National Cancer Institute®
Last Modified: June 1, 2002
UI - 12011229
AU - Pedeux R; Boniol M; Autier P; Dore JF
TI - Re: DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.
SO - J Natl Cancer Inst 2002 May 15;94(10):772-3; discussion 773-4
UI - 11814456
AU - Max N; Wolf K; Thiel E; Keilholz U
TI - Quantitative nested real-time RT-PCR specific for tyrosinase transcripts to quantitate minimal residual disease.
SO - Clin Chim Acta 2002 Mar;317(1-2):39-46
AD - Department of Medicine III, University Hospital Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
BACKGROUND: Quantification of tumor markers expressed by occult-circulating tumor cells may be of prognostic value in a variety of neoplasms and disease stages. Here, we report on a quantitative nested real-time polymerase chain reaction (PCR) assay to quantify rare transcripts using the Light Cycler system. Tyrosinase mRNA, only expressed by melanocytes and melanoma cells, was used as the model tumor marker. METHODS: For the establishment and sensitivity testing of this novel real-time PCR assay, 10 ml EDTA blood from healthy volunteers was spiked with 10(1)-10(5) MKR cells (the melanoma cell line). Following RNA extraction and cDNA synthesis, nested and single round PCRs were performed. Subsequently, 35 blood samples of 22 melanoma patients were analyzed. RESULTS: Nested PCRs provided quantitative data with a quantitative range of five orders of magnitude of tyrosinase mRNA equivalent to 1-10(4) MKR cells/ml of blood. Nested PCR with 35 pre-amplification cycles displayed the quantitative data for nine tyrosinase transcript-positive samples out of 35 blood samples, whereas nested PCR with 20 pre-amplification cycles or single round PCR were less sensitive. CONCLUSIONS: These experiments indicate that nested PCR, which is much more sensitive than single round PCR, is a useful tool even for the quantification of rare transcripts-a result with important implications for the study of minimal residual disease (MRD) in melanoma as well as in other malignancies.
UI - 11828252
AU - Herlyn M
TI - Emerging concepts and technologies in melanoma research.
SO - Melanoma Res 2002 Feb;12(1):3-8
AD - The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. email@example.com
Melanoma research has made great advances in recent years. Particularly in the field of immunology, melanoma researchers have opened new avenues for basic and translational cancer research overall. Emerging research areas such as molecular epidemiology promise to develop a similar leadership role. On the other hand, research in biology, genetics or experimental therapy of melanoma has remained confined to few laboratories and entire research areas are not covered due to lack of researchers and resources. New developments in defining stem cells in skin and bone marrow enable us to develop new concepts for melanoma development and progression. New technologies allow rapid progress but they require close cooperation between laboratories. The field has to better bridge experimental with clinical research and increase communication. Corroboration with advocacy groups should activate the public for increased awareness and funding.
UI - 11828258
AU - Goldstein AM; Chidambaram A; Halpern A; Holly EA; Guerry IV D; Sagebiel
TI - R; Elder DE; Tucker MA Rarity of CDK4 germline mutations in familial melanoma.
SO - Melanoma Res 2002 Feb;12(1):51-5
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. firstname.lastname@example.org
To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons of CDK4 and screened additional members of two previously reported families with the Arg24Cys germline CDK4 mutation to evaluate the penetrance of the mutation. No new CDK4 mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 invasive melanoma patients, none out of one in situ melanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-prone CDK4 families appears to be more complex than just the CDK4 mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, although CDK4 is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma.
UI - 11828259
AU - de Wit NJ; Burtscher HJ; Weidle UH; Ruiter DJ; van Muijen GN
TI - Differentially expressed genes identified in human melanoma cell lines with different metastatic behaviour using high density oligonucleotide arrays.
SO - Melanoma Res 2002 Feb;12(1):57-69
AD - Department of Pathology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands. email@example.com
The increasing incidence of melanoma and the lack of effective treatment, with the exception of tumour excision before the onset of the metastatic phase, make it important to identify genes that may function as new molecular markers for diagnosis and/or prognosis or as new targets for therapy. Recently, a new technique using high density oligonucleotide arrays has been developed to simultaneously screen for the expression of thousands of genes. We used this technique to compare the mRNA expression patterns of two human melanoma cell lines with different metastatic behaviour. Eight differentially expressed genes, namely apolipoprotein CII, tyrosinase-related protein 1, transforming growth factor-beta superfamily, subtilisin-like protein, elongation factor 1 alpha2, alpha2-macroglobulin, human cell division cycle 10 and serine/threonine protein kinase (DYRK1A), were selected to validate the array results by Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, a reliable correlation between differential expression of these genes in the melanoma cell lines and in fresh lesions of melanocytic tumour progression was demonstrated by RT-PCR analysis. Altogether, our data indicate that high density oligonucleotide arrays are a valuable and reliable tool to screen for differentially expressed genes, and that our study may be considered a basic step in the characterization of genes that are involved in the (malignant) progression of melanoma.
