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NCI CANCERLIT® Search: Hereditary Melanoma - September 2002
National Cancer Institute®
Last Modified: September 1, 2002
- Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell lines.
- A melanoma-predisposing germline CDKN2A mutation with functional significance for both p16 and p14ARF.
- DNA mismatch repair enzyme hMSH2 in malignant melanoma: increased immunoreactivity as compared to acquired melanocytic nevi and strong
- DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.
- P gene as an inherited biomarker of human eye color.
- [Gene expression profiles in the diagnosis and prognosis of cancer]
- Bcl-2 overexpression in human melanoma cells increases angiogenesis through VEGF mRNA stabilization and HIF-1-mediated transcriptional
- The genes and genetics of malignant melanoma.
- Mutational analysis of selected genes in the TGFbeta, Wnt, pRb, and p53 pathways in primary uveal melanoma.
- Presence of the human leukocyte antigen class II gene DRB1*1101 predicts interferon gamma levels and disease recurrence in melanoma patients.
- Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines.
- Lack of TTC4 mutations in melanoma.
- Expression of the 90K tumor-associated protein in benign and malignant melanocytic lesions.
- Elevated constitutive IkappaB kinase activity and IkappaB-alpha phosphorylation in Hs294T melanoma cells lead to increased basal
- Activation of nuclear factor-kappa B in human metastatic melanomacells and the effect of oxidative stress.
- Regulation of expression of the multidrug resistance protein MRP1 by p53 in human prostate cancer cells.
- Level of interleukin-8 expression by metastatic human melanoma cells directly correlates with constitutive NF-kappaB activity.
- [Prognostically relevant markers of malignant melanoma of the uvea]
- Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma.
- IFN-gamma priming up-regulates IFN-stimulated gene factor 3 (ISGF3) components, augmenting responsiveness of IFN-resistant melanoma cells to
- SCL gene in human tumors.
- TAL1 gene deletions and TAL1 protein expression in sporadic melanoma.
- Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma.
- Does the PITSLRE gene complex contribute to the pathogenesis of malignant melanoma of the skin? A study of patient-derived tumor
- Multiple complementary transcripts of pCMa1, a novel gene located at chromosome 11p15.1-2, and melanocytic cell transformation.
- Analysis of mutations and identification of several polymorphisms in the putative promoter region of the P34CDC2-related CDC2L1 gene located at
- Variability of chromosomes in the VUP permanent cell line derived from uveal malignant melanoma.
- Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2
- LAGE-1, a new gene with tumor specificity.
- NY-ESO-1 encodes DRB1*0401-restricted epitopes recognized by melanoma-reactive CD4+ T cells.
- Efficient simultaneous presentation of NY-ESO-1/LAGE-1 primary and nonprimary open reading frame-derived CTL epitopes in melanoma.
- Association between DNA repair-deficiency and high level of p53 mutations in melanoma of Xeroderma pigmentosum.
- Promoter methylation controls the expression of MAGE2, 3 and 4 genes in human cutaneous melanoma.
- Decreased expression of Ku70/Ku80 proteins in malignant melanomas of the oral cavity.
- Acridine-modified, clamp-forming antisense oligonucleotides synergize with cisplatin to inhibit c-Myc expression and B16-F0 tumor progression.
- Subcellular trafficking of antisense oligonucleotides and down-regulation of bcl-2 gene expression in human melanoma cells using a
Table of Contents
1
UI - 11930117
AU - Pollock PM; Hayward N
TI -
Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell
lines.
SO - Melanoma Res 2002 Apr;12(2):183-6
AD - Joint Experimental Oncology Program of the Queensland Institute of
Medical Research, The University of Queensland, and the Queensland
Cancer Fund, P.O. Royal Brisbane Hospital, Herston 4029, Australia.
Mutations in exon 3 of the CTNNB1 gene encoding beta-catenin have been
reported in colorectal cancer cell lines and tumours. Although one study
reported mutations or deletions affecting beta-catenin in 20% of
melanoma cell lines, subsequent reports detected a much lower frequency
of aberrations in uncultured melanomas. To determine whether this
difference in mutation frequency reflected an in vitro culturing
artefact, exon 3 of CTNNB1 was screened in a panel of 62 melanoma cell
lines. In addition, reverse transcription-polymerase chain reaction
(RT-PCR) was performed to detect intragenic deletions affecting exon 3.
One out of 62 (1.6%) cell lines was found to carry a mutation,
indicating that aberration of the Wnt-1/wingless pathway through
activation of beta-catenin is a rare event, even in melanoma cell lines.
2
UI - 12175554
AU - Hashemi J; Lindstrom MS; Asker C; Platz A; Hansson J; Wiman KG
TI -
A melanoma-predisposing germline CDKN2A mutation with functional
significance for both p16 and p14ARF.
SO - Cancer Lett 2002 Jun 28;180(2):211-21
AD - Department of Oncology-Pathology, Research Laboratory of Radiumhemmet,
Cancer Center Karolinska, R8:03, Karolinska Hospital, S-171 76
Stockholm, Sweden.
The CDKN2A locus on human chromosome 9p21 encodes two proteins, p16 and
p14ARF, that mainly regulate cell cycle progression and cell survival
via the pRb and p53 pathways, respectively. Germline mutations in CDKN2A
have been linked to development of cutaneous melanoma in some families
with hereditary melanoma. Due to overlapping open reading frames in exon
2, some mutations in this exon affect both p16 and p14ARF. We previously
reported a 24bp deletion in CDKN2A exon 2 in a patient with multiple
primary melanomas and melanoma heredity. To further clarify the possible
role of the 24bp deletion for melanoma development, especially with
respect to p14ARF, we have studied the cellular distribution and
function of the resulting p14ARF del (77-84) and p16 del (62-69) mutant
proteins. We found that p14ARF del (77-84) had decreased nucleolar
localization, and was less efficient than wt p14ARF in stabilizing p53,
inducing G1 cell cycle arrest, and inhibiting colony formation. The p16
del (62-69) mutant localized predominantly to the cytoplasm, did not
induce G1 cell cycle arrest, and failed to suppress colony formation. We
conclude that p14ARF del (77-84) has retained the ability to stabilize
MDM2 and p53, but that it is less potent than wt p14ARF. This partial
functional defect may complement the clearly defective p16 del (62-69)
mutant and thus contribute to melanoma development in patients carrying
the 24bp deletion in CDKN2A.
