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NCI CANCERLIT® Search: Hereditary Melanoma - October 2002
National Cancer Institute®
Last Modified: October 1, 2002
- Association between functional polymorphism in EGF gene and malignant melanoma.
- Effective local control of malignant melanoma by intratumoural injection of a beta-emitting radionuclide.
- Etiology and prevention of melanoma.
- Functional polymorphism in EGF gene and malignant melanoma.
- Characterization of a tyrosine kinase-peptidase A synteny in linkage group XIII of Xiphophorus fishes (Teleostei: Poeciliidae): implications
- In vivo interferon regulatory factor 3 tumor suppressor activity in B16 melanoma tumors.
- Germline mutation of ARF in a melanoma kindred.
- [Eukaryotic vectors of Celo avian adenovirus genome, carrying GFP and human IL-2 genes]
- Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell
- Tumor escape from immune recognition: loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the
- Different requirements for signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 in the
- Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway.
- High frequency of a non-functional TAP1/LMP2 promoter polymorphism in human tumors.
- ATF2 confers radiation resistance to human melanoma cells.
- Type I consensus interferon (CIFN) gene transfer into human melanoma cells up-regulates p53 and enhances cisplatin-induced apoptosis:
- Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1.
- Spitz nevi display allelic deletions.
- The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas.
- Polymerase chain reaction in the staging of solid tumors.
- P gene as an inherited biomarker of human eye color.
- Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human melanomas.
- Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage.
- The melanocyte-specific isoform of the microphthalmia transcription factor affects the phenotype of human melanoma.
- Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor.
- [Cytogenetic and molecular genetic investigation of melanoma]
- Noninvasive dynamic fluorescence imaging of human melanomas reveals that targeted inhibition of bFGF or FGFR-1 in melanoma cells blocks tumor
- Evidence that the elevated levels of proteinase activity in the plasma of melanoma-bearing mice may be of host origin.
- Analysis of losses of heterozygosity of the candidate tumour suppressor gene DMBT1 in melanoma resection specimens.
Table of Contents
1
UI - 11844511
AU - Shahbazi M; Pravica V; Nasreen N; Fakhoury H; Fryer AA; Strange RC;
TI -
Hutchinson PE; Osborne JE; Lear JT; Smith AG; Hutchinson IV
Association between functional polymorphism in EGF gene and malignant
melanoma.
SO - Lancet 2002 Feb 2;359(9304):397-401
AD - Immunology Research Group, School of Biological Sciences, Stopford
Building, University of Manchester, Manchester M13 9PT, UK.
BACKGROUND: Malignant melanoma, the most serious cutaneous malignancy,
has attracted substantial attention because of its rapidly increasing
incidence and the poor prognosis of some tumours. Little is known of the
genetic factors that mediate susceptibility to, and outcome of, sporadic
malignant melanoma. Because of its role in mitogenesis, which is
especially relevant to wound healing, tumorigenesis, and proliferation
of epidermal tissues, epidermal growth factor (EGF) is an attractive
candidate in which to look for genetic polymorphisms. METHODS: We
enrolled 135 white European patients with malignant melanoma and 99
healthy white European controls, and screened a selection of DNA samples
for polymorphisms in the promoter and 5' untranslated region of the EGF
gene by analysis. We then screened DNA samples from all participants for
the identified polymorphism by restriction-fragment-length polymorphism
(RFLP) analysis. In-vitro EGF production was measured in
peripheral-blood mononuclear cells from 34 controls, and the results
were compared with the individuals' EGF genotypes. FINDINGS: We
identified a single nucleotide substitution (G to A) at position 61 of
the EGF gene. Allele frequencies in the controls were 56% EGF 61*A and
44% EGF 61*G. Cells from individuals homozygous for the 61*A allele
produced significantly less EGF than cells from 61*G homozygotes
(p=0.0004) or heterozygous A/G individuals (p=0.001). Compared with the
A/A genotype, G/G was significantly associated with Breslow thickness
(p=0.045) and with risk of malignant melanoma (odds ratio 4.9 [95% CI
2.3-10.2], p<0.0001). INTERPRETATION: This study suggests that high EGF
production might be important in the development of malignant melanoma.
2
UI - 11926384
AU - Lee JD; Yang WI; Lee MG; Ryu YH; Park JH; Shin KH; Kim GE; Suh CO; Seong
TI -
JS; Han BH; Choi CW; Kim EH; Kim KH; Park KB
Effective local control of malignant melanoma by intratumoural injection
of a beta-emitting radionuclide.
SO - Eur J Nucl Med Mol Imaging 2002 Feb;29(2):221-30
AD - Department of Diagnostic Radiology, Yonsei University College of
Medicine, Seoul, Korea.
