Table of Contents
1
UI - 11584064
AU - Lynch HT; Sanger WG; Pirruccello S; Quinn-Laquer B; Weisenburger DD
TI -
Familial multiple myeloma: a family study and review of the literature.
SO - J Natl Cancer Inst 2001 Oct 3;93(19):1479-83
AD - Department of Preventive Medicine, Creighton University School of
Medicine, Omaha, NE 68178, USA. htlynch@creighton.edu
BACKGROUND: The etiology of multiple myeloma (MM) remains obscure,
although reports of familial clustering have implicated both a host
susceptibility factor and environmental effects. Here we describe the
medical histories of members of a family prone to MM. METHODS: We
developed a pedigree for an MM-prone family by using information
obtained from a questionnaire. Protein immunoelectrophoresis of serum
and urine from the proband and from 19 family members was performed to
detect monoclonal immunoproteins. Peripheral blood obtained from the
proband and from five relatives was subjected to standard cytogenetic
studies to detect constitutional chromosomal abnormalities.
Multifluor-fluorescence in situ hybridization (M-FISH) and standard FISH
studies were performed on peripheral blood from the proband and from two
other affected living relatives to determine their karyotypes and to
detect clonal chromosomal abnormalities frequently seen in patients with
MM. RESULTS: Within this family, a sibship of seven included three
individuals (including the proband) with histologically verified MM and
two individuals with a monoclonal gammopathy of unknown significance
(MGUS), as determined by immunoelectrophoresis of serum and urine. This
family also had members with acute lymphocytic leukemia, malignant
melanoma, and prostate cancer. In the family members tested, we detected
no constitutional chromosomal abnormality. None of the three individuals
analyzed by FISH had a deletion of the retinoblastoma (Rb-1) locus,
which is frequently deleted in patients with MM, and only one (the
proband) had a translocation involving chromosomes 11 and 14, a clonal
abnormality commonly seen in MM. CONCLUSION: The study of familial MM
may provide insights into the pathogenesis and, ultimately, the control
and prevention of MM and related disorders.
2
UI - 11904317
AU - Sviderskaya EV; Hill SP; Evans-Whipp TJ; Chin L; Orlow SJ; Easty DJ;
TI -
Cheong SC; Beach D; DePinho RA; Bennett DC
p16(Ink4a) in melanocyte senescence and differentiation.
SO - J Natl Cancer Inst 2002 Mar 20;94(6):446-54
AD - Department of Anatomy and Developmental Biology, St. George's Hospital
Medical School, Cranmer Terrace, London SW17 0RE, U.K.
BACKGROUND: The Ink4a-Arf tumor suppressor locus encodes two growth
inhibitors, p16 and Arf, both of which are also implicated as effectors
in cellular senescence. Because human germline defects in the INK4A-ARF
locus are associated with familial melanoma, melanocytes may have
unusual INK4A-ARF functions or controls of cell senescence. Because
senescence is believed to be an anticancer mechanism, we investigated
the role of Ink4a-Arf and its individual components in melanocyte
senescence. METHODS: Melanocytes were cultured from littermate mice with
zero, one, or two functional copies of the Ink4a-Arf locus. Senescence
was evaluated by cumulative population doubling curves and by the
assessment of acidic beta-galactosidase (an indicator of senescence)
expression. Pigmentation and cell size were evaluated by
spectrophotometry and microscopy. p16 and Arf expression in primary and
spontaneously immortalized melanocyte or melanocyte precursor cell lines
were evaluated by immunoblotting. Retroviral vectors containing normal
p16 and Arf complementary DNAs were used to restore expression of these
genes in Ink4a-Arf(-/-) melanocytes. RESULTS: Wild-type melanocytes
(i.e., Ink4a-Arf(+/+)) senesced within 4-5 weeks of culture.
Ink4a-Arf(-/-) melanocytes did not senesce and readily became immortal.
Ink4a-Arf(+/-) melanocytes showed defective senescence. Senescent
Ink4a-Arf(+/+) melanocytes were heavily pigmented, but Ink4a-Arf(+/-)
and Ink4a-Arf(-/-) melanocytes were less pigmented. All of six
spontaneously immortalized melanocyte or melanocyte precursor lines from
Ink4a-Arf(+/+) mice lacked p16 protein expression, although most
retained Arf protein expression. After restoration of p16 but not Arf
expression, Ink4a-Arf(-/-) melanocytes stopped growing, became highly
melanized, and expressed acidic beta-galactosidase. By contrast,
restoration of Arf but not p16 expression led to cell death without
evidence of senescence. CONCLUSION: Normal mouse melanocyte senescence
and associated pigmentation require both copies of Ink4a-Arf and appear
to depend more on p16 than on Arf function. Mutations of the INK4A-ARF
locus may favor tumorigenesis from melanocytes by impairing senescence,
cell differentiation, and (where ARF is disrupted) cell death.
3
UI - 11552709
AU - Cockburn M; Black W; McKelvey W; Mack T
TI -
Determinants of melanoma in a case-control study of twins (United
States).