UI - 11828261
AU - Hofbauer GF; Boni R; Simmen D; Mihic D; Nestle FO; Burg G; Dummer R
TI - Histological, immunological and molecular features of a nasal mucosa primary melanoma associated with nasal melanosis.
SO - Melanoma Res 2002 Feb;12(1):77-82
AD - Department of Dermatology, Head and Neck Surgery, University Hospital, Gloriastrasse 31, 8091 Zurich, Switzerland.
Nasal mucosa melanoma is a rare entity that may occur together with nasal melanosis. The histological and immunological features and loss of heterozygosity analysis of such lesions have not been reported to date. In the study presented here short-term cell cultures were established from the patient's melanoma and subsequent relapses. Histology, immunohistochemistry, reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay, human leukocyte antigen analysis, microdissection with subsequent polymerase chain reaction for analysis of loss of heterozygosity were used to characterize the tumour and other cells. Melanoma of the nasal cavity was found, with a surrounding proliferation of atypical melanocytes corresponding to nasal melanosis. Immunoreactivity was found for S-100, gp100, tyrosinase and MelanA protein. Loss of heterozygosity for a p16-flanking marker was found in the tumour and the melanotic cells. Short-term cell cultures expressed tyrosinase and MUC18 at the mRNA level and intercellular adhesion molecule-1 (ICAM-1) and interleukin-12 receptor at the protein level. This is the first time short-term cell cultures have been established and analysed from such a tumour. Melanoma-associated antigens were identified within the tumour. The melanoma and the melanotic cells showed loss of heterozygosity for the p16 gene, which is implicated in melanoma development. This points to a common origin in tumorigenesis. Pathways of tumour escape, such as expression of CD54 and interleukin-10, were observed. The clinical, immunological and molecular features suggest that nasal melanosis should be followed closely.
UI - 11828253
AU - Fuzii HT; Travassos LR
TI - Transient resistance to B16F10 melanoma growth and metastasis in CD43-/- mice.
SO - Melanoma Res 2002 Feb;12(1):9-16
AD - Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Sao Paulo, Brazil.
CD43, the major transmembrane sialoglycoprotein of neutrophils, monocytes, T lymphocytes and platelets, is highly glycosylated and its high sialic acid content contributes to the strongly negative charge of cells. In this study the role of CD43 in melanoma development was addressed using CD43 -/- mice (null mutated for the corresponding gene or knockout [KO]). Growth of B16F10 melanoma was retarded in the KO mice compared with the wild-type CD43+/+ control (WT). A marked difference in lung colonization and other metastatic foci was observed in the KO and WT mice up to 15 days after intravenous injection of tumour cells. The initial resistance of KO mice was reversed with time, and in the long term there was no difference in the survival rate of the two animal groups. Transient resistance was attributed to increased adhesion of thrombin-activated platelets and leukocytes to melanoma and endothelial cells in KO mice. In the KO mice tumour emboli were found in the central portion of the lung more than at the lung periphery immediately after intravenous injection, in contrast to the WT mice. Activation of melanoma adhesion receptors by thrombin or TRAP stimulated lung colonization in WT but not KO mice. Therefore, the correlation of tumour embolism and metastasis in short-term experiments depends on the nature and stability of interactions between the tumour and the blood/endothelial cells of the host.
UI - 11836234
AU - Rhodes DR; Miller JC; Haab BB; Furge KA
TI - CIT: identification of differentially expressed clusters of genes from microarray data.
SO - Bioinformatics 2002 Jan;18(1):205-6
AD - Laboratory of DNA and Protein Microarray Technology, Van Andel Research Institute, Grand Rapids, MI 49053, USA.
Cluster Identification Tool (CIT) is a microarray analysis program that identifies differentially expressed genes. Following division of experimental samples based on a parameter of interest, CIT uses a statistical discrimination metric and permutation analysis to identify clusters of genes or individual genes that best differentiate between the experimental groups. CIT integrates with the freely available CLUSTER and TREEVIEW programs to form a more complete microarray analysis package.
UI - 12001124
AU - Blackwood MA; Holmes R; Synnestvedt M; Young M; George C; Yang H; Elder
TI - DE; Schuchter LM; Guerry D; Ganguly A Multiple primary melanoma revisited.
SO - Cancer 2002 Apr 15;94(8):2248-55
AD - Department of Medicine, Hematology-Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6145, USA.
