserhoff A, Golob M, Buettner R, Landthaler M, Hein R, MIA. Biological Functiones and
clinical relevance in malignant melanoma, Hautarzt, 49, 762–769 (1998).
43. Lougheed JC, Holton JM, Alber T, Bazan JF, Handel TM, Structure of melanoma inhibitory
activity protein, a member of a recently identified family of secreted proteins, Proc. Natl. Acad.
Sci. USA, 98, 5515–5520 (2001).
44. Bosserhoff AK, Kondo S, Moser M, Dietz UH, Copeland NG, Gilbert DJ, et al., Mouse CDRAP/MIA gene: structure, chromosomal localization, and expression in cartilage and
chondrosarcoma, Dev. Dyn., 208, 516–525 (1997).
45. Bosserhoff AK, Küster H, Hein R., Elevated MIA levels in the serum of pregnant women and of
children, Clin. Exp. Dermatol., 29, 628–629 (2004).
46. McCarthy JB, Basara ML, Palm SL, Sas DF, Furcht LT, The role of cell adhesion proteins –
laminin and fibronectin – in the movement of malignant and metastatic cells, Cancer Metastasis
Rev., 4, 125–152 (1985).
13
S100, MIA, LDH in malignant melanoma
87
47. Zetter BR, Adhesion molecules in tumor metastasis, Semin. Cancer Biol., 4, 219–229 (1993).
48. Stoll R, Renner C, Zweckstetter M, Brüggert M, Ambrosius D, Palme S, et al, The extracellular
human melanoma inhibitory activity (MIA) protein adopts an SH3 domain-like fold, EMBOJ.,
20, 340–349 (2001).
49. Bauer R, Humphries M, Fässler R, Winklmeier A, Craig SE, Bosserhoff AK, Regulation of
integrin activity by MIA, J. Biol. Chem., 281, 11669–11677 (2006).
50. Aung PP, Oue N, Mitani Y, Nakayama H, Yoshida K, Noguchi T, Bosserhoff AK, Yasui W,
Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory
activity and matrix metalloproteinase–10 are novel prognostic factors in patients with gastric
cancer, Oncogene., 25, 2546–2557 (2006).
51. El Fitori J, Kleeff J, Giese NA, Guweidhi A, Bosserhoff AK, Büchler MW, Friess H, Melanoma
Inhibitory Activity (MIA) increases the invasiveness of pancreatic cancer cells, Cancer Cell Int.,
5, (2005).
52. Hau P, Ruemmele P, Kunz-Schughart LA, Doerfelt A, Hirschmann B, Lohmeier A, et al,
Expression levels of melanoma inhibitory activity correlate with time to progression in patients
with high-grade glioma, Oncol. Rep., 12, 1355–1364 (2004).
53. Hau P, Apfel R, Wiese P, Tschertner I, Blesch A, Bogdahn U, Melanoma-inhibiting activity
(MIA/CD-RAP) is expressed in a variety of malignant tumors of mainly neuroectodermal origin,
Anticancer Res., 22, 577–583 (2002).
54. Bosserhoff AK, Buettner R, Expression, function and clinical relevance of MIA, Histol.
Histopathol., 17, 289–300 (2002).
55. Bosserhoff AK, Stoll R, Sleeman JP, Bataille F, Buettner R, Holak TA, Active detachment
involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of
melanoma inhibitory activity, Lab. Invest., 83, 1583–1594 (2003).
56. Bosserhoff AK, Hauschild A, Hein R, Schadendorf D, Stockfleth E, Bogenrieder T, et al.,
Elevated MIA serum levels are of relevance for management of metastasized malignant
melanomas: results of a German multicenter study, J. Invest. Dermatol., 114, 395–396 (2000).
57. Faries MB, Gupta RK, Ye X, Hsueh EC, Morton DL, Melanoma-inhibiting activity assay
predicts survival in patients receiving a therapeutic cancer vaccine after complete resection of
AJCC Stage III Melanoma, Ann. Surg. Oncol., 11, 85–93 (2004).
58. Cao MG, Auge JM, Molina R, Martí R, Carrera C, Castel T, et al., Melanoma inhibiting activity
protein (MIA), beta–2 microglobulin and lactate dehydrogenase (LDH) in metastatic melanoma,
Anticancer Res., 27, 595–599 (2007).
