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Aspirin as a cancer-preventing drug
Literature
The
MOLECULAR MEDICINE TODAY, DECEMBER 1998
Aspirin as a cancerpreventing drug
aspirin in the prophylactic treatment of hereditary colorectal cancer, particularly in those families with inherited mutations in MSH2, MSH6 and MLH1.
Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection
Eugene Ivanov PhD Staff Scientist, Dept of Molecular Biology, Transkaryotic Therapies Inc., 195 Albany Street, Cambridge, MA 02139, USA.
Ruschoff, J. et al. (1998)
Proc. Natl. Acad. Sci. U. S. A. 95, 11301–11306 As the flu season peaks, so does the consumption of aspirin. Commonly used to treat the symptoms of colds and flu, aspirin has also become a popular prophylactic measure against cardiovascular dysfunction. Additionally, recent epidemiological studies have shown that the prolonged use of aspirin can reduce the risk of developing colorectal cancer by 40–50%. To identify the cancer-preventing mechanism of aspirin, Ruschoff et al. tested its effects on several human colorectal cancer cell lines that have known mutations in mismatch repair (MMR) genes. MMR defects in these cell lines cause microsatellite DNA instability (MSI). The authors of this study followed MSI in human colorectal cancer cell lines by a novel diagnostic technique and showed that the treatment of the cells with aspirin caused a dose-dependent decline in MSI frequency. They also confirmed previous findings that the addition of aspirin to cultured colorectal cancer cells can rapidly induce apoptosis. The onset of aspirin-induced apoptosis is very fast, reaching a maximum after two weeks; however, MSI declines at a slower rate and is only apparent after eight weeks of treatment. Remarkably, during the course of the treatment, MSI remains constant in apoptotic cells, but gradually decreases in nonapoptotic cells, suggesting that aspirin prevents colon cancer by selecting for cells that have a low frequency of MSI and, therefore, stable genomes. Cells with unstable genomes undergo apoptosis and are eliminated from the population. Removing aspirin from the culture of MMRdeficient cells causes the cells to return to high levels of MSI, indicating that constant treatment with aspirin is required for this effect. The effects of aspirin are also cell-line specific, because only cells with mutations in the genes MSH2, MSH6 and MLH1 respond to treatment with aspirin. Those with mutations in the genePMS2 do not. Thus the results of this work strongly suggest a role for 510
An SH2 domain stands between infectious mononucleosis and a fatal lymphoproliferative disease Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene Coffey, A.J. et al. (1998)
Nat. Genet. 20, 129–135
The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM Sayos, J. et al. (1998)
Nature 395, 462–469 X-linked lymphoproliferative disease (XLP) is a rare genetic disorder characterized by a severe immunodeficiency to Epstein–Barr virus (EBV). XLP has a complex phenotype that results from a vigorous uncontrolled polyclonal expansion of T and B cells. Two recent publications describe the cloning of the gene mutated in this disorder and shed light on the immune response to EBV infection in both XLP and other EBV-associated disease states. Coffey and colleagues used a positional cloning approach to identify the XLP gene, which was known to map to Xq25. A physical map was constructed over the critical region (3–5 Mb), as defined by a deletion present in an XLP patient. Bacterial clones from this physical map were selected for genomic sequencing and exon trapping. Only two genes were identified within the critical region. Mutational analyses identified nine