BACKGROUND: Incidence of cutaneous melanoma continues to increase in the Caucasian population worldwide. Approximately 5% of melanoma patients develop additional primary melanoma. This rate is significantly higher than the estimated lifetime risk of an individual for developing the disease (1.4%). These features suggest that a genetic predisposition may underlie multiple primary melanomas (MPMs). Prior studies had identified CDKN2A mutations in a few MPM individuals. The objectives of this study were to determine the frequency of family history of melanoma in MPM cases, to characterize other clinical features including history of other cancer, and to determine the association with functional CDKN2A mutations. METHODS: This study used a case series design. All living patients who had been seen in the Pigmented Lesion Clinic at the University of Pennsylvania and who had more than one primary invasive malignant melanoma or an invasive primary followed by an in situ melanoma were eligible for participation. RESULTS: Individuals with MPM frequently had a family history of melanoma, dysplastic nevi (DN), and/or another cancer including basal cell carcinoma (BCC), and squamous cell carcinoma breast cancer, and a personal history of DN, and basal cell carcinoma. Germline mutations in CDKN2A gene were identified in 8 of 96 MPM cases (8.3%, 95% confidence interval, 6.7-9.9%). CONCLUSIONS: These data indicate that the presence of MPM is associated with a modest incidence of a family history of melanoma, DN, or BCC and a small association with CDKN2A mutations. Therefore, in addition to the MPM index case, other family members can benefit from screening and regular surveillance for melanoma, DN, and BCC. Copyright 2002 American Cancer Society.
UI - 11979433
AU - Papadopoulos S; Benter T; Anastassiou G; Pape M; Gerhard S; Bornfeld N;
TI - Ludwig WD; Dorken B Assessment of genomic instability in breast cancer and uveal melanoma by random amplified polymorphic DNA analysis.
SO - Int J Cancer 2002 May 10;99(2):193-200
AD - Department of Obstetrics and Gynecology, Free University of Berlin, Berlin, Germany.
Some types of cancer have been associated with abnormal DNA fingerprinting. We used random amplified polymorphic DNA (RAPD) to generate fingerprints that detect genomic alterations in human breast cancer. Primers were designed by choosing sequences involved in the development of DNA mutations. Seventeen primers in 44 different combinations were used to screen a total of 6 breast cancer DNA/normal DNA pairs and 6 uveal melanoma DNA/normal DNA pairs. Forty-five percent of these combinations reliably detected quantitative differences in the breast cancer pairs, while only 18% of these combinations detected differences in the uveal melanoma pairs. Fourteen (32%) and 12 (27%) primers generated a smear or did not produce any band patterns in the first and second cases, respectively. Taking into account the ability of RAPD to screen the whole genome, our results suggest that the genomic damage in breast cancer is significantly higher than in uveal melanoma. Our study confirms other reports that the molecular karyotypes produced with random priming, called amplotypes, are very useful for assessing genomic damage in cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 12034846
AU - Stewart DA; Xu X; Thomas SD; Miller DM
TI - Acridine-modified, clamp-forming antisense oligonucleotides synergize with cisplatin to inhibit c-Myc expression and B16-F0 tumor progression.
SO - Nucleic Acids Res 2002 Jun 1;30(11):2565-74
AD - Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
The c-myc protooncogene plays a key role in the abnormal growth regulation of melanoma cells. We have targeted three polypurine sequences within the mouse myc mRNA with acridine-modified, clamp-forming antisense oligonucleotides (AS ODNs) in an effort to inhibit growth of murine melanoma cells. These ODNs are unique in that they hybridize to the target mRNA by both Watson-Crick and Hoogsteen hydrogen bond interactions, forming a triple-stranded structure. At a concentration of 3 microM E1C, E2C and E3C inhibit B16-F0 proliferation by 76, 66 and 78%, respectively. Both immunofluorescent staining and western blot analysis corroborate a proportional reduction in c-Myc expression by all three ODNs. There were clear distinctions in the ability of these ODNs to inhibit tumor progression in C57BL/6 mice as a function of Myc expression. There was no synergy demonstrated between ODN E1C with cisplatin (DDP), which inhibited tumor growth by 77% alone and 82% in combination. Although E2C inhibited growth by 54%, its effect was decreased to 32% with DDP, when compared with controls. E3C, on the other hand, demonstrated a synergistic effect with DDP, inhibiting growth by 72% in combination, but only by 1% as a single agent. Immunofluorescence analysis of tumors for each group revealed a concomitant reduction in c-Myc expression in tumors from mice treated with the most active clamp ODN alone (E1C) or clamp ODN + DDP (E1C/E3C + DDP). Western blot analysis confirmed this decrease in target protein expression. Our results document the growth-inhibitory activity of two myc-targeting antisense clamp ODNs; E1C, which has activity as a single agent, and E3C, which has in vivo synergy with DDP pretreatment. These data confirm the antiproliferative effects of these novel ODNs and document an interesting synergy with the chemotherapeutic agent DDP.
UI - 11774594
AU - Todryk S; Birchall L; Erlich R; Halanek N; Orleans-Lindsay JK; Dalgleish
TI - A Cytokine gene transfection for autologous and allogeneic melanoma vaccines.
SO - Adv Exp Med Biol 2001;495():365-8
AD - Tumour Immunology Group, Institute for Immunology, Department of Biology, National University of Ireland, Maynooth, Ireland.