SO - Cancer Causes Control 2001 Sep;12(7):615-25
AD - Department of Preventive Medicine, Keck School of Medicine, University
of Southern California, Los Angeles 90089-9175, USA. cockburn@usc.edu
OBJECTIVES: To estimate the relative contribution of environmental and
genetic factors disposing towards the development of melanoma. METHODS:
We investigated risk factors for melanoma in a case-control study
conducted among 185 North American twin pairs in which one was diagnosed
with melanoma and the other (the co-twin of the case) was not. We
considered monozygous (MZ) and dyzygous (DZ) twins separately. RESULTS:
While greater risk of melanoma was associated with number of large nevi
in DZ twins (adjusted OR = 26.6 (4.2-170.8) for three or more large
moles), this was not the case for MZ twins (adjusted OR = 1.4 (0.6-3.2)
for three or more large moles). Elevated risks of developing melanoma
with site-specific sun exposures resulting in sunburn also appeared to
be confined to DZ twins. Despite the number of identical twins reporting
a difference in mole prevalence, we observed only a modest and
inconsistent increase in melanoma risk attributable to that factor,
whereas the increase within fraternal twin pairs was larger by an order
of magnitude. CONCLUSIONS: If confirmed, this indicates that the
significance of mole prevalence as a risk factor for melanoma is largely
as a genetic, rather than an environmental, factor. We noticed an
increased risk of developing melanoma among DZ twins who drank moderate
amounts of beer, but we believe this result may be due to the
sun-exposure activities of those people most likely to drink moderate
amounts of beer.
4
UI - 11886507
AU - Chwirot BW; Chwirot S; Sypniewska N; Michniewicz Z; Redzinski J;
TI -
Kurzawski G; Ruka W
Fluorescence in situ detection of human cutaneous melanoma: study of
diagnostic parameters of the method.
SO - J Invest Dermatol 2001 Dec;117(6):1449-51
AD - Interdisciplinary Group of Optical Methods of Early Detection of Cancer,
Institute of General and Molecular Biology, Nicholas Copernicus
University, Torun, Poland. chwirot@biol.uni-torum.pl
Multicenter study of the diagnostic parameters was conducted by three
groups in Poland to determine if in situ fluorescence detection of human
cutaneous melanoma based on digital imaging of spectrally resolved
autofluorescence can be used as a tool for a preliminary selection of
patients at increased risk of the disease. Fluorescence examinations
were performed for 7228 pigmented lesions in 4079 subjects.
Histopathologic examinations showed 56 cases of melanoma. A sensitivity
of fluorescence detection of melanoma was 82.7% in agreement with 82.5%
found in earlier work. Using as a reference only the results of
histopathologic examinations obtained for 568 cases we found a
specificity of 59.9% and a positive predictive value of 17.5% (melanomas
versus all pigmented lesions) or 24% (melanomas versus common and
dysplastic naevi). The specificity and positive predictive value found
in this work are significantly lower than reported earlier but still
comparable with those reported for typical screening programs. In
conclusion, the fluorescence method of in situ detection of melanoma can
be used in screening large populations of patients for a selection of
patients who should be examined by specialists.
5
UI - 11886511
AU - Valery C; Grob JJ; Verrando P
TI -
Identification by cDNA microarray technology of genes modulated by
artificial ultraviolet radiation in normal human melanocytes: relation
to melanocarcinogenesis.
SO - J Invest Dermatol 2001 Dec;117(6):1471-82
AD - Laboratoire d'Investigation des Maladies de la Peau, LIMP -- Universite
de la Mediterranee, Marseille, France.
Target genes of ultraviolet stress response in cutaneous melanocytes,
potentially associated with solar-induced melanocarcinogenesis, were
characterized by cDNA microarray technology. In cultured normal human
melanocytes, 198 genes out of approximately 9000 arrayed were found
modulated > or = 1.9 times following artificial ultraviolet minus sign
mainly ultraviolet-B minus sign irradiation (100 mJ per cm(2)). Among
them, 159 corresponded to known sequences, the encoded proteins being
mostly involved in DNA or RNA binding/synthesis/modification, or
ribosomal proteins. The others were transcription factors, receptors,
tumor suppressors, and (proto)oncogenes. Members of these families have
already been linked to melanoma. In addition, some of the modulated
genes were borne by chromosomes harboring candidate melanoma loci.
Comparisons with genes modified in melanoma samples reported in previous
studies with similar microarray platform showed that 59% of the known
genes sensitive to ultraviolet were modulated in the same way.
Furthermore, 39 expressed sequence tags were modulated, and preliminary
experiments showed that two expressed sequence tags displayed
differential expressions both in melanoma cell lines and in melanoma
tumors. These results provide a basis for further studies on the role of
modulated genes in ultraviolet-induced melanoma. Because some of these
genes are potential markers of the disease, they might help for
developing new molecular-based strategies for risk prediction in
patients.
6
UI - 11886512
AU - Demunter A; Stas M; Degreef H; De Wolf-Peeters C; van den Oord JJ
TI -
Analysis of N- and K-ras mutations in the distinctive tumor progression
phases of melanoma.