mutations in unrelated patients in one of these genes, SH2D1A, which encodes a small protein comprising an SH2 domain followed by a short tail of only 25 residues. The mutations described include two point mutations leading to premature stop codons and a missense mutation affecting an arginine predicted to be essential for SH2 domain function. SH2D1A is predominantly expressed in immunologically important tissues, in a pattern consistent with a defect in T-cell mediated immune regulation. By contrast, Sayos and co-workers were using the yeast two-hybrid system to identify proteins that interact with SLAM (signalling lymphocyte activation molecule), a transmembrane glycoprotein known to be involved in signalling between B and T cells. Eight T-cell cDNA clones encoding the same protein, which they termed SLAM-associated protein (SAP), were isolated. SAP was subsequently found to be the SH2D1A gene product. This study found SAP to be predominantly expressed in T cells, in broad agreement with Coffey and colleagues. Mutations are described in three XLP patients, a splice site mutation in one and the deletion of the entire gene in two brothers. Although these mutations alone would fall short of conclusive evidence for the involvement of the gene in XLP, Sayos’ study provides functional data that suggest a mechanism by which mutations in SH2D1A could give rise to the XLP phenotype. They demonstrate that SAP binds specifically to Tyr281 in the cytoplasmic domain of SLAM and inhibits the recruitment of the tyrosine phosphatase SHP-2 in response to the phosphorylation of SLAM by c-fyn. Two mechanisms are proposed to explain the XLP phenotype. The engagement of SLAM during antigen-specific T-cell stimulation leads to a shift from a T helper 2 (Th2) to a Th1/Th0 phenotype, with the production of the Th1-type cytokine interferon g (IFN-g). Impaired IFN-g production by T-helper cells has been reported in some XLP patients. XLP might, therefore, be a consequence of an inadequate Th1 response caused by impaired SLAM–SAP signalling. Alternatively, T-helper cells lacking SAP might fail to license EBV-infected B cells to activate cytotoxic T cells. The identification of the gene mutated in XLP will allow direct diagnosis of the disease in many cases. Furthermore, the identification of this gene sheds new light on the mechanisms by which EBV infection is controlled, and might have therapeutic implications for a range of EBV-associated disorders including infectious mononucleosis, Burkitt lymphoma, nasopharyngeal carcinoma and various lymphoproliferative disorders that are associated with acquired immunodeficiencies. Kathryn L. Evans PhD Research Associate, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK EH4 2XU.
1357-4310/98/$ - see front matter © 1998 Elsevier Science. All rights reserved.
The
MOLECULAR MEDICINE TODAY, DECEMBER 1998
Aspirin as a cancerpreventing drug
aspirin in the prophylactic treatment of hereditary colorectal cancer, particularly in those families with inherited mutations in MSH2, MSH6 and MLH1.
Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection
Eugene Ivanov PhD Staff Scientist, Dept of Molecular Biology, Transkaryotic Therapies Inc., 195 Albany Street, Cambridge, MA 02139, USA.
Ruschoff, J. et al. (1998)
Proc. Natl. Acad. Sci. U. S. A. 95, 11301–11306 As the flu season peaks, so does the consumption of aspirin. Commonly used to treat the symptoms of colds and flu, aspirin has also become a popular prophylactic measure against cardiovascular dysfunction. Additionally, recent epidemiological studies have shown that the prolonged use of aspirin can reduce the risk of developing colorectal cancer by 40–50%. To identify the cancer-preventing mechanism of aspirin, Ruschoff et al. tested its effects on several human colorectal cancer cell lines that have known mutations in mismatch repair (MMR) genes. MMR defects in these cell lines cause microsatellite DNA instability (MSI). The authors of this study followed MSI in human colorectal cancer cell lines by a novel diagnostic technique and showed that the treatment of the cells with aspirin caused a dose-dependent decline in MSI frequency. They also confirmed previous findings that the addition of aspirin to cultured colorectal cancer cells can rapidly induce apoptosis. The onset of aspirin-induced apoptosis is very fast, reaching a maximum after two weeks; however, MSI declines at a slower rate and is only apparent after eight weeks of treatment. Remarkably, during the course of the treatment, MSI remains constant in apoptotic cells, but gradually decreases in nonapoptotic cells, suggesting that aspirin prevents colon cancer by selecting for cells that have a low frequency of MSI and, therefore, stable genomes. Cells with unstable genomes undergo apoptosis and are eliminated from the population. Removing aspirin from the culture of MMRdeficient cells causes the cells to return to high levels of MSI, indicating that constant treatment with aspirin is required for this effect. The effects of aspirin are also cell-line specific, because only cells with mutations in the genes MSH2, MSH6 and MLH1 respond to treatment with aspirin. Those with mutations in the genePMS2 do not. Thus the results of this work strongly suggest a role for 510