UI - 11774596
AU - Dams-Kozlowska H; Izycki D; Mackiewicz A
TI - IL-11 is a potent anti-melanoma factor.
SO - Adv Exp Med Biol 2001;495():373-7
AD - Department of Cancer Immunology, Academy of Medicine, GreatPoland Cancer Center, Poznan, Poland.
UI - 11774599
AU - Grabarczyk P; Gryska K; Wysocki PJ; Izycki D; Mackiewicz A
TI - Improving the retroviral vector (RV) systems for immunotherapy of cancer.
SO - Adv Exp Med Biol 2001;495():389-92
AD - Department of Cancer Immunology, University School of Medical Sciences, GreatPoland Cancer Center, Poznan, Poland.
UI - 11774600
AU - de Zoeten EF; Li D; Cohen EP
TI - Tumor immunity in mice immunized with fibroblasts transfected with tumor DNA.
SO - Adv Exp Med Biol 2001;495():393-401
AD - Department of Microbiology and Immunology, University of Illinois, Chicago, Illinois 60612, USA.
UI - 11774603
AU - Nawrocki S; Laciak M; Izycki D; Gryska K; Wysocki PJ; Grabarczyk P;
TI - Karczewska A; Kaczmarek A; Murawa P; Malicki J; Rose-John S; Mackiewicz A Humoral responses to melanoma vaccine, genetically modified with interleukin 6 and soluble interleukin 6 receptor.
SO - Adv Exp Med Biol 2001;495():411-8
AD - GreatPoland Cancer Centre, Garbary 15, Poznan, Poland.
UI - 11774606
AU - Skowronek J; Karas Z; Krenz RM; Warchol JB
TI - Flow and video-imaging cytometry--usefulness of DNA ploidy measurements in diagnosis of malignant melanoma.
SO - Adv Exp Med Biol 2001;495():435-8
AD - Department of Radiotherapy, GreatPoland Cancer Center, Poznan, Poland.
UI - 11966686
AU - Campos EI; Cheung KJ Jr; Murray A; Li S; Li G
TI - The novel tumour suppressor gene ING1 is overexpressed in human melanoma cell lines.
SO - Br J Dermatol 2002 Apr;146(4):574-80
AD - Department of Medicine, Division of Dermatology, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, BC, Canada.
BACKGROUND: Epidemiological evidence indicates that exposure to ultraviolet (UV) radiation is directly linked to the increase of both incidence and mortality of melanoma. However, the genetic changes caused by UV radiation that lead to melanoma formation remain poorly understood. Recently, a potential tumour suppressor gene ING1 (inhibitor of growth 1) was shown to inhibit cell growth and induce apoptosis in the presence of p53. We have demonstrated that the expression of ING1 is induced after UV irradiation and that ING1 enhances the repair of UV-damaged DNA. OBJECTIVES: To investigate if ING1 plays a role in melanoma formation. METHODS: We examined p33ING1 expression levels in 14 melanoma cell lines. RESULTS: We found that p33ING1 is overexpressed at both mRNA and protein levels in melanoma cell lines compared with normal melanocytes. Single-strand conformation polymorphism (SSCP) analysis showed band shifting in two melanoma cell lines. DNA sequencing confirmed that there were nucleotide alterations in the ING1 gene in Sk-mel-24 and Sk-mel-110 cell lines. Two silent nucleotide alterations in exon 1a were detected in Sk-mel-110. In Sk-mel-24, the A-->G nucleotide alteration at codon 260 resulted in an amino acid change from Asn to Ser, while seven other nucleotide alterations were silent. To determine if the silent nucleotide alterations in these two melanoma cell lines were due to polymorphism, SSCP analysis of ING1 gene was performed in 25 healthy volunteers. No band shift was observed in the SSCP analysis, suggesting that the nucleotide alterations in the melanoma cell lines are unlikely to be due to polymorphism. CONCLUSIONS: Taken together, our data demonstrate that ING1 is overexpressed, but infrequently mutated, in melanoma cell lines.
UI - 11924907
AU - Sigalotti L; Coral S; Nardi G; Spessotto A; Cortini E; Cattarossi I;
TI - Colizzi F; Altomonte M; Maio M Promoter methylation controls the expression of MAGE2, 3 and 4 genes in human cutaneous melanoma.