3
UI - 11931386
AU - Rass K; Gutwein P; Welter C; Meineke V; Tilgen W; Reichrath J
TI -
DNA mismatch repair enzyme hMSH2 in malignant melanoma: increased
immunoreactivity as compared to acquired melanocytic nevi and strong
mRNA expression in melanoma cell lines.
SO - Histochem J 2001 Aug;33(8):459-67
AD - Department of Dermatology, The Saarland University Hospital,
Homburg/Saar, Germany.
Mutations in the mismatch DNA repair gene human MutS homologen 2 (hMSH2)
are causative for microsatellite instability and carcinogenesis in
various human tumours, including hereditary nonpolyposis colorectal
cancer. Because microsatellite instability has been detected in
malignant melanoma, we have investigated hMSH2 in melanocytic tumours.
We found strong nuclear immunoreactivity for hMSH2 that was elevated in
malignant melanoma and melanoma metastases as compared to acquired nevi.
These findings suggest that increased genomic instability in malignant
melanoma is associated with elevated protein levels of this DNA repair
enzyme. hMSH2 is not exclusively regulated by proliferative activity in
melanocytes, because there was no correlation between staining patterns
of hMSH2 and the proliferation marker Ki-67. In contrast,
immunoreactivity scores for hMSH2 and p53 were both upregulated in
malignant melanocytic tumours. These findings support the concept that
hMSH2 gene expression may be regulated in melanocytes by the p53
protein, as has been reported previously in other tissues. Using the
reverse transcription-polymerase chain reaction, we detected strong
hMSH2 mRNA expression in each of 8 melanoma cell lines analysed (highest
amounts in SK-MEL-25 cells, lowest amounts in MML-I cells). In
conclusion, our findings indicate that hMSH-2 may be of importance for
genetic stability, tumorigenesis and progression of malignant melanoma.
4
UI - 11792747
AU - Landi MT; Baccarelli A; Tarone RE; Pesatori A; Tucker MA; Hedayati M;
TI -
Grossman L
DNA repair, dysplastic nevi, and sunlight sensitivity in the development
of cutaneous malignant melanoma.
SO - J Natl Cancer Inst 2002 Jan 16;94(2):94-101
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, Bethesda, MD 20892-7236, USA.
landim@mail.nih.gov
BACKGROUND: Exposure to UV radiation is associated with cutaneous
malignant melanoma (CMM). In mammalian cells, UV radiation induces DNA
damage that can be repaired by the nucleotide excision repair system. We
designed this case-control study to determine whether DNA repair
capacity (DRC) is associated with the risk of CMM and to identify risk
factors that may interact biologically with DRC in the development of
melanoma. METHODS: Global DRC was measured in lymphocytes with the
host-cell reactivation assay. Data were analyzed by use of multiple
regression models. All statistical tests were two-sided. RESULTS: DRC
could be determined for 132 case patients with incident melanoma and for
145 age- and sex-matched control subjects. No statistically significant
association between melanoma risk and DRC by itself was found (odds
ratio [OR] = 1.0; 95% confidence interval [CI] = 0.6 to 1.7, adjusted
for age, sex, lymphocyte viability, and sample storage time). DRC,
however, strongly influenced CMM risk in individuals with a low tanning
ability or dysplastic nevi. Individuals with a low tanning ability and a
low DRC had a higher risk for CMM (OR = 8.6; 95% CI = 2.7 to 27.5) than
individuals with a higher tanning ability and a high DRC. Likewise,
individuals with dysplastic nevi and a low DRC had a higher relative
risk (OR = 6.7; 95% CI = 2.4 to 18.6) than those lacking dysplastic nevi
and having a high DRC. Subjects with dysplastic nevi and a high DRC had
an intermediate risk. A likelihood-ratio test gave statistically
significant interactions between DRC and tanning response (P =.001) and
between DRC and dysplastic nevus status (P =.04), which were
independently associated with CMM risk. CONCLUSIONS: DRC may modify the
risk for melanoma in the presence of other strong risk factors, such as
a low tanning ability and the presence of dysplastic nevi. The
occurrence of melanoma in subjects without these risk factors appears to
be independent of DRC.
5
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.
6
UI - 12050676
AU - Kopper L; Timar J
TI -
[Gene expression profiles in the diagnosis and prognosis of cancer]
SO - Magy Onkol 2002;46(1):3-9
AD - I.sz.Patologiai es Kiserleti Rakkutato Intezet, Semmelweis Egyetem,
Budapest, H1085, Hungary. kopper@korb1.sote.hu
DNA-microarray technology can be used to assess the expression of
several thousands of genes at the same time.The identification of the
gene expression profiles may help to better characterize human
cancer.These studies may reveal subclasses of tumor types with similar
histopathologic profile but different clinical courses.Furthermore,such
studies could help to define therapeutic sensitivity and to estimate
prognosis of various cancers.Identification of gene expression profiles
of cancer can identify new therapeutic targets or cancer susceptibility
genes.The DNA-microarray technology may write a new chapter in molecular
oncology.
7
UI - 12205045
AU - Iervolino A; Trisciuoglio D; Ribatti D; Candiloro A; Biroccio A; Zupi G;
TI -
Del Bufalo D
Bcl-2 overexpression in human melanoma cells increases angiogenesis
through VEGF mRNA stabilization and HIF-1-mediated transcriptional
activity.
SO - FASEB J 2002 Sep;16(11):1453-5
AD - Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute,
Rome, Italy.