Intratumoural injection of an unsealed beta-emitting radionuclide is a
new technique for the local control of tumours that has the advantage of
delivering a higher radiation dose to tumour while minimising radiation
hazard to the surrounding normal tissues. In this study, therapeutic
effect, morphological alterations and biological responses to the
high-dose continuous irradiation delivered using this new technique were
evaluated in an animal model with B16 melanoma. For evaluation of the
therapeutic effect, 92 C57BL/6 mice with B16 melanoma were divided into
four groups. In each group, intratumoural injections were performed when
the tumour measured approximately 1 cm along its long axis. Group 1
(n=25) received 0.3 ml of normal saline, group 2 (n=15) 37 MBq of
carrier-free holmium-166 in 0.3 ml saline, group 3 (n=27) 185 MBq of
166Ho in 0.3 ml saline and group 4 (n=25) 185 MBq of 166Ho in 0.5 ml
saline. In addition, another 30 mice were used for morphological and
biological analysis of the radiation effect. These 30 mice were injected
with 185 MBq of 166Ho in 0.3 ml saline, and five were sacrificed at each
of the following six time points: before injection and 1, 2, 3, 6 and 14
days post injection. Haematoxylin-eosin (H&E) staining,
immunohistochemical analysis for p53, p21, PCNA and cyclin D1, terminal
deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end
labelling (TUNEL) staining, reverse transcription-polymerase chain
reaction (RT-PCR) and flow cytometry were performed. For visual
side-by-side comparison, melanoma cells were inoculated bilaterally into
the back of ten additional mice, and 185 MBq of 166Ho in 0.3 ml of
saline or an equal volume of normal saline was injected separately into
the bilateral tumours. Nine days after inoculation of melanoma cells,
mean tumour volume reached 492.5-631.9 mm3. Tumours of the control group
(group 1) showed rapid growth, and the mean tumour volume reached
approximately 30 times the original volume. None of the control group
lived for more than 16 days following the injection of normal saline. On
the other hand, mean tumour volume of the treated groups showed a
gradual decrease, and 67%-74% of the treated animals were alive when all
the control animals had died. The median survival of the control group
was 9 days following injection, whereas it was 29 days in group 2, 33
days in group 3 and 33 days in group 4. The survival rate of group 3 was
higher than that of groups 2 and 4, but statistical significance was not
observed. H&E stain of the tumours demonstrated central necrosis and
peripheral residual cells with progressive cytoplasmic and nuclear
swelling without apoptotic features. Expression of proteins and mRNAs of
p53 and bax increased until 3 days, as compared with 48 h for p21;
thereafter, the expression gradually decreased. TUNEL-positive nuclei
could be seen from 2 days until 2 weeks after treatment. Flow cytometry
did not demonstrate an increase in apoptotic features as compared with
the control animals. In conclusion, intratumoural injection of the
unsealed beta-emitting radionuclide 166Ho appears to be a promising
alternative radiotherapeutic modality for the local control of malignant
melanoma. The main cell death mechanisms with this technique seem to be
radiation-induced central necrosis and peripheral growth arrest or
secondary necrosis of tumour cells, rather than apoptosis.
3
UI - 11962258
AU - Mackie BS; Mackie LE
TI -
Etiology and prevention of melanoma.
SO - Nutr Cancer 2001;40(2):211-3
4
UI - 12241682
AU - Rees J
TI -
Functional polymorphism in EGF gene and malignant melanoma.
SO - Lancet 2002 Aug 17;360(9332):570
5
UI - 7608517
AU - Harless J; Obermoeller RD; Walter RB; Svensson R; Nairn RS; Vielkind JR;
TI -
Kallman KD; Morizot DC
Characterization of a tyrosine kinase-peptidase A synteny in linkage
group XIII of Xiphophorus fishes (Teleostei: Poeciliidae): implications
for vertebrate chromosome evolution.
SO - J Hered 1995 May-Jun;86(3):235-40
AD - University of Texas M.D. Anderson Cancer Center, Science Park-Research
Division, Smithville 78957, USA.
6
UI - 12234977
AU - Duguay D; Mercier F; Stagg J; Martineau D; Bramson J; Servant M; Lin R;
TI -
Galipeau J; Hiscott J
In vivo interferon regulatory factor 3 tumor suppressor activity in B16
melanoma tumors.
SO - Cancer Res 2002 Sep 15;62(18):5148-52
AD - Terry Fox Molecular Oncology Group, Lady Davis Institute-Jewish General
Hospital, 3755 Cote-Ste.-Catherine Road, Montreal, Quebec H3T-1E2,
Canada.
Delivery of transcription factors to cancer cells to reprogram gene
expression may represent a novel strategy to augment the production of
immune stimulatory cytokines and trigger a more potent antitumor
response. In the present study, a bicistronic retroviral vector (AP2)
was used to transduce B16-F0 melanoma cells with IFN regulatory factor
(IRF)-3, which has been shown to activate type I IFN genes (IFN-beta and
IFN-alpha) as well as other cytokines. Gene-modified B16 melanoma cells
were inoculated s.c. into C57BL/6 syngeneic mice. In animals receiving
IRF-3 B16 melanoma cells, tumors grew at a 4- to 5-fold reduced rate,
and tumors that developed from these mice had a moderate-to-dense
infiltration of inflammatory cells, whereas only low levels of
lymphocyte infiltration were observed in mock-transduced B16 tumors.
Furthermore, tumor growth was not inhibited in severe-combined
immunodeficient mice after inoculation of IRF-3-expressing B16 cells,
which suggested that IRF-3-mediated antitumor responses were dependent
on a functional adaptive lymphocyte response. Interestingly, these in
vivo effects on tumor growth correlated with higher mRNA expression of
chemokines such as MIP-1beta, RANTES, and IP-10, as well as dramatic
increases in vitro in the inducibility of cytokine mRNA such as
IFN-beta, TNF-alpha and interleukin 6. Our results demonstrate that with
weakly antigenic tumors such as B16 melanoma, IRF-3 gene transfer can
mediate important antitumor responses. These findings suggest a novel
role for IRF-3 as a potential molecular target for gene therapy of
cancer.
7
UI - 12019208
AU - Hewitt C; Lee Wu C; Evans G; Howell A; Elles RG; Jordan R; Sloan P; Read
TI -
AP; Thakker N
Germline mutation of ARF in a melanoma kindred.
SO - Hum Mol Genet 2002 May 15;11(11):1273-9
AD - University of Manchester Department of Medical Genetics and Regional
Genetic Service, Central Manchester Healthcare Trust, St. Mary's
Hospital, Manchester, M13 OJH, UK.
Familial melanoma predisposition is associated with germline mutations
at the CDKN2A/ARF locus in up to 40% of families. The exact role of the
two proteins encoded by this complex locus in this predisposition is
unclear. Most mutations affect either CDKN2A only or products of both
genes. Recently a deletion affecting ARF-specific exon 1beta was
reported in a family with melanoma and neural tumours. However, the
possibility of this deletion also altering the CDKN2A transcript could
not be excluded. More convincingly, a 16 base pair insertion in exon
1beta has been reported in an individual with multiple melanomas
suggesting a direct role for ARF in melanoma predisposition. We report
here a splice mutation in exon 1beta in a family with melanoma that
results in ARF haploinsufficiency. The mutation was observed in a mother
and daughter with melanoma. A sibling of the mother with breast cancer
also had this mutation. Analysis of the melanoma from one individual
revealed a 62 bp deletion in exon 3 of the wildtype allele and loss of
the mutant allele; these somatic changes would affect both CDKN2A and
ARF. These somatic events suggest that concomitant inactivation of both
ARF and CDKN2A may be necessary for melanoma development and that
mutations in ARF and CDKN2A possibly confer different levels of
susceptibility to melanoma, with the former associated with lesser
predisposition. In this situation, the events follow a 'three-hit' model
as observed in tumours from FAP patients with an attenuated phenotype.