SO - J Invest Dermatol 2001 Dec;117(6):1483-9
AD - Department of Pathology, Laboratory of Morphology and Molecular
Pathology, University Hospitals, Katholieke Universiteit Leuven, Leuven,
Belgium. anouk.demunter@uz.kuleuven.ac.be
Mutations in the ras genes are key events in the process of
carcinogenesis; in particular, point mutations in codon 61 of exon 2 of
the N-ras gene occur frequently in cutaneous melanoma. To investigate
whether these mutations occur in early or late tumor progression phases,
we searched for point mutations in the N- and K-ras genes in 69 primary
cutaneous melanoma, 35 metastases, and seven nevocellular nevi in
association with cutaneous melanoma. Lesions were microdissected in
order to procure pure tumor samples from the distinctive growth phases
of the cutaneous melanoma; the very sensitive denaturing gradient gel
electrophoresis technique was used to visualize the mutations, and was
followed by sequencing. Point mutations in the N-ras gene but not in the
K-ras gene were detected on denaturing gradient gel electrophoresis.
Twenty-three primary (33%) and nine metastatic (26%) melanomas showed
bandshifts for N-ras. In the majority of cases, mutations occurring in
early growth phases (i.e., the "intraepidermal" radial growth phase),
were preserved in later growth phases (i.e., the invasive radial growth
phase, vertical growth phase, and metastatic phase), which proves the
clonal relationship between the successive growth phases. In three
cases, however, the mutations differed between the distinctive growth
phases within the same cutaneous melanoma, due to the occurrence of an
additional mutation (especially in codon 61) in a later tumor
progression phase. Our approach also permitted us to analyze the
mutational status of nevi, associated with cutaneous melanoma. Six out
of seven associated nevi carried the same sequence (mutated or
wild-type) as the primary cutaneous melanoma, whereas in one case the
sequence for N-ras differed between the primary melanoma and the
associated nevus. In conclusion, this approach allowed us to demonstrate
the clonal relationship between subsequent growth phases of melanoma and
associated nevi; our results suggest that N-ras exon 1 mutations
preferentially occur during early stages of tumor progression and hence
may be involved in melanoma initiation, whereas those in N-ras exon 2
are found preferentially during later stages and hence are more probably
involved in metastatic spread of cutaneous melanoma.
7
UI - 11886514
AU - Willers J; Urosevic M; Laine E; Geertsen R; Kundig T; Burg G; Dummer R
TI -
Decreased intraindividual HLA class I expression is due to reduced
transcription in advanced melanoma and does not correlate with HLA-G
expression.
SO - J Invest Dermatol 2001 Dec;117(6):1498-504
AD - Department of Dermatology, University Hospital of Zurich, Switzerland.
The presentation of endogenously synthesized peptides in association
with HLA class I molecules allows the activation of CD8(+) lymphocytes.
Tumor cells often fail to present antigenic peptides resulting in the
immune escape of metastasizing cells. The aim of this study was to
elucidate possible molecular mechanisms leading to reduced antigen
presentation in melanoma. Melanoma cell short-time cultures were
genotypically and phenotypically HLA-typed by sequence-specific primer
polymerase chain reaction and complement-mediated
microlymphocytotoxicity assays, respectively. Flow cytometric analysis
of HLA-A2 and HLA-A3 allospecificities were performed to confirm typing
results. Transcriptional levels of classical HLA-A, HLA-B genes and
nonclassical HLA-G genes were detected using quantitative real-time
reverse transcriptase polymerase chain reaction (LightCycler). We found
loss or downregulation of HLA proteins in 18% (for HLA-A) and 53% (for
HLA-B) of all tested metastases. Genomic analysis, however, revealed the
presence of the corresponding HLA class I gene in six out of seven
cases. On the level of gene transcription we observed a differential
regulation of HLA-A, HLA-B, and HLA-G mRNA expression. There was no
correlation between classical and nonclassical HLA gene transcription,
but the transcriptional levels of classical HLA corresponded to the
protein expression levels. Furthermore, an overall reduced amount of HLA
class I gene transcription was observed in melanoma metastases during
disease progression in three individuals. We postulate that there is a
transcriptional regulation of HLA class I gene expression in melanoma
cells. These data suggest that treatment approaches aimed at activating
specific cytotoxic T lymphocytes are most successful in early disease.
8
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.
9
UI - 11731274
AU - Giambernardi TA; Sakaguchi AY; Gluhak J; Pavlin D; Troyer DA; Das G;
TI -
Rodeck U; Klebe RJ
Neutrophil collagenase (MMP-8) is expressed during early development in
neural crest cells as well as in adult melanoma cells.
SO - Matrix Biol 2001 Dec;20(8):577-87
AD - Department of Cellular and Structural Biology, University of Texas
Health Science Center, San Antonio, TX 78284, USA.
troy.giambernardi@vai.org
Matrix metalloproteinase-8 (MMP-8) is a neutral metalloproteinase of the
fibrillar collagenase family that also includes MMP-1 and MMP-13. In
contrast to the other collagenases, MMP-8 has a very limited tissue
distribution, thought to be restricted to neutrophils and chondrocytes.