The aim of this paper was to study the molecular mechanisms by which
bcl-2 increases hypoxia-induced vascular endothelial growth factor
(VEGF) expression. We demonstrated that bcl-2 overexpression in M14
human melanoma cell line enhances hypoxia-induced VEGF mRNA stability
and promoter activation. In particular, the half-life of the message was
longer in bcl-2 transfectants (approximately 330 min) than in control
cells (approximately 180 min). In addition, bcl-2 overexpression
increased VEGF promoter activity through the hypoxia-inducible factor-1
(HIF-1) transcription factor. Increased HIF-1a protein expression and
DNA binding activity were detected in bcl-2 overexpressing cells
compared with control cells. An enhanced functional activity of secreted
VEGF was found both in in vitro and in vivo angiogenic assays, and the
use of VEGF specific antibodies validated the role of VEGF on
bcl-2-induced angiogenesis. Taken together our results indicate that
bcl-2 plays an important role in melanoma angiogenesis, and that VEGF
mRNA stabilization and HIF-1-mediated transcriptional activity are two
important control points in bcl-2/hypoxia-induced VEGF expression.
8
UI - 11951125
AU - Gibbs P; Brady BM; Robinson WA
TI -
The genes and genetics of malignant melanoma.
SO - J Cutan Med Surg 2002 May-Jun;6(3):229-35
AD - Royal Melbourne Hospital, Parkville, Victoria, Australia.
BACKGROUND: Population-based studies have identified several clinical
variables associated with an increased risk of developing cutaneous
melanoma that include phenotype, amount of and response to sun exposure,
and family history. However, these observations are of limited relevance
to clinical practice as the risk associated with each factor is
individually modest and the characteristics of these variables lack
precision when applied to a particular individual. OBJECTIVE: To review
the literature regarding recent advances made in the understanding of
the genes and genetics of clinical variables associated with an
increased risk of melanoma. CONCLUSION: Variants of the MC1R
(melanocortin-1 receptor) have been identified as major determinants of
high-risk phenotypes, such as red hair and pale skin, and the ability to
tan in response to UV exposure. Several studies also suggest that such
variants may increase melanoma risk independent of their contribution to
phenotype. A strong genetic basis for both nevus density and size has
been demonstrated and the link between nevi and the development of MM
has become better defined. Finally, germline defects in several genes
involved in cell cycle regulation, namely, p16 and CDK4, have been
demonstrated in many familial melanoma kindreds. This progress has
introduced the prospect of genetic testing as a means of identifying a
limited number of high-risk individuals who can be targeted with regular
screening and education regarding UV exposure and skin self-examination.
Ultimately, through rational genetic therapy targeted to correcting the
underlying molecular defect, altering the natural history of melanoma
development may be possible.
9
UI - 12202501
AU - Edmunds SC; Kelsell DP; Hungerford JL; Cree IA
TI -
Mutational analysis of selected genes in the TGFbeta, Wnt, pRb, and p53
pathways in primary uveal melanoma.
SO - Invest Ophthalmol Vis Sci 2002 Sep;43(9):2845-51
AD - Centre for Cutaneous Research, St Bartholomew's and the London School of
Medicine and Dentistry, Queen Mary College, University of London,
London, United Kingdom.
PURPOSE: It is known that the pRb pathway cell-cycle inhibitor
p16(INK4A) plays a significant role in cutaneous melanoma and that
alteration of p16(INK4A), which resides within the 9p21-22 locus that
also contains p15(INK4B) and p14(ARF), may occur in up to one third of
uveal melanomas. The absence of TGFbeta responsiveness noted in cultured
uveal melanoma cells also suggests that the TGFbeta pathway plays a role
in the formation of this tumor. Therefore, mutational screening was
performed in several key genes in tumor-suppressor pathways that are
known to be altered in some uveal melanomas. METHODS: Using denaturing
high-performance liquid chromatography (DHPLC) analysis and DNA
sequencing, a series of 67 uveal melanomas were screened for
inactivating mutations in the TGFbeta pathway members Smad4 and TGFbeta
receptor type 2 (TGFbetaR2), the downstream cell-cycle inhibitor
p15(INK4B), and the cell-cycle inhibitors p14(ARF) and p16(INK4A).
p16(INK4A) was also investigated for promoter hypermethylation.
Mutational analysis was also performed on the Wnt pathway gene
beta-catenin, known to be mutated in approximately one quarter of
cutaneous melanoma cell lines. RESULTS: Polymorphisms in p16(INK4A) were
detected in 3 of 50 samples, but no inactivating mutations were detected
in any of the genes screened. Promoter hypermethylation of p16(INK4A)
was detected in 5 of 55 tumors, and loss of heterozygosity of the
p16(INK4A) locus was detected in 5 of 16 tumors. CONCLUSIONS: Most
primary uveal melanomas do not appear to contain somatic mutations in
Smad4, TGFbetaR2, p14(ARF), p15(INK4B), p16(INK4A), or beta-catenin.
However, methylation of the p16(INK4A) promoter and loss of
heterozygosity of the p14(ARF)-p16(INK4A) locus occurs in some tumors.
10
UI - 12095976
AU - Lee JE; Abdalla J; Porter GA; Bradford L; Grimm EA; Reveille JD;
TI -
Mansfield PF; Gershenwald JE; Ross MI
Presence of the human leukocyte antigen class II gene DRB1*1101 predicts
interferon gamma levels and disease recurrence in melanoma patients.
SO - Ann Surg Oncol 2002 Jul;9(6):587-93
AD - Department of Surgical Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston 77030, USA. jelee@notes.mdacc.tmc.edu
BACKGROUND: Increased interferon gamma (IFN-gamma) levels are an
independent predictor of melanoma recurrence. Human leukocyte antigen
(HLA) class II genes can regulate cytokine production; we investigated
whether these genes would predict IFN-gamma levels and recurrence in
melanoma patients. METHODS: Of 591 patients who presented with localized
melanoma, 579 underwent identification of HLA class II alleles; 233
melanoma patients and 90 controls underwent determination of plasma
IFN-gamma levels. HLA class II genes were examined for association with
IFN-gamma levels and disease recurrence. RESULTS: After a median
follow-up of 60 months, melanoma patients with IFN-gamma levels above
the mean control value were more likely to have developed disease
recurrence compared with patients with levels below the mean. The HLA
class II gene HLA-DRB1*1101 was the strongest predictor of recurrence,
and HLA-DRB1*1101-positive melanoma patients had increased levels of
IFN-gamma compared with patients lacking the gene. CONCLUSIONS: Among
patients with localized melanoma, both HLA-DRB1*1101 and increased
IFN-gamma levels were associated with an increased risk for recurrence;
HLA-DRB1*1101-positive patients had relatively increased levels of
IFN-gamma. HLA class II genes may mediate cytokine production in
melanoma patients, and this mechanism may help determine the risk of
disease recurrence.