Overall, the data suggest a direct role for ARF haploinsufficiency in
melanoma predisposition and co-operation between ARF and CDKN2A in
tumour formation, consistent with recent observations in Cdkn2a-specific
knockout mice.
8
UI - 12180023
AU - Shmarov MM; Cherenova LV; Shashkova EV; Logunov DIu; Verkhovskaia LV;
TI -
Kapitonov AV; Neugodova GL; Doronin KK; Naroditskii BS
[Eukaryotic vectors of Celo avian adenovirus genome, carrying GFP and
human IL-2 genes]
SO - Mol Gen Mikrobiol Virusol 2002;(2):30-5
AD - All-Russian Institute of Agricultural Biotechnology, Russian Academy of
Agricultural Sciences, Moscow.
Recombinant CELO avian adenoviruses carrying green fluorescent protein
(GFP) and and human interleukin-2 (IL-2) genes were obtained by
homologous recombination in cell culture. The resultant recombinant CELO
viruses are reproduced in chick embryos in the renal tubular and
chorionic allantoic membrane cells. The ability of CELO vectors to
transduce human and animal cells was studied in vitro (in cell cultures)
and in vivo (in laboratory animals). GFP gene delivery and expression in
recombinant CELO virus in tumors in C57BL/6 mice were for the first time
demonstrated for B16 melanoma. Human IL-2 gene expression and protein
accumulation in allantoic fluid of chick embryos infected with CELO-IL-2
vector were detected for the first time.
9
UI - 12208877
AU - Tatsumi T; Kierstead LS; Ranieri E; Gesualdo L; Schena FP; Finke JH;
TI -
Bukowski RM; Mueller-Berghaus J; Kirkwood JM; Kwok WW; Storkus WJ
Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell
responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell
carcinoma or melanoma.
SO - J Exp Med 2002 Sep 2;196(5):619-28
AD - Department of Surgery, University of Pittsburgh School of Medicine,
Pittsburgh, PA 15261, USA.
T helper type 1 (Th1)-type CD4(+) antitumor T cell help appears critical
to the induction and maintenance of antitumor cytotoxic T lymphocyte
(CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4(+) T cell
responses may subvert Th1-type cell-mediated immunity, providing a
microenvironment conducive to disease progression. We have recently
identified helper T cell epitopes derived from the MAGE-6 gene product;
a tumor-associated antigen expressed by most melanomas and renal cell
carcinomas. In this study, we have assessed whether peripheral blood
CD4(+) T cells from human histocompatibility leukocyte antigens
(HLA)-DRbeta1*0401(+) patients are Th1- or Th2-biased to MAGE-6 epitopes
using interferon (IFN)-gamma and interleukin (IL)-5 enzyme-linked
immunospot assays, respectively. Strikingly, the vast majority of
patients with active disease were highly-skewed toward Th2-type
responses against MAGE-6-derived epitopes, regardless of their stage
(stage I versus IV) of disease, but retained Th1-type responses against
Epstein-Barr virus- or influenza-derived epitopes. In marked contrast,
normal donors and cancer patients with no current evidence of disease
tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized
responses to MAGE-6 peptides, respectively. CD4(+) T cell secretion of
IL-10 and transforming growth factor (TGF)-beta1 against MAGE-6 peptides
was not observed, suggesting that specific Th3/Tr-type CD4(+) subsets
were not common events in these patients. Our data suggest that
immunotherapeutic approaches will likely have to overcome or complement
systemic Th2-dominated, tumor-reactive CD4(+) T cell responses to
provide optimal clinical benefit.
10
UI - 9816214
AU - Maeurer MJ; Gollin SM; Storkus WJ; Swaney W; Karbach J; Martin D;
TI -
Castelli C; Salter R; Knuth A; Lotze MT
Tumor escape from immune recognition: loss of HLA-A2 melanoma cell
surface expression is associated with a complex rearrangement of the
short arm of chromosome 6.
SO - Clin Cancer Res 1996 Apr;2(4):641-52
AD - Departments of Surgery, Biochemistry, University of Pittsburgh Schools
of Medicine and Public Health, University of Pittsburgh Cancer
Institute, Pittsburgh, Pennsylvania 15261, USA.
Specific CD8(+) CTL recognition of melanoma requires expression of MHC
class I molecules as well as melanoma-associated peptide epitopes. Human
melanoma cells may escape immune recognition by a variety of means,
including global or allelic down-regulation of MHC class I molecules.
Stable MHC class I cell surface expression requires delivery of
cytosolic peptides into the endoplasmic reticulum by the peptide
transporter molecules TAP1 and TAP2, with peptides subsequently
transported to the cell surface in complexes containing MHC class I
heavy chain and beta2-microglobulin. We have evaluated a series of
mechanisms resulting in MHC class I down-regulation in a human melanoma
cell line, Mz18, typed as HLA-A2(+), A3(+), B7(+), B57(+), Cw1(+), and
Cw6(+) by genomic PCR analysis. The melanoma cell line Mz18 exhibits a
global down-regulation of MHC class I heavy chain transcripts;
beta2-microglobulin; the proteasome subunits LMP2/7, involved in
generating cytosolic peptide fragments; and the peptide transporter
molecules TAP1 and TAP2, involved in peptide transport from the cytosol
into the endoplasmic reticulum. IFN-gamma treatment of Mz18 melanoma
cells leads to up-regulation of LMP2/7 and TAP1/2, as well as to
up-regulation of HLA-B and HLA-C MHC loci alleles, but not HLA-A2 or
HLA-A3. Karyotypic analysis and fluorescence in situ hybridization with
chromosome 6 and MHC class I-specific probes showed complex
rearrangement of one chromosome 6 involving the MHC class I locus on 6p
and translocation of 6q to the long arm of chromosome 19. To evaluate
the capability of melanoma Mz18 to present tumor-specific peptides to
HLA-A2-restricted, melanoma-specific CTLs, we restored HLA-A2 surface
expression by retroviral-mediated transfer of functional HLA-A2 cDNA.