An SH2 domain stands between infectious mononucleosis and a fatal lymphoproliferative disease Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene Coffey, A.J. et al. (1998)
Nat. Genet. 20, 129–135
The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM Sayos, J. et al. (1998)
Nature 395, 462–469 X-linked lymphoproliferative disease (XLP) is a rare genetic disorder characterized by a severe immunodeficiency to Epstein–Barr virus (EBV). XLP has a complex phenotype that results from a vigorous uncontrolled polyclonal expansion of T and B cells. Two recent publications describe the cloning of the gene mutated in this disorder and shed light on the immune response to EBV infection in both XLP and other EBV-associated disease states. Coffey and colleagues used a positional cloning approach to identify the XLP gene, which was known to map to Xq25. A physical map was constructed over the critical region (3–5 Mb), as defined by a deletion present in an XLP patient. Bacterial clones from this physical map were selected for genomic sequencing and exon trapping. Only two genes were identified within the critical region. Mutational analyses identified nine
mutations in unrelated patients in one of these genes, SH2D1A, which encodes a small protein comprising an SH2 domain followed by a short tail of only 25 residues. The mutations described include two point mutations leading to premature stop codons and a missense mutation affecting an arginine predicted to be essential for SH2 domain function. SH2D1A is predominantly expressed in immunologically important tissues, in a pattern consistent with a defect in T-cell mediated immune regulation. By contrast, Sayos and co-workers were using the yeast two-hybrid system to identify proteins that interact with SLAM (signalling lymphocyte activation molecule), a transmembrane glycoprotein known to be involved in signalling between B and T cells. Eight T-cell cDNA clones encoding the same protein, which they termed SLAM-associated protein (SAP), were isolated. SAP was subsequently found to be the SH2D1A gene product. This study found SAP to be predominantly expressed in T cells, in broad agreement with Coffey and colleagues. Mutations are described in three XLP patients, a splice site mutation in one and the deletion of the entire gene in two brothers. Although these mutations alone would fall short of conclusive evidence for the involvement of the gene in XLP, Sayos’ study provides functional data that suggest a mechanism by which mutations in SH2D1A could give rise to the XLP phenotype. They demonstrate that SAP binds specifically to Tyr281 in the cytoplasmic domain of SLAM and inhibits the recruitment of the tyrosine phosphatase SHP-2 in response to the phosphorylation of SLAM by c-fyn. Two mechanisms are proposed to explain the XLP phenotype. The engagement of SLAM during antigen-specific T-cell stimulation leads to a shift from a T helper 2 (Th2) to a Th1/Th0 phenotype, with the production of the Th1-type cytokine interferon g (IFN-g). Impaired IFN-g production by T-helper cells has been reported in some XLP patients. XLP might, therefore, be a consequence of an inadequate Th1 response caused by impaired SLAM–SAP signalling. Alternatively, T-helper cells lacking SAP might fail to license EBV-infected B cells to activate cytotoxic T cells. The identification of the gene mutated in XLP will allow direct diagnosis of the disease in many cases. Furthermore, the identification of this gene sheds new light on the mechanisms by which EBV infection is controlled, and might have therapeutic implications for a range of EBV-associated disorders including infectious mononucleosis, Burkitt lymphoma, nasopharyngeal carcinoma and various lymphoproliferative disorders that are associated with acquired immunodeficiencies. Kathryn L. Evans PhD Research Associate, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK EH4 2XU.
1357-4310/98/$ - see front matter © 1998 Elsevier Science. All rights reserved.