11
UI - 12198773
AU - Shiras A; Bhosale A; Patekar A; Shepal V; Shastry P
TI -
Differential expression of CD44(S) and variant isoforms v3, v10 in
three-dimensional cultures of mouse melanoma cell lines.
SO - Clin Exp Metastasis 2002;19(5):445-55
AD - National Centre for Cell Science (NCCS), NCCS Complex, Ganeshkhind, Pune
411007, India. shiras99@hotmail.com
Multi-cellular spheroids (MCS) generated from tumor cells serve as
excellent in vitro models for understanding the mechanisms of tumor
progression and micro-metastasis. We have compared the expression of
molecular markers with reference to their growth as conventional
adherent monolayers (2-D) and anchorage independent cultures (3-D) using
two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines
differed in their ability to form spheroids with respect to their
aggregation potential, with B16F10 forming large clusters compared to
Clone M3. A panel of molecular markers comprising cell adhesion
molecules, cyclin dependent kinase inhibitors and members of the
cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D
cultures. There was a distinct difference in the patterns of expression
of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells
grown as monolayers in both cell lines. Also, there was an increase in
cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10
cell line. The expression of alpha and gamma catenin was down regulated
in spheroids. As these molecules are implicated in the regulation of
cell proliferation, alterations in the expression of these molecules in
3-D cultures compared to their 2-D counterparts suggests the importance
of spheroids as experimental model for tumorigenesis.
12
UI - 12164943
AU - Irwin N; Walker G; Hayward N
TI -
Lack of TTC4 mutations in melanoma.
SO - J Invest Dermatol 2002 Jul;119(1):186-7
13
UI - 12164944
AU - Cesinaro AM; Natoli C; Grassadonia A; Tinari N; Iacobelli S; Trentini GP
TI -
Expression of the 90K tumor-associated protein in benign and malignant
melanocytic lesions.
SO - J Invest Dermatol 2002 Jul;119(1):187-90
14
UI - 10096573
AU - Devalaraja MN; Wang DZ; Ballard DW; Richmond A
TI -
Elevated constitutive IkappaB kinase activity and IkappaB-alpha
phosphorylation in Hs294T melanoma cells lead to increased basal
MGSA/GRO-alpha transcription.
SO - Cancer Res 1999 Mar 15;59(6):1372-7
AD - Department of Cell Biology, Vanderbilt University School of Medicine,
Nashville, Tennessee 37212-2637, USA.
The basal transcription of the CXC chemokine, melanocyte growth
stimulatory activity (MGSA)/growth-regulated protein (GRO)-alpha, is
up-regulated in Hs294T melanoma cells compared with the normal retinal
pigment epithelial (RPE) cells. Previous studies characterized a
cytokine-inducible, functional nuclear factor (NF)-kappaB consensus
element in the immediate 5' regulatory region of the MGSA/GRO-alpha gene
at -78 bp. Although the cytokine-inducible mechanisms for transcription
of this gene are fairly well delineated, the mechanisms involved in its
basal up-regulation of transcription in Hs294T melanoma cells are poorly
understood. Recently, we demonstrated an increased rate of IkappaB-alpha
degradation in Hs294T cells, which leads to an increased nuclear
localization of NF-kappaB (R. L. Shattuck-Brandt and A. Richmond. Cancer
Res., 57: 3032-3039, 1997). Here we demonstrate that Hs294T melanoma
cells have elevated basal IkappaB kinase (IKK) activity relative to RPE
cells, causing an increased constitutive IkappaB-alpha phosphorylation
and degradation. We also show here that the resultant elevated nuclear
NF-kappaB (p50/p65) in these cells is responsible for the increased
basal transcription of MGSA/GRO-alpha. Pretreatment of Hs294T or RPE
cells with proteasome inhibitors MG115 or MG132 captures the slower
migrating, constitutively phosphorylated form of IkappaB-alpha in Hs294T
melanoma cells, but not in RPE cells. In addition, a phospho-specific
antibody that specifically recognizes the inhibitory form of IkappaB
that is phosphorylated at Ser-32 reacted with IkappaB-alpha in Hs294T
cell, but not in unstimulated RPE cells. Although the basal level of
protein expression of IKK-alpha or IKK-beta are the same in both Hs294T
and RPE cells, immunoprecipitation with IKK-alpha antibody combined with
activity assay reveal a constitutively active IKK complex in Hs294T
melanoma cells. Cotransfection of a 350-bp MGSA/GRO-alpha
promoter-luciferase reporter construct with either the dominant negative
IKK-alpha or the repressors of NF-kappaB, the IkappaB-alpha wild type or
mutants lacking the inducible phosphorylation sites, demonstrates that
the increased basal MGSA/GRO-alpha transcription in the Hs294T cells is
due to the enhanced nuclear activation of NF-kappaB.
15
UI - 10353757
AU - Meyskens FL Jr; Buckmeier JA; McNulty SE; Tohidian NB
TI -
Activation of nuclear factor-kappa B in human metastatic melanomacells
and the effect of oxidative stress.