Melanoma peptides could only be presented and recognized by CTLs if the
HLA-A2-transfected Mz18 cell line was first treated with IFN-gamma,
thereby restoring LMP2/7 and TAP1/2 expression and function. Because
several melanoma antigens recognized by T cells have been reported to be
presented by HLA-A2 (MART-1/Melan-A, tyrosinase, gp100, and MAGE-3), the
loss of HLA-A2 molecules may represent an important mechanism by which
many melanomas evade immune recognition. These findings suggest that
patients entering clinical trials for immunotherapy with melanoma
vaccines should be carefully examined for tumor cell allelic MHC class I
loss and whether such MHC class I antigen down-regulation can be
restored by cytokines.
11
UI - 9632673
AU - Chatterjee-Kishore M; Kishore R; Hicklin DJ; Marincola FM; Ferrone S
TI -
Different requirements for signal transducer and activator of
transcription 1alpha and interferon regulatory factor 1 in the
regulation of low molecular mass polypeptide 2 and transporter
associated with antigen processing 1 gene expression.
SO - J Biol Chem 1998 Jun 26;273(26):16177-83
AD - Department of Microbiology and Immunology, New York Medical College,
Valhalla, New York 10595, USA.
The components of the antigen processing machinery, low molecular mass
polypeptide (LMP) 2 and transporter associated with antigen processing
(TAP) 1, are encoded by closely linked genes within the major
histocompatibility complex class II subregion. Although the two genes
share a bi-directional promoter, LMP2 and TAP1 have differential
cellular expression. TAP1 is expressed constitutively. However, LMP2
expression requires induction by interferon-gamma in most cells. The
regulatory elements within the LMP2/TAP1 promoter and the transcription
factors that bind these elements have been defined. However, how these
transactivators regulate differential TAP1 and LMP2 gene transcription
is not known. We have addressed this question by analyzing three human
melanoma cell lines with distinct phenotypes of LMP2 and TAP1
expression. Whereas binding of either interferon regulatory factor 1 or
Stat1 to the overlapping interferon consensus sequence-2/GAS is
sufficient for regulating transcription of the TAP1 gene, binding of
both factors is required for LMP2 gene transcription. This conclusion is
supported by restoration of LMP2 gene transcription following
transfection of wild type Stat1alpha or interferon regulatory factor 1
cDNA into cells lacking these transcription factors. The flexibility in
the regulation of the TAP1 gene may reflect its role in maintaining
immune surveillance. Furthermore, lack of LMP2 gene transcription in
quiescent human cells suggests that LMP2 expression reflects a state of
cell activation.
12
UI - 11751378
AU - Seliger B; Ritz U; Abele R; Bock M; Tampe R; Sutter G; Drexler I; Huber
TI -
C; Ferrone S
Immune escape of melanoma: first evidence of structural alterations in
two distinct components of the MHC class I antigen processing pathway.
SO - Cancer Res 2001 Dec 15;61(24):8647-50
AD - Johannes Gutenberg-University, Third Department of Internal Medicine,
55101 Mainz, Germany. B.Seliger@3-med.klinik.uni-mainz.de
Sequence analyses of the transporter associated with antigen processing
(TAP) in tumor cell lines with deficient MHC class I surface expression
identified a bp deletion at position 1489 near the ATP-binding domain of
Tap1, causing a frameshift in one melanoma cell line. The impaired TAP1
protein expression was associated with deficient TAP2 protein
expression, peptide binding, translocation, and MHC class I surface
expression. Stable TAP1 gene transfer reconstitutes the described
defects, whereas lysis by HLA-A2-restricted CTLs was still abrogated.
This was attributable to a 2-bp insertion at position 890 in the HLA-A2
gene and was corrected after HLA-A2 cotransfection. This study describes
for the first time mutations in two distinct components of the MHC class
I antigen processing pathway, suggesting an immune selection against
CTLs recognizing both TAP-dependent and -independent T-cell epitopes.
13
UI - 11788900
AU - Seliger B; Bock M; Ritz U; Huber C
TI -
High frequency of a non-functional TAP1/LMP2 promoter polymorphism in
human tumors.
SO - Int J Oncol 2002 Feb;20(2):349-53
AD - Johannes Gutenberg University, Third Department of Internal Medicine,
D-55101 Mainz, Germany. b.seliger@3-med.klinik.uni-mainz.de
The Tap1 and Tap2 genes encoding for a heterodimeric peptide transporter
play a key role in antigen processing and presentation. The TAP complex
mediates the transport of peptides generated by the IFN-gamma-inducible
proteasome subunits LMP2, 7 and 10 from the cytosol into the endoplasmic
reticulum (ER), where they bind to MHC class I molecules. In contrast to
the frequent polymorphisms within the rat Tap genes which exert
functional differences, polymorphic regions within the human Tap genes
have been demonstrated, but not systematically analyzed in terms of
their functional significance. Both the Tap1 and Lmp2 genes are
transcribed from a bidirectional intergenic promoter which is regulated
by at least three sequences located in the Tap1 proximal region. We
describe here a polymorphic site in the shared TAP1/LMP2 promoter which
frequently occurred in human tumor cells of distinct origin. This
polymorphism resulted in a Gright curved arrow T substitution 151 bp
upstream of the translation start of Tap1. Using transient transfection
assays with luciferase reporter constructs, the transcriptional
activities of the different allelic variants of the TAP1/LMP2 promoter
were comparable suggesting no functional consequences of this TAP1/LMP2
promoter polymorphism.
14
UI - 9484842
AU - Ronai Z; Yang YM; Fuchs SY; Adler V; Sardana M; Herlyn M
TI -
ATF2 confers radiation resistance to human melanoma cells.
SO - Oncogene 1998 Jan 29;16(4):523-31
AD - The Ruttenberg Cancer Center, Mount Sinai Medical School, New York, NY
10029-6574, USA.