In a previous study, we observed MMP-8 expression in human melanoma
cells. This observation led us to assess in more detail the expression
of MMP-8 in normal and malignant melanocytic cells. We found that MMP-8
was expressed by 11 out of 12 human melanoma cell lines tested and all
10 primary melanomas we examined, but was not expressed by four primary
neonatal melanocyte strains. Since melanocytes arise from highly motile
neural crest cells, we examined the hypothesis that MMP-8 might be
expressed by neural crest cells. RT-PCR analysis of post-implantation
mouse embryos indicated the presence of MMP-8 transcripts at E9.5. In
situ hybridization and immunohistochemistry of mouse embryos between
E9.5-E14.5 demonstrated MMP-8 expression in the surface ectoderm, neural
crest cells and chondrocytes. MMP-8 was also detected in neural crest
cell migration located in the circumference of the neural tube,
branchial arches and the notochord. In addition, MMP-8 expression was
observed between the somites, in circumscriptive areas of the developing
brain, heart, and eye, and in the interdigital zones of the limbs. In
summary, we found MMP-8 to be the first fibrillar collagenase expressed
during development. In contrast to its restricted tissue expression
post-partum, MMP-8 was present in multiple embryonic tissues, including
neural crest cells. The production of MMP-8 by migrating neural crest
cells may contribute to their ability to degrade fibrillar collagen
matrices while in transit.
10
UI - 11896616
AU - Foletti A; Ackermann J; Schmidt A; Hummler E; Beermann F
TI -
Absence of fibroblast growth factor 2 does not prevent tumor formation
originating from the RPE.
SO - Oncogene 2002 Mar 14;21(12):1841-7
AD - ISREC (Swiss Institute for Experimental Cancer Research), Chemin des
Boveresses 155, CH-1066 Epalinges, Switzerland.
We have analysed the importance of fibroblast growth factor 2 (FGF2) in
tumor development. In a transgenic mouse model (Tyrp1-Tag) tumors form
in the retinal pigment epithelium (RPE), invade surrounding tissues, and
metastasize to lymph node and spleen. To address whether RPE tumor
formation is dependent on FGF2, we generated FGF2-deficient mice. Such
mice appeared healthy and exhibited no impairment of growth or
development. Tyrp1-Tag transgenic mice, which are lacking FGF2 (FGF2-/-)
developed RPE tumors that metastasize to spleen and lymph nodes. Tumor
growth and survival rate are identical to Tyrp1-Tag transgenic
littermates expressing FGF2. Cell lines were isolated from RPE tumors of
wild-type and FGF2-deficient mice. They grow in culture, are pigmented
and form vascularized tumors, when injected subcutaneously into nude
mice of either FGF2-/- or FGF2+/+ genetic background. Kinetics of tumor
growth was identical and independent of presence of FGF2. Together,
these results demonstrate that FGF2 is not essential for tumor formation
of the RPE thus suggesting that tumor growth in general may not be
dependent on FGF2.
11
UI - 11720168
AU - Kroiss MM; Vogt TM; Schlegel J; Landthaler M; Stolz W
TI -
Microsatellite instability in malignant melanomas.
SO - Acta Derm Venereol 2001 Aug-Sep;81(4):242-5
AD - Department of Dermatology, University of Regensburg, Germany.
wilhelm.stolz@klinik.uni-regensburg.de
Microsatellite instability (MSI) is caused by deficient DNA mismatch
repair, and results in a "mutator" phenotype. Recent studies have
produced contradictory results about the frequency and significance of
MSI in malignant melanomas. In this study, we therefore determined the
time of onset and relative frequency of MSI during the progression of
melanocytic tumours, including benign melanocytic naevi. We examined 7
different microsatellite loci in 9 melanocytic naevi, 25 primary
malignant melanomas and 8 melanoma metastases. None of the melanocytic
naevi showed MSI. In contrast, moderate frequency of MSI in 1/12 (8%)
was detected in thin melanomas of <0.75 mm vertical thickness and in 1/8
(12%) of those with a thickness >0.75 mm and < 1.5 mm. The rate of MSI
was increased in tumours thicker than 1.5 mm (2/5) and in melanoma
metastases, with over 25% (2/8) of the lesions investigated. We conclude
that MSI occurs in a considerable subset of malignant melanomas and that
there is a pattern consistent with increasing frequency of MSI with
progression of melanocytic tumours.
12
UI - 11884449
AU - Markel G; Lieberman N; Katz G; Arnon TI; Lotem M; Drize O; Blumberg RS;
TI -
Bar-Haim E; Mader R; Eisenbach L; Mandelboim O
CD66a interactions between human melanoma and NK cells: a novel class I
MHC-independent inhibitory mechanism of cytotoxicity.
SO - J Immunol 2002 Mar 15;168(6):2803-10
AD - Lautenberg Center for General and Tumor Immunology and Sharet Institute
of Oncology, Hadassah Medical School, Jerusalem, Israel.