SO - J Immunother 2002 Jan-Feb;25(1):16-26
AD - Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Cancer-testis antigens expressed by different-histotype transformed cells are suitable targets for tumor immunotherapy. However, their heterogeneous expression in neoplastic lesions limits the eligibility of patients for cancer-testis antigen-directed vaccination, and low levels of cancer-testis antigens' expression may impair immune recognition of malignant cells. Because of the primary clinical relevance of cancer-testis antigens' expression in neoplastic tissues, 68 unrelated or sequential metastatic lesions from 56 patients were used to characterize the molecular mechanisms regulating the presence and levels of expression of different cancer-testis antigens of the MAGE family (i.e., MAGE2, 3 and 4) in cutaneous melanoma. Polymerase chain reaction-based methylation analyses showed that methylation status of specific cytosine-guanine dinucleotides in the promoters of investigated cancer-testis antigens correlated with their heterogeneous expression within unrelated metastatic melanoma lesions, and with their homogeneous expression among sequential metastases from three patients with melanoma. Unlike methylated promoters, unmethylated promoters of MAGE2, 3 and 4 genes drove the expression of reporter gene-enhanced green fluorescent protein after transient transfection of cancer-testis antigen-positive Mel 142 melanoma cells. Furthermore, de novo expression of MAGE3 gene induced by the treatment of Mel 195 melanoma cells with the DNA hypomethylating agent 5-aza-2'-deoxycytidine was associated with a 6%-12% demethylation of selected cytosine-guanine dinucleotides in its promoter. Finally, 5-aza-2'-deoxycytidine induced a 16-fold increase of MAGE3 expression in Mel 313 melanoma cells expressing constitutively low levels of the antigen, but did not affect that of Mel 275 melanoma cells expressing high baseline levels of MAGE3. Overall, these findings identify promoter methylation as a shared mechanism directly regulating the expression of therapeutic cancer-testis antigens in metastatic melanomas, and foresee the clinical use of 5-aza-2'-deoxycytidine to design new chemoimmunotherapeutic strategies in patients with melanoma.
UI - 11921401
AU - Tietze LF; Griesbach U; Bothe U; Nakamura H; Yamamoto Y
TI - Novel carboranes with a DNA binding unit for the treatment of cancer by boron neutron capture therapy.
SO - Chembiochem 2002 Mar 1;3(2-3):219-25
AD - Institut fur Organische, Chemie Georg-August-Universitat Gottingen, Tammannstrasse 2, 37077 Gottingen, Germany. firstname.lastname@example.org
The synthesis and biological evaluation of two ortho-carborane derivatives which contain a 5,6,7-trimethoxyindole (TMI) unit for use in boron neutron capture therapy is described. The TMI moiety is known to be the DNA-binding part of the highly potent anticancer agent duocarmycin A. The ortho-carborane derivatives were prepared from amino alkynes which were bound to a protected TMI carboxylic acid. Addition of decaborane(14) to the alkyne triple bond with subsequent removal of the tert-butoxycarbonyl (Boc) and benzyl protecting groups gave the desired product. Boron uptake from the ortho-carborane derivatives into B-16 melanoma cells was higher and faster than that observed with L-p-boronophenylalanine (BPA), which is in use in the clinic.
UI - 11992404
AU - Zendman AJ; Van Kraats AA; Weidle UH; Ruiter DJ; Van Muijen GN
TI - The XAGE family of cancer/testis-associated genes: alignment and expression profile in normal tissues, melanoma lesions and Ewing's sarcoma.
SO - Int J Cancer 2002 May 20;99(3):361-9
AD - Department of Pathology, University Medical Center St. Radboud, Nijmegen, The Netherlands. H.Zendeman@pathol.azn.nl
The existence of XAGE genes was first reported after database homology searches for PAGE-like sequences identified 3 XAGE EST clusters. One of these clusters, XAGE-1, has in later studies been identified as a cancer/testis-associated gene. Here, we report the expression profiles of all 3 reported XAGE genes, as well as several splice variants of XAGE-1, in normal human tissues, Ewing's sarcoma and melanocytic tumors. We also provide the genetic structure of the corresponding genes. Moreover, by searching the databases for XAGE homologues, we identified 3 additional GAGE-like genes. RT-PCR studies showed frequent expression in melanoma metastases and Ewing's sarcoma for 2 XAGE-1-derived transcripts. XAGE-2 was expressed at lower frequency in these tissues, while XAGE-3 was seen only in normal placenta. Due to a frameshift, the largest XAGE-1 putative protein is far less homologous to GAGE-like proteins than the other XAGEs. Interestingly, all GAGE-like genes contain a large secondary open reading frame, coding for putative proteins homologues to the XAGE-1 primary protein. The XAGE family of cancer/testis-associated genes is located on chromosome Xp11.21-Xp11.22. The data outline a superfamily of GAGE-like cancer/testis antigens, consisting of at least 19 genes. Copyright 2002 Wiley-Liss, Inc.
UI - 11966726
AU - Ortonne JP
TI - Photobiology and genetics of malignant melanoma.