We have previously identified a U.V.-response element (URE; TGACAACA)
and its bound proteins, members of the AP1 and ATF transcription factor
families, in melanoma cells. Using a mutant form of cylic AMP response
element binding (CREB), we found that CREB-associated-URE-bound proteins
conferred characteristic melanoma phenotypes, including radiation
resistance (Oncogene 12: 2223, 1996). In the present study we sought to
determine which of the CREB-associated proteins confers radiation
resistance on human melanoma cells. To this end we purified and
identified via microsequencing ATF2 as a major URE- bound and
CREB-associated protein in MeWo cells--a late stage human melanoma cell
line. To determine the contribution of ATF2 to radiation resistance,
MeWo cells were transfected with ATF2 cDNA lacking the trans-activation
domain (ATF2(delta1-195)). MeWo cells that stably express
ATF2(delta1-195) showed weaker transcriptional activities and an altered
pattern of homo/hetero dimers. ATF2(delta1-195) clones exhibited up to
tenfold lower resistance to irradiation by either U.V. or X-rays. The
degree of resistance to radiation in the ATF2(delta1-195)-expressing
clones could be increased upon transient transfection with ATF2(wt), but
not with phosphorylation-defective mutant ATF2(69,71). Similarly,
transfection of ATF2(wt) to WM3211, an early stage human melanoma cells
line, increased resistance to radiation. Finally, changes elicited
through ATF2(delta1-195) also led to reduced drug resistance, as shown
for MMC, araC and cisplatinum. Our results suggest that ATF2 is a
regulator of radiation and drug resistance in melanomas, and that tumor
targeted ATF2 modulators may be useful sensitizers in the treatment of
tumors of this type.
15
UI - 10673721
AU - Mecchia M; Matarrese P; Malorni W; D'Agostino G; Sestili P; Santini SM;
TI -
Gauzzi MC; Venditti M; Mazzocchi A; Parmiani G; Belardelli F; Ferrantini
M
Type I consensus interferon (CIFN) gene transfer into human melanoma
cells up-regulates p53 and enhances cisplatin-induced apoptosis:
implications for new therapeutic strategies with IFN-alpha.
SO - Gene Ther 2000 Jan;7(2):167-79
AD - Laboratory of Virology, Istituto Superiore di Sanita, Rome, Italy.
In this study, we describe the effects produced by the retroviral
transduction of human type I consensus IFN (CIFN) coding sequence into
the 8863 and 1B6 human melanoma cell lines, derived from a metastatic
and a primary human melanoma, respectively. Melanoma cell lines
producing approximately 103 IU/ml of IFN were obtained. Interestingly,
cisplatin treatment of IFN-producing 8863 and 1B6 melanoma cells
resulted in a three- to four-fold increase in the percentage of
apoptotic cells with respect to similarly treated parental or
control-transduced cell cultures. A similar effect, although less
intense, was caused by cultivation of parental melanoma cells in the
presence of exogenous CIFN. The increased susceptibility of the
IFN-producing melanoma cell lines to cisplatin-induced apoptosis was
associated with an IFN-dependent accumulation of p53, which also
correlated with a decrease in Bcl-2 expression. Addition of exogenous
CIFN to parental melanoma cells resulted in similar although weaker
modulations of p53 and Bcl-2 expression. Cisplatin administration to
nude mice bearing 3-day-old IFN-producing 8863 tumors resulted in
complete tumor regression, while only a partial tumor inhibition was
observed upon cisplatin treatment of mice bearing parental or
control-transduced 8863 tumors. Starting the cisplatin treatment 7 days
after tumor cell injection still resulted in a stronger inhibition of
tumor growth in the mice bearing IFN-producing 8863 tumors as compared
with parental tumor-bearing mice. A comparable therapeutic effect was
obtained after repeated peritumoral administration of 103 IU of
exogenous CIFN and cisplatin treatment. Interestingly, a spontaneous
tumor regression was observed in nude mice injected with IFN-producing
1B6 cells, in contrast to the progressive tumor growth occurring in mice
receiving a similar inoculum of the parental or control-transduced 1B6
melanoma cells. Repeated peritumoral administration of 103 IU of
exogenous CIFN to mice bearing parental 1B6 tumors caused only a
transient inhibition of tumor growth. These results indicate that type I
IFN gene transfer is an effective approach for suppressing the
tumorigenic phenotype of human melanoma cells and for increasing the
efficacy of anticancer drugs. These observations, together with our
previous findings showing the importance of IFN-alpha-T cell
interactions in the generation of an antitumor response in mouse models,
underline the interest of using type I IFN in gene therapy strategies
for the treatment of human melanoma.
16
UI - 11850817
AU - Recio JA; Merlino G
TI -
Hepatocyte growth factor/scatter factor activates proliferation in
melanoma cells through p38 MAPK, ATF-2 and cyclin D1.
SO - Oncogene 2002 Feb 7;21(7):1000-8
AD - Laboratory of Molecular Biology, National Cancer Institute, National
Institutes of Health, Bethesda, MD 20892-4264, USA.
Members of the mitogen-activated protein kinase (MAPK) superfamily,
including p38 kinase and SAPK/JNK, play a central role in mediating
cellular response to environmental stress, growth factors and cytokines.
Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional
cytokine capable of eliciting mitogenic, motogenic and morphogenetic
activities in responsive cells, and has been implicated in tumor
development and metastasis. Binding of HGF/SF to its tyrosine kinase
receptor c-Met stimulates multiple signal transduction pathways, leading
to the activation of numerous transcription factors. We here report that
HGF/SF can induce cyclin D1 expression in mouse melanoma cells, and that
this up-regulation is mediated in part by the activating transcription
factor-2 (ATF-2). HGF/SF-mediated phosphorylation of ATF-2 was reduced
in the presence of either the p38 kinase-specific inhibitor SB203580, a
dominant negative p38 mutant, the SAPK/JNK inhibitor JNK-interacting
protein-1 (JIP-1), or the phosphatidylinositol 3-kinase (PI3K)-specific
inhibitor LY294002. Activation of p38 kinase by HGF/SF was partially
blocked by the PI3K-specific inhibitor as well. The upstream kinases for
p38, MKK3/6, did not become activated following HGF/SF exposure, and
ATF-2 activation was undiminished by transient transfection of a
dominant negative MKK6 mutant. However, transcriptional up-regulation of
cyclin D1 by HGF/SF was partially inhibited by the p38 kinase-specific
inhibitor, and cyclin D1 protein induction was partially blocked by a
dominant negative ATF-2 mutant. Notably, the p38 kinase-specific
inhibitor was able to block melanoma cell proliferation but not
motility. We conclude that the ATF-2 transcription factor becomes
activated by HGF/SF through p38 MAPK and SAPK/JNK. Moreover, the
p38-ATF-2 pathway can help mediate proliferation signals in tumor cells
through transcriptional activation of key cell cycle regulators.