NK cells are able to kill virus-infected and tumor cells via a panel of
lysis receptors. Cells expressing class I MHC proteins are protected
from lysis primarily due to the interactions of several families of NK
receptors with both classical and nonclassical class I MHC proteins. In
this study we show that a class I MHC-deficient melanoma cell line
(1106mel) is stained with several Ig-fused lysis receptors, suggesting
the expression of the appropriate lysis ligands. Surprisingly, however,
this melanoma line was not killed by CD16-negative NK clones. The lack
of killing is shown to be the result of homotypic CD66a interactions
between the melanoma line and the NK cells. Furthermore, 721.221 cells
expressing the CD66a protein were protected from lysis by YTS cells and
by NK cells expressing the CD66a protein. Redirected lysis experiments
demonstrated that the strength of the inhibitory effect is correlated
with the levels of CD66a expression. Finally, the expression of CD66a
protein was observed on NK cells derived from patients with malignant
melanoma. These findings suggest the existence of a novel class I
MHC-independent inhibitory mechanism of human NK cell cytotoxicity. This
may be a mechanism that is used by some of the class I MHC-negative
melanoma cells to evade attack by CD66a-positive NK cells.
13
UI - 11897551
AU - Cleaver JE; Crowley E
TI -
UV damage, DNA repair and skin carcinogenesis.
SO - Front Biosci 2002 Apr 1;7():d1024-43
AD - UCSF Cancer Center and Department of Dermatology, Box 0808,University of
California, San Francisco, CA 94143-0808, USA. jcleeaver@cc.ucsf.edu
Skin cancer is unique among human cancers in its etiology, accessibility
and the volume of detailed knowledge now assembled concerning its
molecular mechanisms of origin. The major carcinogenic agent for most
skin cancers is well established as solar ultraviolet light. This is
absorbed in DNA with the formation of UV-specific dipyrimidine
photoproducts. These can be repaired by nucleotide excision repair or
replicated by low fidelity class Y polymerases. Insufficient repair
followed by errors in replication produce characteristic mutations in
dipyrimidine sequences that may represent initiation events in
carcinogenesis. Chronic exposure to UVB results in disruption of the
epithelial structure and expansion of pre-malignant clones which undergo
further genomic changes leading to full malignancy. Genetic diseases in
DNA repair, xeroderma pigmentosum, Cockayne syndrome and
trichothiodystrophy, show varied elevated symptoms of sun sensitivity
involving skin cancers and other symptoms including neurological
degeneration and developmental delays. In humans, only xeroderma
pigmentosum shows high levels of cancer, but mouse strains, with any of
the genes corresponding to these diseases knocked-out, show elevated
skin carcinogenesis. The three major skin cancers exhibit characteristic
molecular changes defined by certain genes and associated pathways.
Squamous cell carcinoma involves mutations in the p53 gene; basal cell
carcinoma involves mutations in the PATCHED gene, and melanoma in the
p16 gene. The subsequent development of malignant tumors involves many
additional genomic changes that have yet to be fully cataloged.
14
UI - 11897559
AU - Matsumura Y; Ananthaswamy HN
TI -
Molecular mechanisms of photocarcinogenesis.
SO - Front Biosci 2002 Apr 1;7():d765-83
AD - Department of Immunology, The University of Texas M.D. Anderson Cancer
Center, 1515 Holcombe Blvd., Box 178, Houston, TX, 77030, USA.
Photocarcinogenesis represents the accumulation of genetic changes as
well as immune system modulation, which ultimately lead to the
development of skin cancers. The recent advances in molecular and
cellular biology have clarified the mechanisms of photocarcinogenesis,
including the formation of DNA photoproducts, DNA repair, mutation of
proto-oncogenes and tumor suppressor genes, and UV-induced
immunosuppression. The understanding and further investigation of
photocarcinogenesis is critical to the development of effective
prevention and intervention strategies for human skin cancer.
15
UI - 8674707
AU - Govind S
TI -
Rel signalling pathway and the melanotic tumour phenotype of Drosophila.
SO - Biochem Soc Trans 1996 Feb;24(1):39-44
AD - Department of Biology, City College of CUNY, NY 10031, USA.
16
UI - 9247250
AU - Jang A; Hill RP
TI -
An examination of the effects of hypoxia, acidosis, and glucose
starvation on the expression of metastasis-associated genes in murine
tumor cells.
SO - Clin Exp Metastasis 1997 Sep;15(5):469-83
AD - Ontario Cancer Institute, and Department of Medical Biophysics,
University of Toronto, Canada.
Tumor cells exposed to a growth stress such as low pH, glucose
starvation and hypoxia have been shown to exhibit a transient increase
in experimental metastatic potential, particularly when allowed to
recover under normal growth conditions for a period of 24-48 h. In this
study we examined whether this increase in metastatic ability could be
explained by changes in the expression of a number of different
metastasis-associated genes, when the cells were exposed to similar
conditions (24-48 h exposure to the stress condition followed by 0-48 h
recovery under normal growth conditions). Although the cell lines used
(KHT fibrosarcoma, SCC VII squamous cell carcinoma, and B16F1 melanoma)
demonstrated altered metastatic ability after the treatment, no overall
temporal correlation between changes in the mRNA levels for cathepsin B,
cathepsin L, nm23, TIMP-1, osteopontin, or VEGF and metastatic ability
in the three cell lines was observed. The production of gelatinase A (72
kDa collagenase) and gelatinase B (92 kDa collagenase) was also measured
by gelatin zymography. There was an increase in production of these
enzymes with increasing recovery time, but it did not parallel changes
in metastatic potential. Although these results suggest that the
products of most of the genes studied may not be involved in the
transient metastatic changes, further studies are required to establish
whether changes in protein levels track with changes in mRNA levels for
these genes.
