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View the Table of Contents for the April 1 issue of Cancer Research
Page 2537
Histone deacetylase (HDAC)-inhibitors (HDI) are able to induce differentiation or apoptosis in several leukemia cell models in vitro. Bug et al. found that clinical observations obtained on patients with acute myeloid leukemia (AML) treated with the HDI valproic acid (VPA) were incompatible with a pro-differentiation or apoptotic effect of VPA in vivo. The researchers then investigated the impact of VPA on the biology of hematopoietic stem cells (HSC). Their current findings suggest that VPA elicits a dual effect. Whereas it induces apoptosis or differentiation in blast cells, it increases the self-renewal potential in HSC. This has to be considered when employing HDI in the treatment of AML.
Page 2565
The presence of common genomic deletions at 19q13 in neuroblastomas and gliomas suggests the placement of a tumor-suppressor gene in this region that, despite much effort, has not yet been identified. Using microarray expression analysis, Aliminos et al. found a gene located at 19q13.3 that significantly down-regulated the epithelial membrane protein 3 (EMP3), a myelin-related gene. EMP3 undergoes hypermethylation-mediated transcriptional silencing and has tumor-suppressor–like features including reducing colony formation and tumor growth in mouse xenograft models. Furthermore, EMP3 hypermethylation predicts poor outcome in neuroblastoma patients. Thus, EMP3 is a good candidate for being the long-sought tumor-suppressor gene located at 19q13.
Page 2636
Disruption of arachidonic acid homeostasis can shift the balance of cell turnover in favor of tumorigenesis via over-production of tumor-promoting eicosanoids or, alternatively, by limiting pro-apoptotic signals. In this study, Ilsley et al. evaluated the influence of genetic deletion of cPLA2, a key enzyme responsible for arachidonic acid release, on azoxymethane-induced colon tumorigenesis. The researchers found that cPLA2 deletion resulted in a significant increase in colon tumor multiplicity. The prostaglandin E2-independent tumor promotion was accompanied by a decreased frequency of apoptosis and reduced levels of ceramide. Collectively, these data contribute new information that supports a fundamental role of cPLA2 in the pathogenesis of colon cancer.
Page 2662
The molecular pathogenesis of chronic myeloproliferative disorders (CMPDs) is largely unknown. Molecular cloning of acquired reciprocal chromosomal translocations has revealed diverse tyrosine kinase fusion genes, most commonly involving the receptors PDGFRA, PDGFRB, or FGFR1. Reiter et al. have identified seven patients with diverse hematological malignancies who presented with a reciprocal translocation t(8;9)(p22;p24), an abnormality that they demonstrate fuses the human autoantigen pericentriolar material (PCM1) gene to the janus kinase 2 (JAK2) gene, a non-receptor tyrosine kinase. This finding supports the hypothesis that deregulated tyrosine kinases play a major role in the pathogenesis of CMPDs and further widens the role of JAK2 in malignancy.
Page 2746
Wei et al. found that the expression of Krüppel-Like Factor 4 (KLF4) was substantially decreased or lost in gastric cancer tissues and was inversely correlated with patient’s survival. Restoration of KLF4 expression caused significant tumor growth inhibition and abrogation of metastasis in vivo. The promoter hypermethylation and hemizygous deletion contributed to the down-regulation of KLF4 expression and the induction of apoptosis contributed to the antitumor activity of KLF4. These results indicated that KLF4 plays a critical role in gastric cancer development and progression, and thus may provide the basis for designing effective therapeutic modalities for gastric cancer.