17
UI - 11708943
AU - Bogdan I; Burg G; Boni R
TI -
Spitz nevi display allelic deletions.
SO - Arch Dermatol 2001 Nov;137(11):1417-20
AD - Department of Dermatology, University Hospital Zurich, Gloriastr 31,
8091 Zurich, Switzerland.
BACKGROUND: Spitz nevi are acquired benign melanocytic lesions that
occur in childhood and adolescence. Histologically, they resemble
malignant melanoma and were first termed benign juvenile melanoma.
Several studies have attempted the difficult task of establishing
diagnostic criteria to differentiate between Spitz nevi and malignant
melanoma. OBJECTIVE: To elucidate sets of diagnostic criteria for
differentiation between the 2 lesions. DESIGN: We aimed to search for
allelic deletions in Spitz nevi and to evaluate whether loss of
heterozygosity (LOH) or microsatellite instability (MSI) would be a
valuable diagnostic tool to differentiate between Spitz nevi and
malignant melanoma. SETTING: Two areas within each of 5 lesions were
microdissected, and LOH and MSI were evaluated at chromosomes 6q (using
polymorphic DNA marker D6S305), 9p21 (D9S171, IFNA, D9S265, and D9S270),
10q (D10S185), and 14q (D14S53). PATIENTS: Five Swiss patients with
Spitz nevi. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Allelic deletions
may serve as a diagnostic tool to distinguish Spitz nevi from melanoma.
RESULTS: All lesions were informative, displaying LOH or MSI with at
least one marker. No LOHs were found at 14q. At 6q, MSI was found in 2
dissected areas from the same lesion; the remaining lesions were
noninformative. Loss of heterozygosity was found in 2 of 6 areas at
D9S171, 2 of 6 at IFNA, 3 of 6 at D9S270, 3 of 4 at D9S265, and 1 of 4
at D10S185. Microsatellite instability was found in 1 of 4 areas at
D9S265. CONCLUSIONS: With the markers used in our study, Spitz nevi
display LOH and MSI similar to those in melanoma. Analysis of LOH or MSI
is therefore not a suitable diagnostic tool in distinguishing Spitz nevi
from melanoma.
18
UI - 11507043
AU - Polsky D; Young AZ; Busam KJ; Alani RM
TI -
The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in
early melanomas.
SO - Cancer Res 2001 Aug 15;61(16):6008-11
AD - Oncology Center, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21231-1000, USA.
The helix-loop-helix transcription factor Id1 coordinates cell growth
and differentiation pathways within mammalian cells and has been
implicated in regulating G(1)-S phase cell cycle transitions. Recently
Id1 has been shown to repress Ets- and E-protein-mediated
transactivation of p16/Ink4a. Because the p16/Ink4a protein has been
demonstrated to be inactivated in subsets of familial and sporadic
melanomas, we sought to determine whether Id1 regulation of p16/Ink4a
expression might be involved in the development of this human tumor.
Here we evaluate 21 melanocytic lesions at various stages of malignant
progression from common melanocytic nevi to metastatic melanomas and
examine these lesions for Id1 and p16/Ink4a expression. We demonstrate
that Id1 expression correlates with loss of p16/Ink4a expression in
melanoma in situ; however, more advanced stages of melanoma do not
express Id1 except within perivascular regions, despite overall
decreased p16/Ink4a expression in these lesions. Microdissected lesions
were evaluated for p16/Ink4a sequence, and invasive melanomas that did
not express Id1 were found to have sustained inactivating p16/ink4a
mutations. These data suggest a role for Id1 in regulating p16/Ink4a
expression in early melanomas and demonstrate that later genetic changes
may provide for irreversible loss of p16 expression in advanced stages
of this tumor.
19
UI - 11999947
AU - Davis EG; Chao C; McMasters KM
TI -
Polymerase chain reaction in the staging of solid tumors.
SO - Cancer J 2002 Mar-Apr;8(2):135-43
AD - Division of Surgical Oncology, University of Louisville, James Graham
Brown Cancer Center, Kentucky 40202, USA.
Polymerasechain reaction (PCR) is a molecular biology technique that
holds great promise as a way to perform molecular staging of cancer by
detecting very early metastatic disease. Significant data suggest that
PCR analysis may play an important role in the management of colorectal
cancer in the future. However, for PCR staging of breast cancer,
progress awaits identification of gene markers that have sufficient
sensitivity and specificity. Within the next few years, the results of
the Sunbelt Melanoma Trial and other ongoing studies will determine
whether PCR evaluation of sentinel lymph nodes and peripheral blood
cells has prognostic relevance in melanoma. The future of cancer
management will likely revolve around the molecular staging of tumors,
and PCR is but one method that may better define subgroups of patients
that are appropriate candidates forvarious anticancer therapies.
20
UI - 12163334
AU - Rebbeck TR; Kanetsky PA; Walker AH; Holmes R; Halpern AC; Schuchter LM;
TI -
Elder DE; Guerry D
P gene as an inherited biomarker of human eye color.
SO - Cancer Epidemiol Biomarkers Prev 2002 Aug;11(8):782-4
AD - Department of Biostatistics and Epidemiology, University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania 19104, USA.
trebbeck@cceb.med.upenn.edu
Human pigmentation, including eye color, has been associated with skin
cancer risk. The P gene is the human homologue to the mouse pink-eye
dilution locus and is responsible for oculocutaneous albinism type 2 and
other phenotypes that confer eye hypopigmentation. The P gene is located
on chromosome 15q11.2-q12, which is also the location of a putative eye
pigmentation gene (EYCL3) inferred to exist by linkage analysis.