17
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.
18
UI - 10201537
AU - Rowan A; Bataille V; MacKie R; Healy E; Bicknell D; Bodmer W; Tomlinson
TI -
I
Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic
malignant melanomas.
SO - J Invest Dermatol 1999 Apr;112(4):509-11
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research
Fund, London, UK.
Germline mutations in the LKB1/STK11 gene cause characteristic
hamartomas and freckling to develop in patients with Peutz-Jeghers
syndrome (PJS). The hamartomas arise as a result of somatic "second
hits" at LKB1/STK11 and therefore contain a neoplastic element. The
origin of the pigmented lesions in PJS is unknown and difficult to test,
as these are hardly ever biopsied. PJS patients are at increased risk of
benign and malignant tumors, particularly of the colon, breast,
pancreas, testis, and ovary, although the increased risk for any one of
these sites may be quite modest. Somatic LKB1/STK11 mutations have been
found, albeit at a low frequency, in sporadic tumors of the colon,
stomach, ovary, and testis. Although PJS patients are not known to have
an excess of skin tumors, if the freckles of PJS patients are actually
small, benign tumors, LKB1/STK11 mutations must provide these lesions
with a selective advantage, and similar mutations might also give a
selective advantage to related malignant tumors, such as melanomas. We
have therefore screened 16 melanoma cell lines, 15 primary melanomas,
and 19 metastases for LKB1/STK11 mutations. Two LKB1/STK11 mutations
were found: a missense change (Y49D) accompanied by allele loss in a
cell line; and a missense change (G135R), without a detected mutation in
the other allele, in a primary tumor. Both these mutations are highly
likely to be pathogenic. Novel polymorphisms, including an unusual
heptanucleotide repeat, were also found in introns 2 and 3. LKB1/STK11
mutations occur in a significant minority of tumors of several sites,
including malignant melanomas.
19
UI - 10373682
AU - Korabiowska M; Brinck U; Ruschenburg I; Honig JF; Stachura J; Droese M
TI -
Loss of DNA-mismatch repair gene expression in oral melanomas.
SO - Oncol Rep 1999 Jul-Aug;6(4):921-3
AD - Department of Cytopathology, Georg August University Gottingen, D-37075
Gottingen, Germany.
The defect of DNA mismatch repair is postulated to be responsible for
malignant transformation in many types of tumours. The main aim of this
study was to evaluate the expression of DNA mismatch repair proteins in
29 cases of oral melanomas and to relate this to the ploidy status of
the lesions. MLH1 expression was found in 4/29, MSH2 in 6/29, PMS2 in
2/29 and PMS1 in 0/29 cases investigated. The range of positively
stained cells did not exceed 50% with MSH2, and PMS2, or 5% with MLH1.
Loss of the DNA mismatch repair gene expression correlated with high
aneuploidy ratio, observed in totally negative cases.
20
UI - 11198475
AU - Korabiowska M; Brinck U; Kotthaus I; Berger H; Droese M
TI -
Comparative study of the expression of DNA mismatch repair genes, the
adenomatous polyposis coli gene and growth arrest DNA damage genes in
melanoma recurrences and metastases.
SO - Melanoma Res 2000 Dec;10(6):537-44
AD - Department of Cytopathology, Georg-August University Gottingen, Germany.
The main goal of this study was to examine the expression of DNA
mismatch repair genes (MLH1, MSH2, PMS1 and PMS2), the adenomatous
polyposis coli (APC) gene and growth arrest DNA damage inducible (GADD)
genes (GADD34, GADD45 and GADD153) in the different stages of melanoma
recurrences and metastases, and to identify any mutual consistencies in
their expression pattern. All the cases of primary melanoma examined
showed a reduced expression of DNA repair genes. These results
demonstrate that disturbances of DNA repair begin in the early stages of
melanoma. No significant differences were found in the expression of
these markers between cutaneous melanomas and their recurrences and
metastases (P> 0.05). Eighteen significant correlations between markers
were found in the primary melanomas, and 10 significant correlations
were observed in the first recurrences of melanoma. In contrast, 27
statistically significant relationships were demonstrated in metastatic
lymph nodes. The different correlations found in primary and metastatic
tumours confirmed the hypothetical difference in marker interaction in
the diagnostic groups investigated. Our results suggest that DNA repair
genes may play an important role in the recurrence and metastasis of
melanomas.
21
UI - 11205295
AU - Korabiowska M; Brinck U; Dengler H; Stachura J; Schauer A; Droese M
TI -
Analysis of the DNA mismatch repair proteins expression in malignant
melanomas.
SO - Anticancer Res 2000 Nov-Dec;20(6B):4499-505
AD - Department of Cytopathology, Georg August University Gottingen, Robert
Koch Str. 40, 37075 Gottingen, Germany.
