Synthetic lethality-based targets for discovery of new cancer therapeutics.

Synthetic lethality is based on the incompatibility of cell survival with the loss of function of two or more genes, not with loss of function of a single gene. If targets of synthetic lethality are deregulated or mutated in cancer cells, the strategy of synthetic lethality can result in significant increase of therapeutic efficacy and a favourable therapeutic window. In this review, we discuss synthetic lethality based on deficient DNA repair mechanisms, activating mutations of RAS, loss of function mutations of the tumor suppressor genes p53, Rb and von Hippel-Lindau, and disruption of interactive protein kinase networks in the context of development of new anticancer agents

Localization of the components of the plasminogen activation system in cutaneous melanocytic lesions - a minireview

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Decreased expression of both the low-density lipoprotein receptor-related protein/alpha-2-macroglobulin receptor and its receptor-associated protein in late stages of cutaneous melanocytic tumor progression

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Loss of heterozygosity of gene THW is frequently found in melanoma metastases.

We have recently described a new member of the PMP22/gas3 family of plasma membrane proteins referred to as THW. This gene is located on chromosome 6q and preliminary data have indicated a possible tumor suppressor gene function. We have therefore investigated LOH for gene THW in a panel of cancer cell lines and in a series of primary human melanomas as well as in melanoma metastases. We have detected LOH for gene THW in cell lines derived from melanoma, breast, pancreas, cervical, prostate and colon carcinoma with different prevalence, whereas the ovary carcinoma cell lines (n = 3) were negative. For melanomas we found a prevalence of LOH for gene THW of 10-20% in primary tumors, whereas in melanoma metastases we found a score of 50%. These data and the fact that the recently identified murine homologue PERP of gene THW mediates cell death in murine fibroblasts support the possible tumor suppressor function of gene THW

Loss of heterozygosity of gene THW is frequently found in melanoma metastases.

Item does not contain fulltextWe have recently described a new member of the PMP22/gas3 family of plasma membrane proteins referred to as THW. This gene is located on chromosome 6q and preliminary data have indicated a possible tumor suppressor gene function. We have therefore investigated LOH for gene THW in a panel of cancer cell lines and in a series of primary human melanomas as well as in melanoma metastases. We have detected LOH for gene THW in cell lines derived from melanoma, breast, pancreas, cervical, prostate and colon carcinoma with different prevalence, whereas the ovary carcinoma cell lines (n = 3) were negative. For melanomas we found a prevalence of LOH for gene THW of 10-20% in primary tumors, whereas in melanoma metastases we found a score of 50%. These data and the fact that the recently identified murine homologue PERP of gene THW mediates cell death in murine fibroblasts support the possible tumor suppressor function of gene THW

Expression profiling of MMA-1a and splice variant MMA-1b: new cancer/testis antigens identified in human melanoma.

Item does not contain fulltextUsing high-density oligonucleotide array analysis, we have recently compared the gene expression profiles of 2 human melanoma cell lines with marked difference in metastatic behavior after subcutaneous inoculation into nude mice (de Wit et al., Melanoma Res, in press). We identified an expressed sequence tag (EST), which we called malignant melanoma-associated 1 (MMA-1a), showing evident differential expression between the 2 cell lines. The MMA-1a gene is localized on chromosome 21q22.2 and its mRNA exists of 4 exons. Homology search displayed a splice variant of MMA-1a that lacks exon 3 and that was called MMA-1b. Expression profiles of MMA-1a and MMA-1b are determined by reverse transciptase polymerase chain reaction (RT-PCR) analysis. Among 30 different normal tissue samples, expression of MMA-1a and MMA-1b was exclusively found in the testis after a first PCR of 30 cycles. Even more sensitive screening achieved by performing multiple semi-nested RT-PCR showed no or very low expression in the other normal tissues tested. During melanocytic tumor progression, MMA-1a and/or MMA-1b exhibited an emergence of expression in primary melanoma (20%) and melanoma metastasis samples (30%) after only 1 round of PCR. Expression of MMA-1a and/or MMA-1b was also identified in other tumor cell lines and fresh tumor samples of variable origin, e.g., lung, liver, bladder and soft tissues (sarcomas). We conclude that MMA-1a and MMA-1b are new members of the family of cancer/testis antigens

Identification of metastasis-associated genes by transcriptional profiling of a metastasizing versus a non-metastasizing human melanoma cell line.

In order to identify genes associated with the metastatic phenotype we have compared the expression pattern of 6800 genes in a metastatic (NMCL-1) versus a non-metastatic (530) human melanoma cell line making use of DNA microarrays. The differentially expressed genes identified are involved in control of transcription, regulation of the cell-cycle, proteolysis, cell adhesion, immune response and signaling. A remarkable feature of the system under investigation is the consistent down-regulation of MHC-related and cell adhesion mediating genes in the metastatic cell line

TM7XN1, a novel human EGF-TM7-like cDNA, detected with mRNA differential display using human melanoma cell lines with different metastatic potential.

AbstractWe have identified a novel 3845 bp cDNA differentially expressed in a human melanoma metastasis model. Northern blot analysis showed expression in the poorly and intermediately metastasizing cell lines and a marked downregulation in the highly metastatic cell lines. Using RT-PCR expression was also seen in several other tumor cell lines and normal cell types of human origin. cDNA sequence analysis revealed an ORF of 687 amino acids containing seven putative transmembrane domains C-terminally and a long N-terminus. The gene was mapped to 16q13. Highest homology was observed with members of the EGF-TM7 subfamily of the secretin/calcitonin receptor family. We propose the delineation of a subfamily of TM7 proteins, LN-TM7, containing seven transmembrane proteins with a long N-terminal extracellular part

Identification of metastasis-associated genes by transcriptional profiling of a metastasizing versus a non-metastasizing human melanoma cell line.

Item does not contain fulltextIn order to identify genes associated with the metastatic phenotype we have compared the expression pattern of 6800 genes in a metastatic (NMCL-1) versus a non-metastatic (530) human melanoma cell line making use of DNA microarrays. The differentially expressed genes identified are involved in control of transcription, regulation of the cell-cycle, proteolysis, cell adhesion, immune response and signaling. A remarkable feature of the system under investigation is the consistent down-regulation of MHC-related and cell adhesion mediating genes in the metastatic cell line