SO - Br J Dermatol 2002 Apr;146 Suppl 61():11-6
AD - CHU Nice, Service de Dermatologie, Hopital l'Archet 2, BP 3079, 06202 Nice cedex, France. email@example.com
The current state of knowledge of melanoma genetics is reviewed. Mutations in the tumour suppressor gene CDKN2A and in the oncogenes N-ras and H-ras seem to play the most important roles in the development and progression of malignant melanoma. Experimental studies to determine the role of ultraviolet (UV) light in the induction of melanoma have been hampered by a lack of suitable animal models. The commonly used laboratory animals are not susceptible to the induction of melanoma upon exposure to UV radiation (UVR) alone. Recent observations with four different animals have suggested, however, that UVR may be involved in the induction of melanoma. The most recent model consists of human skin grafted onto immunodeficient mice. To date, using this model, only the combination of UVB (280-320 nm) exposure and topical promoter treatment has led to the development of malignant melanoma. The wavelength dependency of the induction of melanoma has been established in the fish model Xiphophorus. The application of such an action spectrum to humans looks possible.
UI - 8977549
AU - Nelson MA; Thompson FH; Emerson J; Aickin M; Adair L; Trent JM; Leong
TI - SP; Taetle R Clinical implications of cytogenetic abnormalities in melanoma.
SO - Surg Clin North Am 1996 Dec;76(6):1257-71
AD - Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, USA.
Unlike leukemia, in which specific reciprocal translocations are frequently observed, melanomas involve complex recurring chromosome anomalies. Analysis of the constituted genome of melanoma patients should identify cancer susceptibility genes and at-risk individuals in families with a history of melanoma. The first of these genes to be cloned is the cell cycle regulatory protein inhibitor--the p16 gene-- and a second gene locus for melanoma predisposition has been linked to the chromosome 1p36 band region. Detection of the most common somatic genetic alterations in melanoma enhances our understanding of molecular mechanisms of melanoma development and may lead to genetic markers in melanoma. Some alterations may be used to identify interesting subpopulations. Others may be of prognostic value when they are considered in tandem with clinical data.
UI - 11916485
AU - Nakamura T; Sato K; Hamada H
TI - Effective gene transfer to human melanomas via integrin-targeted adenoviral vectors.
SO - Hum Gene Ther 2002 Mar 20;13(5):613-26
AD - Department of Molecular Medicine, Sapporo Medical University, S1 W17, Chuo-ku, Sapporo 060-8556, Japan.
The utility of recombinant adenoviral vectors (Adv) for gene therapy is limited by their low transduction efficiency and lack of specificity for target cells. The low transduction efficiency is often recognized as due to deficiency of the primary adenoviral receptor, the coxsackievirus-adenovirus receptor (CAR). In this paper, studies of CAR levels on human melanoma cell lines confirmed that low transduction efficiency was closely related to deficiency of the adenoviral receptor. To achieve CAR-independent gene transfer via Adv, we modified viral tropism via genetic alteration of the adenovirus type 5 (Ad5) fiber protein. Insertion of an Arg-Gly-Asp (RGD)-containing peptide in the HI loop of the fiber knob domain allowed the virus to use an alternative receptor, the integrin receptor, during the cell entry process. With this modified vector (Adv-F/RGD) transduction was increased 5- to 96-fold relative to a vector containing wild-type fiber (Adv-F/wt) in five human melanoma cells expressing integrins of the alpha(v)beta(3), alpha(v)beta(5) class, which are recognized by the RGD peptide motif. In contrast, no significant difference in transduction efficiency between Adv-F/RGD and Adv-F/wt was observed in 293 cells, which show high-level expression of CAR. In this study, we attempted to apply Adv-F/RGD for gene therapy for malignant melanoma. At the same multiplicity of infection, melanoma cells infected with Adv-F/RGD carrying human interleukin 2 (AxCAhIL2-F/RGD) produced a higher level of cytokine than cells infected with AxCAhIL2-F/wt. Treatment by intratumoral injection of AxCAhIL2-F/RGD was more effective than intratumoral injection of AxCAhIL2-F/wt in regressing tumors in a melanoma xenograft model. These data suggest that integrin-targeted adenoviral vectors may be a powerful tool in gene therapy for CAR-deficient melanomas.
UI - 12017286
AU - Korabiowska M; Tscherny M; Grohmann U; Honig JF; Bartkowski SB;
TI - Cordon-Cardo C; Brinck U Decreased expression of Ku70/Ku80 proteins in malignant melanomas of the oral cavity.
SO - Anticancer Res 2002 Jan-Feb;22(1A):193-6
AD - Department of Cytopathology, University of Gottingen, Germany.
Ku70/80 are genes responsible for the repairing of DNA double-strand breaks and they function as a regulatory subunit of the DNA-dependent protein kinase. Their expression has not yet been investigated in malignant melanomas of the oral cavity. These tumours are characterized by very poor prognosis and etiology independent of UV-radiation. We investigated 29 malignant melanomas of the oral cavity for the expression of Ku70/80 proteins. Ku70 expression was preserved in 21 out of 29 tumours and the percentage of Ku70-positive cells did not exceed 76%. Ku80 was found in 19 out of 29 tumours and the percentage of Ku80-positive cells peaked at 62%. Correlations between Ku70 and Ku80 expression were lost (p>0.05). We conclude that decreased Ku70/80 expression in malignant melanomas of the oral cavity and loss of correlation between these markers may influence progression of oral melanomas.