The importance of properly functioning DNA mismatch repair has been
shown in several tumour types both hereditary and sporadic, but not yet
in malignant melanomas. The aim of this study was to examine the
expression of DNA mismatch repair genes (MLH1, MSH2, PMS1 and PMS2) in
primary melanomas and to define their possible prognostic impact in 106
primary melanomas. MLH1 was found in 64 and MSH2 in 61 out of 106
melanomas. PMS1 and PMS2 proteins were present in 69 and 67 tumours,
respectively. Loss of the expression of DNA mismatch repair proteins
correlated with the increase of Clark levels. Cox regression analysis
demonstrated some prognostic significance for PMS1 (forward p = 0.0018
and backward selections p = 0.0277), MLH1 (only forward selection p =
0.0081) and MSH2 (only backward selection p = 0.0115).
22
UI - 11295034
AU - Yu YX; Heller A; Liehr T; Smith CC; Aurelian L
TI -
Expression analysis and chromosome location of a novel gene (H11)
associated with the growth of human melanoma cells.
SO - Int J Oncol 2001 May;18(5):905-11
AD - Virology/Immunology Laboratories, Department of Pharmacology and
Experimental Therapeutics, University of Maryland School of Medicine,
Baltimore, MD 21201, USA.
We have previously described the isolation of a new human gene, H11,
that codes for a 25 kDa phosphoprotein with autokinase activity the
expression of which is required for cell growth. The data described in
this report extend these findings. Using FISH and M-FISH we show that
H11 which maps at chromosome site 12q24.1-12q24.31 is not involved in
chromosomal translocations. The tissue distribution of H11 mRNA is
restricted, with expression being most abundant in skeletal muscle,
heart, prostate and placenta. The H11 protein is cytoplasmic and it is
associated with the plasma membrane. Cell surface localization in
particulate aggregate formations suggests that it may be complexed to
proteins involved in the transfer of extracellular growth signals.
23
UI - 11309305
AU - Tschentscher F; Prescher G; Horsman DE; White VA; Rieder H; Anastassiou
TI -
G; Schilling H; Bornfeld N; Bartz-Schmidt KU; Horsthemke B; Lohmann DR;
Zeschnigk M
Partial deletions of the long and short arm of chromosome 3 point to two
tumor suppressor genes in uveal melanoma.
SO - Cancer Res 2001 Apr 15;61(8):3439-42
AD - Institut fur Humangenetik, Universitatsklinikum Essen, Hufelandstrasse
55, D-45122 Essen, Germany.
Uveal melanoma is the most common form of primary eye cancer. Monosomy
3, which is an unusual finding in tumors but is present in approximately
50% of uveal melanomas, is significantly correlated with metastatic
disease. To obtain positional information on putative tumor suppressor
genes on this chromosome, we have investigated tumors from 333 patients
by comparative genomic hybridization, microsatellite analysis, or
conventional karyotype analysis. A partial deletion of the long arm was
found in eight tumors, and the smallest region of deletion overlap (SRO)
spans 3q24-q26. We found six tumors with a partial deletion of the short
arm and were able to define a second SRO of about 2.5 Mb in 3p25. This
SRO does not overlap with the VHL gene. Our finding suggests a role for
two tumor suppressor genes in metastasizing uveal melanoma and may
explain the loss of an entire chromosome 3 in these tumors.
24
UI - 11911283
AU - Giermasz A; Grzela T; Nowis D; Makowski M; Czajka A; Stoklosa T; Lasek
TI -
W; Dabrowsk A; Wiznerowicz M; Mackiewicz A; Jakobisiak M
Butyric acid enhances in vivo expression of hTNF-alpha in transduced
melanoma cell line.
SO - Anticancer Res 2001 Nov-Dec;21(6A):4001-4
AD - Department of Immunology, Centre for Biostructure Research, The Medical
University of Warsaw, Poland.
Butyric acid (NaBut) and its derivatives are well-known agents eliciting
tumor cell differentiation and apoptosis. In experimental models, NaBut
is also used to enhance the efficacy of viral vectors. With the use of
B78 murine melanoma cells transduced with the retroviral vector
containing human tumor necrosis factor alpha (hTNF-alpha) gene, we
investigated the ability of NaBut to increase the cytokine expression.
We observed an increase in hTNF-alpha expression in vitro after
incubation with NaBut. We also describe that the NaBut pro-drug
tributyrin is able to increase hTNF-alpha expression in transduced B78
cells in a tumor vaccination model in mice. This observation strongly
suggests a novel potential role for NaBut and its derivatives in tumor
therapy. It could be used not only as a therapeutic directly acting on
tumor cells but, in parallel, as a genetic vaccine "enhancer".
25
UI - 11918086
AU - Denkert C; Siegert A; Leclere A; Turzynski A; Hauptmann S
TI -
An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2
expression of malignant melanoma cells.
SO - Clin Exp Metastasis 2002;19(1):79-85
AD - Institute of Pathology, Charite Hospital, Berlin, Germany.
A lot of parallels have been described between invasion of malignant
tumor cells and leukocyte movement during inflammatory responses.