Therefore, the P gene is a strong candidate for determination of human
eye color. Using a sample of 629 normally pigmented individuals, we
found that individuals were less likely to have blue or gray eyes if
they had P gene variants Arg305Trp (P = 0.002), Arg419Gln (P = 0.001),
or the combination of both variants (P = 0.003). These results suggest
that P gene, in part, determines normal phenotypic variation in human
eye color and may therefore represent an inherited biomarker of
cutaneous cancer risk.
21
UI - 10644012
AU - Vachtenheim J; Novotna H
TI -
Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human
melanomas.
SO - Cell Mol Biol (Noisy-le-grand) 1999 Nov;45(7):1075-82
AD - Laboratory of Molecular Biology, University Hospital, 3rd Medical
Faculty, Charles University, Prague 8-Bulovka, Czech Republic.
jivach@upn.anet.cz
Microphthalmia (MITF) gene product, a transcription factor of the
basic-helix-loop-helix type, is thought to play a role in the regulation
of genes encoding the enzymes necessary for melanogenesis. These include
tyrosinase, TRP-1 and TRP-2. Melanocyte-specific isoform of
microphthalmia, MITF-M, is expressed in normal and malignant
melanocytes. The presence of two other isoforms of microphthalmia,
MITF-A and MITF-H, which differ from MITF-M in the amino-terminus, was
demonstrated also in some non-melanocytic lineages. Here we have
analyzed the presence of all three known isoforms of MITF mRNA in a
panel of 17 human melanoma cell lines by a reverse
transcriptase-polymerase chain reaction using isoform-specific primers.
While, as expected, the predominant form in melanoma cell lines was
MITF-M, low amounts of MITF-A mRNA was found in almost all melanomas, as
well as in most of 20 tumor cell lines of the non-melanocyte origin
(lung and colon carcinomas, osteosarcomas and neuroblastomas). The
expression of MITF-H was not detected, with a few exceptions, in the
tested cell lines. Pax3 transcription factor was reported earlier to
regulate positively the melanocyte-specific promoter of the MITF gene.
We found here that the Pax 3 mRNA was expressed in all melanoma cell
lines, even in those that had repressed the MITF-M and were amelanotic.
This suggests that additional factors, besides Pax3, are required for
the MITF expression. The MSG1 (melanocyte-specific gene 1), a gene
originally isolated from melanocytes and containing a strong
transcription activation domain, was also found expressed in all
melanomas and most non-melanocyte tumor cell lines. Together, these data
indicate that the MITF-M isoform is the major type of MITF mRNA present
in human melanoma cell lines and show that the expression of the isoform
MITF-A and the MSG1 is not restricted to malignant melanocytes and
occurs in a wide range of tumor cell lines.
22
UI - 10898786
AU - Goding CR
TI -
Mitf from neural crest to melanoma: signal transduction and
transcription in the melanocyte lineage.
SO - Genes Dev 2000 Jul 15;14(14):1712-28
AD - Eukaryotic Transcription Laboratory, Marie Curie Research Institute, The
Chart, Oxted Surrey, RH8 OTL, UK. c.goding@mcri.ac.uk
23
UI - 11929831
AU - Selzer E; Wacheck V; Lucas T; Heere-Ress E; Wu M; Weilbaecher KN;
TI -
Schlegel W; Valent P; Wrba F; Pehamberger H; Fisher D; Jansen B
The melanocyte-specific isoform of the microphthalmia transcription
factor affects the phenotype of human melanoma.
SO - Cancer Res 2002 Apr 1;62(7):2098-103
AD - Department of Radiotherapy and Radiobiology, University Hospital Vienna,
1090 Vienna, Austria. Edgar.Selzer@AKH-Wien.ac.at
The microphthalmia transcription factor MITF plays a pivotal role in the
development and differentiation of melanocytes. The purpose of this work
was to investigate the expression and function of the
melanocyte-specific isoform MITF-M in human melanoma. We found that
MITF-M is repressed in 8 of 14 established melanoma cell lines tested.
Transfection of MITF-M into a melanoma cell line (518A2) lacking the
M-isoform and into a permanent cell line established from normal
melanocytes (NMel-II) resulted in slower tumor growth in a severe
combined immunodeficient-mouse xenotransplantation model. The growth
difference between vector control-transfected tumors derived from the
NMel-II cell line (mean tumor weight +/- SD, 3.2 g +/- 1.13) and MITF-M
(+) transfectants (mean tumor weight +/- SD, 1.1 g +/- 0.49) was
significant (P = 0.018). The mean tumor weight of control-transfected
518A2 tumors was 0.99 g +/- 0.22 and of MITF-M (+) transfectants, 0.69 g
+/- 0.32. The difference in growth between 518A2 controls and the MITF-M
(+) transfectants was clear, however it did not reach statistical
significance (P = 0.08). In addition to the growth-inhibitory effects,
MITF-M expression led to a change in the histopathological appearance of
tumors from epitheloid toward a spindle-cell type in vivo. These results
indicate a role for the MITF-M isoform in the in vivo growth control and
the phenotype of human melanoma. In conclusion, MITF-M may qualify as a
marker capable of identifying subgroups of melanoma patients with
different tumor biology and prognosis.
24
UI - 12235125
AU - Widlund HR; Horstmann MA; Price ER; Cui J; Lessnick SL; Wu M; He X;
TI -
Fisher DE
Beta-catenin-induced melanoma growth requires the downstream target
Microphthalmia-associated transcription factor.
SO - J Cell Biol 2002 Sep 16;158(6):1079-87
AD - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Dana
630, 44 Binney Street, Boston, MA 02115, USA.
The transcription factor Microphthalmia-associated transcription factor
(MITF) is a lineage-determination factor, which modulates melanocyte
differentiation and pigmentation. MITF was recently shown to reside
downstream of the canonical Wnt pathway during melanocyte
differentiation from pluripotent neural crest cells in zebrafish as well
as in mammalian melanocyte lineage cells. Although expression of many
melanocytic/pigmentation markers is lost in human melanoma, MITF
expression remains intact, even in unpigmented tumors, suggesting a role
for MITF beyond its role in differentiation. A significant fraction of
primary human melanomas exhibit deregulation (via aberrant nuclear
accumulation) of beta-catenin, leading us to examine its role in
melanoma growth and survival. Here, we show that beta-catenin is a
potent mediator of growth for melanoma cells in a manner dependent on
its downstream target MITF. Moreover, suppression of melanoma clonogenic
growth by disruption of beta-catenin-T-cell transcription factor/LEF is
rescued by constitutive MITF. This rescue occurs largely through a
prosurvival mechanism. Thus, beta-catenin regulation of MITF expression
represents a tissue-restricted pathway that significantly influences the
growth and survival behavior of this notoriously treatment-resistant
neoplasm.