59. Loppin M, Quillien V, Adamski H, Ollivier I, Garlantézec R, Chevrant-Breton J, Protein S100
beta and Melanoma Inhibitory Activity: a prospective study of their clinical value for the early
detection of metastasis in malignant melanoma, Ann. Dermatol. Venereol., 134, 535–540
(2007).
60. Vucetić B, Rogan SA, Hrabac P, Hudorović N, Cupić H, Lukinac L, et al, Biological value of
melanoma inhibitory activity serum concentration in patients with primary skin melanoma.
Melanoma Res., 18, 201–207 (2008).
61. Müller-Ladner U, Bosserhoff AK, Dreher K, Hein R, Neidhart M, Gay S, Schölmerich J,
Buettner R, Lang B, MIA (melanoma inhibitory activity): a potential serum marker for
rheumatoid arthritis, Rheumatology (Oxford), 38, 148–154 (1999).
62. Meral R, Duranyildiz D, Tas F, Camlica H, Yasasever V, Kurul S, Dalay N, Prognostic
significance of melanoma inhibiting activity levels in malignant melanoma, Melanoma Res., 11,
627–632 (2001).
63. Hofmann MA, Gussmann F, Fritsche A, Biesold S, Schicke B, Küchler I, et al., Diagnostic value
of melanoma inhibitory activity serum marker in the follow-up of patients with stage I or II
cutaneous melanoma, Melanoma Res., 19, 17–23 (2009).
64. Klimek VM, Williams L, Chapman PB, Serum levels of melanoma-inhibiting activity do not
predict relapse in melanoma patients, Cytokines Cell. Mol. Ther., 7, 71–74 (2002).
88
Angela Sandru et al.
14
65. Lugović L, Situm M, Buljan M, Poduje S, Sebetić K, Results of the determination of serum
markers in patients with malignant melanoma, Coll. Antropol., 31, 7–11 (2007).
66. Matsushita Y, Hatta N, Wakamatsu K, Takehara K, Ito S, Takata M, Melanoma inhibitory
activity as a serum marker for early detection of post-surgical relapse in melanoma patients:
comparison with 5-S-cysteinyldopa, Melanoma Res., 12, 319–323 (2002).
67. http://www.worthington-biochem.com/LDH/default.html (accessed Jan 2011).
68. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al, Final version of the
American Joint Committee on Cancer staging system for cutaneous melanoma, J. Clin. Oncol.,
19, 3635–3648 (2001).
69. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al, Final version
of 2009 AJCC melanoma staging and classification, J. Clin. Oncol., 27, 6199–6206 (2009).
70. Deichmann M, Benner A, Bock M, Jäckel A, Uhl K, Waldmann V, Näher H, S100-Beta,
melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from
nonprogressive AJCC stage IV melanoma, J. Clin. Oncol., 17, 1891–1896 (1999).
71. Garbe C, Leiter U, Ellwanger U, Blaheta HJ, Meier F, Rassner G, Schittek B, Diagnostic value
and prognostic significance of protein S–100beta, melanoma-inhibitory activity, and
tyrosinase/MART–1 reverse transcription-polymerase chain reaction in the follow-up of highrisk melanoma patients, Cancer, 97, 1737–1745 (2003).
72. Kruijff S, Bastiaannet E, Speijers MJ, Kobold AC, Brouwers AH, Hoekstra HJ, The value of pre
operative S–100B and SUV in clinically stage III melanoma patients undergoing therapeutic
lymph node dissection, Eur. J. Surg. Oncol., 37, 225–232 (2011).
73. Bouwhuis MG, Suciu S, Kruit W, Salès F, Stoitchkov K, Patel P, et al., European Organisation
for Research and Treatment of Cancer Melanoma Group. Prognostic value of serial blood S100B
determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952,
Eur. J. Cancer, 47, 361–368 (2011).
74. Deichmann M, Kahle B, Moser K, Wacker J, Wüst K, Diagnosing melanoma patients entering
American Joint Committee on Cancer stage IV, C-reactive protein in serum is superior to lactate
dehydrogenase, Br. J. Cancer, 91, 699–702 (2004).