SO - Clin Cancer Res 1999 May;5(5):1197-202
AD - Department of Medicine and the Chao Family Comprehensive Cancer Center,
University of California-Irvine, Orange 92868, USA. flmeyske@uci.edu
The biological basis for the general pharmacological resistance of human
melanoma is unknown. A unique biochemical feature of the melanocyte is
the synthesis of melanin, which leads to the generation of hydrogen
peroxide and the consumption of reduced glutathione. This activity
produces a state of chronic oxidative stress in these cells. We
demonstrated previously that the expression of the c-jun family was
dysregulated in metastatic melanoma cells compared with normal human
melanocytes (D. T. Yamanishi et al., J. Invest. Dermatol., 97: 349-353,
1991). In the current investigation, we measured the levels of two major
redox response transcription factors, nuclear factor-kappaB (NF-kappaB)
and activator protein-1, in metastatic melanoma cells and normal
melanocytes and their response to oxidative stress. The basal
DNA-binding activity of NF-kappaB as measured by the electrophoretic
mobility shift assay in metastatic melanoma cells was increased 4-fold
compared with that of normal melanocytes. This level of binding was
paralleled by a 1.5- to 4-fold increase in the expression of p50
(NF-kappaB1), p65 (Rel-A), and IkappaB-alpha as measured by Northern
blot analysis. In contrast, the expression of p75 (c-rel) was markedly
decreased (60%) in melanoma cells compared with normal melanocytes.
Following oxidative stress produced by enzyme-generated H2O2, free H2O2,
or incubation with buthionine sulfoximine, NF-kappaB binding activity
increased 1.5- to 2.5-fold in melanoma cells (buthionine sulfoximine >
H2O2), but only slightly in normal melanocytes. In contrast, activator
protein-1 binding activity was unaffected or increased in normal
melanocytes in response to oxidative stress, but was either unaffected
or decreased in melanoma cells. These results suggest that the redox
regulation of melanoma cells at the molecular level is fundamentally
different from normal melanocytes and may offer a unique avenue for
preventive or therapeutic intervention as well as new insights into the
pathogenesis of melanocyte transformation.
16
UI - 10792001
AU - Sullivan GF; Yang JM; Vassil A; Yang J; Bash-Babula J; Hait WN
TI -
Regulation of expression of the multidrug resistance protein MRP1 by p53
in human prostate cancer cells.
SO - J Clin Invest 2000 May;105(9):1261-7
AD - Department of Pharmacology, University of Medicine and Dentistry of New
Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey
08901, USA.
The expression of several drug-resistance genes, including MRP and p53,
increases with advancing stage of human prostate cancer. Altered
transcription could account for the genotypic alterations associated
with prostate cancer progression, and it was recently reported that the
promoter of MRP1 is activated in the presence of mutant p53. To
determine whether there is a relationship between p53 status and the
expression of MRP1, a human, temperature-sensitive p53 mutant (tsp
Val(138)) was transfected into LNCaP human prostate cancer cells. In the
transfected cell line (LVCaP), the wild-type p53 produced growth arrest
at the G1/S interface of the cell cycle, inhibited colony formation, and
induced p21(waf1/cip1). Temperature shifting to 38 degrees C (p53
mutant) produced a time-dependent increase in expression of MRP1. This
change in MRP1 expression was also seen in isogenic cell lines in which
p53 was inactivated by human papilloma virus (HPV)16E6 protein or by a
dominant-negative mutant. Functional assays revealed a decrease in drug
accumulation and drug sensitivity associated with mutant p53 and
increased MRP1 expression. These results provide the first mechanistic
link between expression of MRP1 and mutation of p53 in human prostate
cancer and support recent clinical associations. Furthermore, these data
suggest a mechanism tying accumulation of p53 mutations to the multidrug
resistance phenotype seen in this disease.
17
UI - 10976534
AU - Huang S; DeGuzman A; Bucana CD; Fidler IJ
TI -
Level of interleukin-8 expression by metastatic human melanoma cells
directly correlates with constitutive NF-kappaB activity.
SO - Cytokines Cell Mol Ther 2000 Mar;6(1):9-17
AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer
Center, Houston 77030, USA.
The purpose of this study was to determine whether constitutive
NF-kappaB activity regulates the expression level of interleukin-8
(IL-8) in metastatic human melanoma cells. Cultures of metastatic human
A375 melanoma cells expressed higher levels of IL-8 mRNA and protein
than nonmetastatic A375 human melanoma cells. No discernible differences
in IL-8 half-life were found between metastatic and nonmetastatic cells,
but cells that overexpressed IL-8 had a higher transcription rate and
increased IL-8 promoter activity. Analysis of the IL-8 promoter using
deletion mutants revealed that the region within -133 was essential for
constitutive IL-8 promoter activity and that mutation of NF-kappaB
binding sites eliminated the constitutive IL-8 promoter activity. The
activation of constitutive IL-8 transcription directly correlated with
the level of constitutive NF-kappaB activity. Transfection of melanoma
cells with a dominant-negative mutant IkappaBalpha expression vector
(pLXSN-IkappaBalphaM) significantly decreased the level of constitutive
NF-kappaB activity and expression of IL-8, demonstrating that
constitutive NF-kappaB/relA activities contribute to overexpression of
IL-8 in highly metastatic human melanoma cells.
18
UI - 12043285
AU - Anastassiou G; Tschentscher F; Zeschnigk M
TI -
[Prognostically relevant markers of malignant melanoma of the uvea]
SO - Ophthalmologe 2002 May;99(5):327-32
AD - Augenklinik, Universitatsklinikum Essen, Hufelandstrasse 55, 45122
Essen. gerasimos.anastassion@uni-essen.de
In addition to classic risk factors such as tumor size, tumor location,
and histological cell type, a range of other potentially prognostic
parameters have been discovered in the past few years. Many of these
have only been described once so that they cannot be considered
established markers. A few, however, such as vascular patterns or
monosomy 3, were independently identified by several groups and now
constitute recognized prognostic markers. The association of these
factors with the disease course provides us with ever-new insights into
the biology of this tumor. In particular, with the aid of new
technologies such as microarray analysis, researchers around the globe
hope that new and exciting discoveries will be made that can also modify
therapy concepts.
19
UI - 9353349
AU - Wong LH; Krauer KG; Hatzinisiriou I; Estcourt MJ; Hersey P; Tam ND;
TI -
Edmondson S; Devenish RJ; Ralph SJ
Interferon-resistant human melanoma cells are deficient in ISGF3
components, STAT1, STAT2, and p48-ISGF3gamma.