25
UI - 12227065
AU - Monakhov AS; Aksenov AV; Kniazev PG; Anisimov VV; Barchuk AS
TI -
[Cytogenetic and molecular genetic investigation of melanoma]
SO - Vopr Onkol 2002;48(2):179-85
26
UI - 12080186
AU - Valesky M; Spang AJ; Fisher GW; Farkas DL; Becker D
TI -
Noninvasive dynamic fluorescence imaging of human melanomas reveals that
targeted inhibition of bFGF or FGFR-1 in melanoma cells blocks tumor
growth by apoptosis.
SO - Mol Med 2002 Feb;8(2):103-12
AD - Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213,
USA.
BACKGROUND: Two prominent biological features of the advanced stages of
human melanoma are their high degree of vascularity and high-level
expression of basic fibroblast growth factor (bFGF) and fibroblast
growth factor receptor-1 (FGFR-1). Given these characteristics, human
melanoma serves as an ideal model to address an important question
regarding the efficacy of angiogenesis-based cancer therapy. To induce
tumor growth arrest and regression, does it suffice to block expression
of bFGF and/or FGFR-1 in only the melanoma cells, or is it essential to
inhibit expression of bFGF and/or FGFR-1 in both the melanoma cells and
the melanoma cell-interspersing vasculature? MATERIALS AND METHODS:
Primary and metastatic human melanomas, grown as subcutaneous tumors in
nude mice, were injected twice a week with vector constructs containing
the human tyrosinase promoter and antisense- oriented human bFGF or
FGFR-1 cDNA. On alternating days, the bFGF and FGFR-1 antisense-targeted
tumors received injections of cyanine fluorochrome-conjugated antibodies
to a human melanoma and mouse blood vessel marker. Noninvasive, dynamic
fluorescence imaging was used to document the cellular events that took
place inside the tumors as the result of blocking expression of bFGF or
FGFR-1 in the melanoma cells. RESULTS: In vivo, ex vivo, and in vitro
fluorescence imaging of the bFGF and FGFR-1 antisense-targeted tumors
demonstrated that inhibiting bFGF and FGFR-1 signaling in only the
melanoma cells suffices to inhibit tumor growth due to massive induction
of melanoma cell apoptosis. CONCLUSIONS: The investigations presented in
this study document that inhibiting expression of bFGF or FGFR-1 in only
the melanoma cells is as effective in blocking tumor growth as
simultaneously inhibiting bFGF or FGFR-1 synthesis in the melanoma cells
and the melanoma cell-interspersing vasculature. Furthermore, blocking
expression of bFGF or FGFR-1 in the melanoma cells did not lead to
activation or increased production of another angiogenic molecule,
suggesting the absence of a "salvage pathway" that can circumvent or
rescue the blockage of bFGF/FGFR-1 in the melanoma cells.
27
UI - 3516806
AU - Hart DA
TI -
Evidence that the elevated levels of proteinase activity in the plasma
of melanoma-bearing mice may be of host origin.
SO - Haemostasis 1986;16(1):34-42
C57B1/6 mice bearing the B16-F1 melanoma, an invasive variant (BL6) or a
highly 'metastatic' variant (B16-F10) were found to develop elevated
levels (200-300% of control) of neutral proteinase activity in their
plasma during the progression of the disease. The magnitude of the level
of proteinase activity detected was not dependent on tumor burden.
Similar elevations in activity were detected with all 3 variants when
they were transplanted either subcutaneously or intraperitoneally.
However, transplantation of the B16-F10 line to the anterior chamber of
the eye did not induce elevated plasma proteinase activity. Animals
bearing intraocular tumors developed splenomegaly and lived the same
length of time as animals bearing intraperitoneal or subcutaneous
tumors. The development of increased levels of activity appeared to
occur equally in male and female mice and was not dependent on the
presence of a spleen, which undergoes enlargement during the disease
process. These various lines of evidence support the hypothesis that the
elevated level of plasma proteinase activity observed in
melanoma-bearing mice is regulated by the host.
28
UI - 12239452
AU - Deichmann M; Mollenhauer J; Helmke B; Thome M; Hartschuh W; Poustka A;
TI -
Naher H
Analysis of losses of heterozygosity of the candidate tumour suppressor
gene DMBT1 in melanoma resection specimens.
SO - Oncology 2002;63(2):166-72
AD - Department of Dermatology, University Hospital Heidelberg, Heidelberg,
Germany. martin_deichmann@med.uni-heidelberg.de
Deleted in malignant brain tumours 1 (DMBT1), a candidate tumour
suppressor gene located on chromosome 10q25.3-q26.1, has recently been
identified and found to be deleted in several different types of human
tumours. In melanomas, the chromosomal region 10q22-qter is commonly
affected by losses, hence we screened primary melanoma samples for
losses of heterozygosity (LOH), and acquired melanocytic naevi and
melanomas for transcription of DMBT1 and protein expression. Of 38
informative melanomas, 1 nodular melanoma and 2 subcutaneous metastases
showed LOH of both microsatellites flanking the gene, suggesting loss of
1 DMBT1 allele. Three further melanomas showed LOH at 1 informative
locus but were heterozygous for the second marker. Applying
reverse-transcription polymerase chain reaction (RT-PCR), DMBT1
transcription was not found in melanomas. However, DMBT1 transcription
was also absent from the majority of naevi from which melanomas
frequently arise, making down-regulation of gene transcription during
transformation from naevus to melanoma unlikely. Immunohistochemistry
showed nerves, sweat glands and the stratum spinosum of the epidermis to
be DMBT1 protein positive, whereas the naevi and melanoma cells
themselves were negative. All considered, the candidate tumour
suppressor gene DMBT1 does not appear to be a major inactivation target
in the development of melanomas. Copyright 2002 S. Karger AG, Basel
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