Concerning these similarities, we investigated the function of
cytokine-suppressive anti-inflammatory drugs (CSAIDs), which act via
inhibition of stress-activated MAP-kinases, in regulation of expression
of proteolytic enzymes and in vitro invasion of malignant melanoma
cells. The p38MAPK inhibitor SB203580 reduced matrigel invasion of MeWo
cells by 60%, while the MEK-1 inhibitor PD98059 did not have any effect
on invasion. Active p38MAPK was detected in MeWo cells by immunoblotting
and confocal microscopy. Cells showed a constitutive expression of
matrix-metalloproteinase (MMP)-2 as well as tissue inhibitor of
metalloproteinases (TIMP)-1 and TIMP-2 mRNAs. Expression of MMP-1 or
urokinase-type plasminogen activator (uPA) was not detected by Northern
blot. Inhibition of p38MAPK by the specific inhibitor SB203580 resulted
in downregulation of MMP-2 mRNA and protein levels as well as
gelatinolytic activity, while expression levels of TIMP-1 and TIMP-2
mRNAs were not changed. The specific MEK-1 inhibitor PD98059 did not
change expression of MMP-2 or TIMPs. Neither SB203580 nor PD98059
changed proliferation of cells. The results suggest that
stress-activated protein kinases like p38MAPK are involved in regulation
of expression of MMP-2 as well as in vitro invasion of malignant
melanoma cells. Inhibitors of p38MAPK may be promising substances to
interfere with a signaling cascade associated with invasion of malignant
tumor cells.
26
UI - 11904424
AU - Lewis JM; Truong TN; Schwartz MA
TI -
Integrins regulate the apoptotic response to DNA damage through
modulation of p53.
SO - Proc Natl Acad Sci U S A 2002 Mar 19;99(6):3627-32
AD - Department of Vascular Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, CVN228/VB4, La Jolla, CA 92037, USA.
p53 mediates apoptosis of cells after DNA damage including tumor cells
after radiation or chemotherapy. Survival of isolated cancer cells after
therapy leads to recurrence of therapy-resistant tumors. We now show
that for some melanoma, sarcoma, or fibroblastic cell types that survive
without integrin-mediated adhesion, apoptosis in response to DNA damage
requires cell adhesion. This effect correlates with rapid changes in
levels of p14/p19 Arf and its downstream component, p53. Killing of
nonadherent cells is increased by treatment with antiintegrin antibodies
or by increasing levels of p53 or Arf. Consistent with low p53 levels,
suspended cells show chromosomal instability after irradiation. Thus,
loss of normal adhesion in susceptible tumor cells during genotoxic
stress may play a role in therapy resistance and promote survival of
cells with aberrant DNA.
27
UI - 11891271
AU - Kashani-Sabet M; Liu Y; Fong S; Desprez PY; Liu S; Tu G; Nosrati M;
TI -
Handumrongkul C; Liggitt D; Thor AD; Debs RJ
Identification of gene function and functional pathways by systemic
plasmid-based ribozyme targeting in adult mice.
SO - Proc Natl Acad Sci U S A 2002 Mar 19;99(6):3878-83
AD - Auerback Melanoma Research Laboratory, Cutaneous Oncology Program,
University of California at San Francisco Cancer Center and Department
of Dermatology, University of California, San Francisco, CA 94115, USA.
To date, functional genomic studies have been confined to either
cell-based assays or germline mutations, using transgenic or knockout
animals. However, these approaches are often unable either to
recapitulate complex biologic phenotypes, such as tumor metastasis, or
to identify the specific genes and functional pathways that produce
serious diseases in adult animals. Although the transcription factor
NF-kappaB transactivates many metastasis-related genes in cells, the
precise genes and functional-pathways through which NF-kappaB regulates
metastasis in tumor-bearing hosts are poorly understood. Here, we show
that the systemic delivery of plasmid-based ribozymes targeting
NF-kappaB in adult, tumor-bearing mice suppressed NF-kappaB expression
in metastatic melanoma cells, as well as in normal cell types, and
significantly reduced metastatic spread. Plasmid-based ribozymes
suppressed target-gene expression with sequence specificity not
achievable by using synthetic oligonucleotide-based approaches.
NF-kappaB seemed to regulate tumor metastasis through invasion-related,
rather than angiogenesis-, cell-cycle- or apoptosis-related pathways in
tumor-bearing mice. Furthermore, ribozymes targeting either of the
NF-kappaB-regulated genes, integrin beta(3) or PECAM-1 (a
ligand-receptor pair linked to cell adhesion), reduced tumor metastasis
at a level comparable to NF-kappaB. These studies demonstrate the
utility of gene targeting by means of systemic, plasmid-based ribozymes
to dissect out the functional genomics of complex biologic phenotypes,
including tumor metastasis.
28
UI - 11841510
AU - Hussein MR; Wood GS
TI -
Microsatellite instability in human melanocytic skin tumors: an
incidental finding or a pathogenetic mechanism?
SO - J Cutan Pathol 2002 Jan;29(1):1-4
AD - The Department of Medicine (Dermatology), University of Wisconsin,
Madison, Wisconsin 53705, USA.
29
UI - 11805321
AU - Kang DC; Gopalkrishnan RV; Wu Q; Jankowsky E; Pyle AM; Fisher PB
TI -
mda-5: An interferon-inducible putative RNA helicase with
double-stranded RNA-dependent ATPase activity and melanoma
growth-suppressive properties.
SO - Proc N
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