SO - J Biol Chem 1997 Nov 7;272(45):28779-85
AD - Department of Biochemistry and Molecular Biology, Monash University,
Wellington Road, Clayton, Victoria 3168, Australia.
The mechanism of IFN resistance was examined in three long-term cell
lines, SK-MEL-28, SK-MEL-3, and MM96, exhibiting significant variation
in responsiveness to the antiproliferative and antiviral effects of type
I IFNs. The JAK-STAT components involved in IFN signal transduction were
analyzed in detail. After exposure to IFN, activation of the IFN type I
receptor-linked tyrosine kinases, JAK-1 and TYK-2, was detected at
similar levels in both IFN-sensitive and IFN-resistant cell types,
indicating that IFN resistance did not result from a deficiency in
signaling at the level of receptor-associated kinase activation.
However, analysis of ISGF3 transcription factor components, STAT1,
STAT2, and p48-ISGF3gamma, revealed that their expression and activation
correlated with cellular IFN responsiveness. The analysis was extended
to also include IFN-sensitive primary melanocytes, three additional
IFN-resistant melanoma cell lines, and seven cell cultures recently
established from melanoma patient biopsies. It was consistently observed
that the most marked difference in ISGF3 was a lack of STAT1 in the
resistant versus the sensitive cells. Transfection of the IFN-resistant
MM96 cell line to express increased levels of STAT1 protein partially
restored IFN responsiveness in an antiviral assay. We conclude that a
defect in the level of STAT1 and possibly all three ISGF3 components in
IFN-resistant human melanoma cells may be a general phenomenon
responsible for reduced cellular responsiveness of melanomas to IFNs.
20
UI - 9605150
AU - Wong LH; Hatzinisiriou I; Devenish RJ; Ralph SJ
TI -
IFN-gamma priming up-regulates IFN-stimulated gene factor 3 (ISGF3)
components, augmenting responsiveness of IFN-resistant melanoma cells to
type I IFNs.
SO - J Immunol 1998 Jun 1;160(11):5475-84
AD - Department of Biochemistry and Molecular Biology, Monash University,
Clayton, Victoria, Australia.
IFN-stimulated gene factor 3 (ISGF3) mediates transcriptional activation
of IFN-sensitive genes (ISGs). The component subunits of ISGF3,
STAT1alphabeta, STAT2, and p48-ISGF3gamma, are tyrosine phosphorylated
before their assembly into a complex. Subsequently, the ISGF3 complex is
translocated to the nucleus. We have recently established that the
responsiveness of human melanoma cell lines to type I IFNs correlates
directly with their intracellular levels of ISGF3 components,
particularly STAT1. In the present study, we show that pretreating
IFN-resistant melanoma cell lines with IFN-gamma (IFN-gamma priming)
before stimulation with type I IFN also results in increased levels of
ISGF3 components and enhanced DNA-binding activation of ISGF3. In
addition, IFN-gamma priming of IFN-resistant melanoma cell lines
increased expression of type I IFN-induced ISG products, including
ISG54, 2'-5'-oligoadenylate synthase, HLA class I, B7-1, and ICAM-1 Ags.
Furthermore, IFN-gamma priming enhanced the antiviral effect of IFN-beta
on the IFN-resistant melanoma cell line, MM96. These results support a
role for IFN-gamma priming in up-regulating ISGF3, thereby augmenting
the responsiveness of IFN-resistant melanoma cell lines to type I IFN
and providing a molecular basis and justification for using sequential
IFN therapy, as proposed by others, to enhance the use of IFNs in the
treatment of melanoma.
21
UI - 1625484
AU - Rockman S; Begley CG; Kannourakis G; Mann GJ; Dobrovic AN; Kefford RF;
TI -
McGrath K
SCL gene in human tumors.
SO - Leukemia 1992 Jul;6(7):623-5
AD - Walter and Eliza Hall Institute of Medical Research, Victoria,
Australia.
The SCL gene encodes a member of the helix-loop-helix (HLH) family of
transcription factors and is reportedly involved in up to 25% of T-cell
acute lymphoblastic leukemia (T-ALL). We have surveyed over 120 primary
human tumors including melanomas, myeloid, and lymphoid leukemias, and
other solid tumors without evidence of rearrangements involving SCL.
These results are further supported by low level expression of SCL in
these tumors (as assessed by a polymerase chain-reaction-based method).
We conclude that rearrangement/translocation with subsequent activation
of SCL occurs infrequently in myeloid leukemias and melanomas.
22
UI - 7496160
AU - Chetty R; Cerroni L; Pulford K; Giatromanolaki A; Biddolph S; Kaklamanis
TI -
L; Gatter K
TAL1 gene deletions and TAL1 protein expression in sporadic melanoma.
SO - Melanoma Res 1995 Aug;5(4):251-4
AD - University Department of Cellular Science, University of Oxford, UK.
Studies on cytogenetic abnormalities and cell lines have implicated
chromosome 1p32 as being important in the pathogenesis of melanoma.
Genetic linkage studies have also mapped a melanoma-susceptibility locus
to chromosome 1p. The gene TAL1 is present on chromosome 1p32, and
deletions within it are the commonest chromosomal abnormality in T-acute
lymphoblastic leukaemia (T-ALL). A melanoma cell line harbouring a 1p32
deletion involving the TAL1 gene and the presence of TAL1 protein in
developing mouse melanocytes led us to investigate whether TAL1
deletions and/or TAL1 protein expression occur in sporadic melanomas.
DNA extracted from 32 fresh melanomas was amplified by standard
polymerase chain reaction for the four common deletions of the TAL1 gene
that occur in T-ALL. In addition, frozen and paraffin-embedded sections
of these melanomas were stained with monoclonal antibodies that detect
full-length and truncated TAL1 protein. The results of the study show
that deletions of TAL1 do not occur in melanoma. Indeed, full and
truncated TAL1 protein also could not be detected immunohistochemically
in the paraffin-embedded and frozen sections of the melanomas. We
conclude that the TAL1 gene and its protein are probably not directly
involved in the oncogenesis of melanomas.