UI - 11775059
AU - Cohen-Solal KA; Reuhl KR; Ryan KB; Roberts KG; Chen S
TI - Development of cutaneous amelanotic melanoma in the absence of a functional tyrosinase.
SO - Pigment Cell Res 2001 Dec;14(6):466-74
AD - Department of Chemical Biology, College of Pharmacy, Rutgers, the State University of New Jersey, Piscataway 08854, USA.
Lack of characteristic pigmentation and a wide range of clinical presentations account for the diagnostic challenge associated with amelanotic malignant melanoma. Experimental studies of this important human cancer have been hampered by the lack of an appropriate animal model. We previously described a transgenic mouse line (TG-3) that spontaneously develops pigmented cutaneous melanoma. F1 crosses were generated with TG-3 and several albino strains, and backcrosses were then made with the albinos. In the present report, we describe the restricted development and characterization of cutaneous amelanotic melanoma in these albino transgenic backcrosses. The incidence and behavior of melanoma in these mice were monitored. A high incidence (80-100%) of spontaneous amelanotic melanoma was observed in albino transgenic mice derived from backcrosses with A, AKR, FVB, and SJL strains. The lowest incidence (30%) was obtained in BALB/c-derived crosses. No tumors were observed in non-transgenic mice. Immunohistochemical and western blot analyses using antibodies against three melanocyte-specific markers of the tyrosinase family of proteins confirmed that the tumors were composed of amelanotic melanocytes. Furthermore, the presence of numerous premelanosomes observed by electron microscopy further supported the melanocytic origin of these tumors. Previous in vitro studies on human melanoma have suggested that cutaneous amelanotic melanoma was evolving from preexisting pigmented cutaneous melanoma. However, our results indicate that it can occur directly, as evidenced by the appearance of cutaneous amelanotic melanoma in the tyrosinase-deficient albino mice. These mice represent a potentially valuable model for studying the mechanistic, diagnostic, and therapeutic features of this highly malignant neoplasm.
UI - 12014627
AU - Warren P; Song W; Holle E; Holmes L; Wei Y; Li J; Wagner T; Yu X
TI - Combined HSV-TK/GCV and secondary lymphoid tissue chemokine gene therapy inhibits tumor growth and elicits potent antitumor CTL response in tumor-bearing mice.
SO - Anticancer Res 2002 Mar-Apr;22(2A):599-604
AD - Oncology Research Institute, Greenville Hospital System, SC 29605, USA.
Suicide gene therapy in combination with pro-drugs represents an attractive approach to the treatment of cancer. Unfortunately this approach is limited by difficulty in targeting all tumor cells, especially those at the distant metastases associated with the most complex tumors. For this reason, attempts to stimulate global anti-tumor immune responses at the sites of effective suicide gene/pro-drug-mediated tumor cell destruction are appealing. Here we show that, by including a gene coding for secreted secondary lymphoid tissue chemokine (SLC) along with the herpes simplex virus thymide kinase (HSV-TK) gene in a bicistronic vector for anti-tumor gene therapy in conjunction with the pro-drug ganciclovir (GCV), we are able to mediate a greatly enhanced anti-tumor effect in the murine B16 melanoma tumor model. The data presented suggests that this enhanced antitumor effect is the result of a strong induced CTL immune response resulting from the recruitment of immune cells to the site of HSV-TK/GCV-induced tumor destruction by the potent chemokine SLC.
UI - 12067204
AU - Seftor EA; Meltzer PS; Kirschmann DA; Pe'er J; Maniotis AJ; Trent JM;
TI - Folberg R; Hendrix MJ Molecular determinants of human uveal melanoma invasion and metastasis.
SO - Clin Exp Metastasis 2002;19(3):233-46
AD - Department of Anatomy and Cell Biology, College of Medicine and The Holden Comprehensive Cancer Center, University of Iowa, Iowa City 52242-1109, USA.