23
UI - 9973934
AU - Nelson MA; Ariza ME; Yang JM; Thompson FH; Taetle R; Trent JM; Wymer J;
TI -
Massey-Brown K; Broome-Powell M; Easton J; Lahti JM; Kidd VJ
Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex
(CDC2L) on chromosome band 1p36 in melanoma.
SO - Cancer Genet Cytogenet 1999 Jan 15;108(2):91-9
AD - Arizona Cancer Center, Tucson 85724, USA.
The two genes encoding the PITSLRE protein kinase isoforms, CDC2L1 and
CDC2L2, are localized to human chromosome band 1p36. The PITSLRE protein
kinases are a part of the p34cdc2 supergene family. Several protein
products of the CDC2L locus may be effector(s) in apoptotic signaling.
The larger PITSLRE p110 isoforms appear to regulate some aspect of RNA
splicing/transcription during the cell cycle. One or more of these genes
may function as tumor suppressor genes in melanoma. Using fluorescence
in situ hybridization, one allele of the CDC2L gene complex on
chromosome 1 was either deleted or translocated in 8 of 14 different
melanoma cell lines. We also observed mutations in the 5' promoter
region of the CDC2L1 gene in four different cell lines relative to
normal melanocytes using PCR-SSCP analysis and direct DNA sequencing.
Western blot analysis revealed decreased level of PITSLRE protein
expression in several cell lines, as well as in four surgical malignant
melanoma specimens relative to normal melanocytes. Thus, the decreased
PITSLRE protein expression appears to result from deletion of the CDC2L
alleles and possibly by mutations within the 5' promoter region. We
propose that aberrations in the CDC2L genes may contribute to the
pathogenesis or progression of melanoma.
24
UI - 11478303
AU - Poetsch M; Dittberner T; Woenckhaus C
TI -
Does the PITSLRE gene complex contribute to the pathogenesis of
malignant melanoma of the skin? A study of patient-derived tumor
samples?
SO - Cancer Genet Cytogenet 2001 Jul 15;128(2):181-2
25
UI - 12210088
AU - Meije CB; Das PK; Jans MM; Hau C; van der Wal AC; Alders M; Hakvoort TB;
TI -
Weidle UH; Lamers WH; Swart GW
Multiple complementary transcripts of pCMa1, a novel gene located at
chromosome 11p15.1-2, and melanocytic cell transformation.
SO - J Pathol 2002 Aug;197(5):668-76
AD - Department of Biochemistry, University of Nijmegen, The Netherlands.
The cDNA clone pCMa1 (0.45 kb) is one of the 12 novel cDNAs, previously
identified when comparing RNA expression profiles of melanocytes, naevus
cells, and non-metastatic melanoma cells. This clone did not reveal a
unique long open reading frame. The pCMa1 gene localized to the distal,
telomere proximal region on the short arm of chromosome 11.p15.1-2.
Northern blot analyses with single-stranded cRNA probes revealed the
presence of various complementary pCMa1 transcripts of different
lengths, which are not enriched in the poly(A)(+) RNA fraction. The
arbitrarily defined plus strand (used as a probe) mainly hybridized to
0.45 kb and 4.0 kb minus transcripts in total RNA samples, and the minus
strand (used as a probe) hybridized to a major plus transcript of 4.0
kb. By RNA in situ hybridization, the highest levels of the plus
transcripts were observed in melanocytic naevi (12/12), particularly in
congenital naevi, whereas normal skin melanocytes (12/12) were negative.
pCMa1 plus transcripts were detected in naevus cell nests (100%) near
the dermo-epidermal junction. Expression, however, diminished to some
extent in the deeper parts of the melanocytic naevi. Although most of
the cutaneous primary melanoma lesions (11/15) showed detectable, but
variable levels of plus transcripts of pCMa1 in the papillary to
reticular dermis, not more than 10% of the melanoma cells were positive.
The majority of melanoma metastases (6/7) were negative, while the
positive lesion originated from a patient with a positive primary
melanoma. Furthermore, plus transcripts were present in the nuclei of
non-metastatic melanoma cells in culture, whereas metastatic cells
showed elevated expression both in the nucleus and in the cytoplasm.
Briefly, the data show transient up-regulation of pCMa1 in neoplastic
progression of melanocytic cells, with peak levels occurring during
naevus stages, and suggest that pCMa1 is a molecular marker in
melanocytes for the early changes from the proliferating phenotype to
malignant transformation. Copyright 2002 John Wiley & Sons, Ltd.
26
UI - 12115485
AU - Feng Y; Shi J; Goldstein AM; Tucker MA; Nelson MA
TI -
Analysis of mutations and identification of several polymorphisms in the
putative promoter region of the P34CDC2-related CDC2L1 gene located at
1P36 in melanoma cell lines and melanoma families.
SO - Int J Cancer 2002 Jun 20;99(6):834-8
AD - Arizona Cancer Center, Tucson, AZ 85724, USA.
Chromosome 1 abnormalities are the most commonly detected aberrations in
many cancers including malignant melanoma. Partial deletions and an
allelic loss of the chromosome 1p36 region observed in melanoma indicate
the presence of putative tumor suppressor gene(s) in this region. A
candidate gene, CDC2L1, which encodes PITSLRE proteins related to
p34(cdc2), is mapped to 1p36. To determine whether CDC2L1 mutation is
involved in melanoma development, we examined 20 melanoma cell lines and
11 members of melanoma-prone families linked to chromosome 1p36.
Mutation analysis throughout the entire coding region of the CDC2L1 gene
revealed only 1 mutation (C-->T at nucleotide location 97 of exon 7,
Ser-->Leu) in the melanoma cell line UACC 903 out of 20 melanoma cell
lines and 6 melanoma cases. However, 4 polymorphic nucleotide changes,
C-48T, G-53C, T-103C and T-210C, in the putative promoter region of
CDC2L1 were identified. The 4 variants were located within or beside the
conserved binding sites of transcription factors TCF11, MZF1 and TAAC
box, indicating their potential effects on the regulation of CDC2L1
expression. No aberrant methylation of the CDC2L1 CpG island in the
promoter region was observed by sodium bisulfite genomic sequencing.
These results indicate that mutations are rare in the CDC2L1 gene in
these melanoma cell lines and melanoma families and that the aberrant
cytosine methylation of the CDC2L1 CpG island is not the mechanism of
CDC2L1 repression in melanoma. The contribution of 4 promoter
polymorphisms to the transcriptional regulation of the gene and its
association with melanoma warrants further investigation. Copyright 2002
Wiley-Liss, Inc.
27
UI - 12098005
AU - Vrba M; Cihalova V; Juraskova V
TI -
Variability of chromosomes in the VUP permanent cell line derived from
uveal malignant melanoma.
SO - Neoplasma 2002;49(3):184-8
AD - Research Institute of Child Health, Brno, 662 62 Czech Republic.
A permanent cell line [VUP] derived 31 years ago from human malignant
melanoma of the choroid has been characterized by genetically firmly
anchored heteronuclearity. The most significant chromosomal changes of
this cell line are: high instability of the chromosome No. 13 with the
rise of new chromosomes formed by translocations, homologous stability
of chromosomes 6, 15, and X. Structural changes were not revealed in
chromosomes 15 and 22. The variability of chromosomes was studied both
by classical conventional methods as well as with GTG banding and DNA
hybridization in situ (FISH). Structural diversity was demonstrated in a
number of morphologically congruent chromosomes. For example, X
chromosome classified morphologically as chromosome No. 10 was
determined by means of FISH technique, as a centric fragment Xq with
translocated acentric fragment of other chromosomes. Furthermore, mar-t,
previously considered to be q arm of chromosome No. 4, is formed by a
centric fragment of chromosome No. 13 and an acentric fragment of
chromosome No. 1.
28
UI - 12184809
AU - Panelli MC; Wang E; Phan G; Puhlmann M; Miller L; Ohnmacht GA; Klein HG;
TI -
Marincola FM
Gene-expression profiling of the response of peripheral blood
mononuclear cells and melanoma metastases to systemic IL-2
administration.
SO - Genome Biol 2002 Jun 25;3(7):RESEARCH0035
AD - Immunogenetics Section, Department of Transfusion Medicine, Clinical
Center, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland 20892, USA.
Early changes in transcriptional profiles of circulating mononuclear
cells were compared with those occurring within the microenvironment of
melanoma metastases following systemic IL-2 administration. The results
suggest that the immediate effects of IL-2 administration on the tumor
microenvironment is transcriptional activation of genes predominantly
associated with monocyte cell function.
29
UI - 9626360
AU - Lethe B; Lucas S; Michaux L; De Smet C; Godelaine D; Serrano A; De Plaen
TI -
E; Boon T
LAGE-1, a new gene with tumor specificity.
SO - Int J Cancer 1998 Jun 10;76(6):903-8
AD - Ludwig Institute for Cancer Research, Brussels Branch, Universite
Catholique de Louvain. lethe@licr.ucl.ac.be
Representational difference analysis was used to identify genes that are
expressed in a human melanoma cell line and not in normal skin. A cDNA
clone that appeared to be specific for tumors was obtained and the
corresponding gene was sequenced. This new gene was named LAGE-I. Using
a LAGE-I probe to screen a cDNA library from the same melanoma cell
line, we identified a closely related gene, which proved to be identical
to NY-ESO-I, a gene recently reported to code for an antigen recognized
by autologous antibodies in an esophageal squamous cell carcinoma. Gene
LAGE-I maps to Xq28. It comprises 3 exons. Alternative splicing produces
2 major transcripts encoding polypeptides of 210 and 180 residues,
respectively. Expression of LAGE-I was observed in 25-50% of tumor
samples of melanomas, non-small-cell lung carcinomas, bladder, prostate
and head and neck cancers. The only normal tissue that expressed the
gene was testis. As for MAGE-AI, expression of LAGE-I is induced by
deoxy-azacytidine in lymphoblastoid cells, suggesting that tumoral
expression is due to demethylation. The expression of LAGE-I is strongly
correlated with that of NY-ESO-I. It is also clearly correlated with the
expression of MAGE genes.
30
UI - 10987311
AU - Zarour HM; Storkus WJ; Brusic V; Williams E; Kirkwood JM
TI -
NY-ESO-1 encodes DRB1*0401-restricted epitopes recognized by
melanoma-reactive CD4+ T cells.
SO - Cancer Res 2000 Sep 1;60(17):4946-52
AD - Department of Medicine and Melanoma Center, University of Pittsburgh
Cancer Institute, Pennsylvania 15213, USA. zarourhm@msx.upmc.edu
The NY-ESO-1 gene is expressed by a range of human tumors and encodes
HLA-A2-restricted melanoma peptides recognized by CD8+ CTLs. Here we
report that the NY-ESO-1 gene also encodes two overlapping, but
non-cross-reactive, HLA-DRB1*0401-presented peptides that are recognized
by CD4+ T cells. The NY-ESO-1(119-143) peptide was able to induce
specific CD4+ T cells in vitro from both an HLA-DRB1*0401+ normal donor
and an HLA-DRB1*0401+ patient with melanoma. Bulk and cloned CD4+ T
cells produced IFN-gamma specifically in response to, and also lysed,
T2.DR4 cells pulsed with peptide NY-ESO-1(119-143) and the autologous
tumor cell line, but not a DRB1*0401+ melanoma cell line that does not
express NY-ESO-1. Interestingly, the NY-ESO119-143 peptide contains two
overlapping putative "core" epitopes recognized by non-cross-reactive
anti-NY-ESO-1(119-143) CD4+ T-cell clones. Taken together, these data
support the use of this novel DR4-restricted tumor peptide,
NY-ESO-1(119-143), or its two "sub-epitopes" in immunotherapeutic trials
designed to generate or enhance specific CD4+ T-cell responses against
tumors expressing NY-ESO-1 in vivo.
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