The molecular analysis of cancer has benefited tremendously from the sequencing of the human genome integrated with the science of bioinformatics. Microarray analysis technology has the potential to classify tumors based on the differential expression of genes. In the current study, a collaborative, multidisciplinary approach was utilized to study the molecular determinants of human uveal melanoma invasion and metastasis. Uveal melanoma is considered the most common primary intraocular cancer in adults, resulting in the death of approximately 50% of patients affected. Unfortunately, at the time of diagnosis, many patients already harbor microscopic metastases, thus underscoring a critical need to identify prognostic markers indicative of metastatic potential. The investigative strategy consisted of isolating highly invasive vs. poorly invasive uveal melanoma cells from a heterogeneous tumor derived from cells that had metastasized from the eye to the liver. The heterogeneous tissue explant MUM-2 led to the derivation of two clonal cell lines: MUM-2B and MUM-2C. Further morphological and functional analyses revealed that the MUM-2B cells were epithelioid, interconverted (expressing mesenchymal and epithelial phenotypes) highly invasive, and demonstrated vasculogenic mimicry. The MUM-2C cells were spindle-like, expressed only a vimentin mesenchymal phenotype, poorly invasive, and were incapable of vasculogenic mimicry. The molecular analysis of the MUM-2B vs. the MUM-2C clones resulted in the differential expression of 210 known genes. Overall, the molecular signature of the MUM-2B cells resembled that of multiple phenotypes--similar to a pluripotent, embryonic-like genotype. Validation of select genes that were upregulated and down-regulated was conducted by semiquantitative RT-PCR measurement. This study provides a molecular profile that will hopefully lead to the development of new molecular targets for therapeutic intervention and possible diagnostic markers to predict the clinical outcome of patients with uveal melanoma.
UI - 11950413
AU - Parney IF; Farr-Jones MA; Koshal A; Chang LJ; Petruk KC
TI - Human brain tumor cell culture characterization after immunostimulatory gene transfer.
SO - Neurosurgery 2002 May;50(5):1094-102
AD - Division of Neurosurgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. firstname.lastname@example.org
OBJECTIVE: Immunogene therapy is a novel cancer treatment strategy based on vaccination with irradiated autologous tumor cells transduced with immunostimulatory genes. To characterize such cells before clinical applications, we studied a human glioma cell line (D54 MG) and early passage human glioma (Ed147.BT, Ed149.BT) and melanoma (Ed141.MEL) cultures after immunostimulatory gene transfer. METHODS: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-12 (IL-12), and B7-2 genes were retrovirally transferred to tumor cells. Gene expression before and after irradiation (200 Gy) was assessed by enzyme-linked immunosorbent assay (GM-CSF, IL-12) and flow cytometry (B7-2). Viability and clonogenicity were determined via trypan blue staining before and after irradiation. Growth rates were determined by serial cell counts. RESULTS: GM-CSF expression was high in GM-CSF-transduced (10.36-162.10 ng/10(6) cells/d preirradiation and 10.22-122.02 ng/10(6) cells/d postirradiation) but lower in B7-2/GM-CSF-transduced cultures (1.41-2.90 ng/10(6) cells/d preirradiation, 1.96-5.02 ng/10(6) cells/d postirradiation). IL-12 expression also was lower (1.30-2.10 ng/10(6) cells/d preirradiation, 0.47-1.70 ng/10(6) cells/d postirradiation). B7-2 expression was high (one- to two-logarithm increase in fluorescence) and unaffected by radiation. Postirradiation viability was initially high (94.20 +/- 8.46%, Day 1) but decreased rapidly (28.13 +/- 4.64%, Day 10). No cultures demonstrated evidence of clonogenicity (i.e., cell division) after 200-Gy irradiation. Growth rates were similar in wild-type and gene-transduced Ed141.MEL, Ed147.BT, and Ed149.BT. However, D54MG-IL-12 growth was slower than that of wild-type D54MG. CONCLUSION: GM-CSF, IL-12, and B7-2 genes can be transferred to human glioma and melanoma cell cultures efficiently by use of our retroviral vectors. Irradiation (200 Gy) does not significantly alter therapeutic gene expression. Irradiated cells remain viable for several days but cannot undergo further cell division. Early passage culture growth rates are not altered by therapeutic gene expression but are decreased by IL-12 in an immortalized cell line (D54MG). These results suggest that it is feasible to create vaccines with irradiated, autologous, genetically modified brain tumor cells.
UI - 12009890
AU - Zhang B; Peng ZY
TI - Structural consequences of tumor-derived mutations in p16INK4a probed by limited proteolysis.
SO - Biochemistry 2002 May 21;41(20):6293-302
AD - Department of Biochemistry, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06032, USA.
The cyclin-dependent kinase inhibitor p16(INK4a) (hereafter p16) functions as a multiple tumor suppressor. Mutations in p16, which are distributed throughout the entire protein, have been identified in a variety of human cancers and cancer-derived cell lines. It is unclear how tumor-derived mutations disrupt the structure and function of p16, especially since many of these mutations are located far away from the cyclin-dependent kinase binding site. In this study, we investigated the effect of two tumor-derived mutations, P81L and V126D, on the structure of p16 by limited proteolysis. The proteolytic products were characterized by gel electrophoresis, HPLC, and mass spectrometry. Our results show that the N-terminal half of p16 is significantly more sensitive to proteolysis in both tumor-derived mutant proteins than in the wild type, suggesting that this region is particularly unstable. Interestingly, the N-terminal half of p16 contains many residues that are important for cyclin-dependent kinase binding. Thus, our results provide a structural mechanism by which tumor-derived mutations inactivate the function of p16 and suggest that stabilization of the N-terminal region could be a useful strategy for future therapeutic development.
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