RAD51D Protects against 6-thioG–Induced Toxicity
Rajesh et al., Page 206
Long-term thiopurine use increases the risk of therapy-induced cancers. This study found that deficiency in the Rad51d homologous recombination (HR) gene caused extreme sensitization to 6-thioguanine that was almost completely dependent on mismatch repair. Moreover, Rad51d-deficient cells show a striking increase in the induction of radial chromosomes that can drive carcinogenesis. Thus, thiopurine effectiveness is dependent on an intact mismatch repair, and HR-insufficiency is likely a risk factor for developing secondary cancers. Monitoring the status of these pathways will be important to increase the effectiveness of thiopurines for suppressing immunity and treating childhood cancers.
S100A8/A9 Activate Key Genes and Signaling Pathways in Colon Tumor Progression
Ichikawa et al., Page 133
It is becoming increasingly clear that hostderived cells of the tumor microenvironment contribute significantly to tumor invasion and metastasis. In this issue, Ichikawa and colleagues show that myeloid-derived S100A8/A9 in the colon tumor microenvironment interact with receptors on tumor cells and turn on transcriptional activation of specific downstream genes whose products promote leukocyte recruitment, angiogenesis, tumor migration, and metastasis. Tumor growth and metastasis are significantly reduced in S100A9 null mice. The study thus defines a novel role for S100A8/A9 in tumors and identifies novel biomarkers and targets for therapeutic interventions.
Cellular Processes Regulating Response to Oxaliplatin
Harradine et al., Page 173
Oxaliplatin is widely used to treat colorectal cancer, however, a significant number of patients experience serious side effects, creating an urgent need for biomarkers of oxaliplatin response to direct therapy to those most likely to benefit. Using an in vitro cell-based small interfering RNA targeting 500 genes, Harradine and coworkers identified 27 genes that significantly influence colon tumor cell line sensitivity to oxaliplatin, implicating diverse gene networks that may influence tumor survival in response to DNA damage, thus revealing promising therapeutic targets to increase patient response to oxaliplatin.
Hypoxia Induces Snail Expression via HIF
Luo et al., Page 234
Intratumoral hypoxia induces expression of Snail, thereby stimulating epithelial–mesenchymal transition (EMT) and metastasis. Luo and colleagues show that hypoxia induces Snail expression via interaction of HIF proteins with a functional HRE in the mouse snail promoter. Overexpression of stable HIF at normoxia stimulates Snail expression and cell migration, whereas short interfering RNA–mediated knockdown of HIF attenuates hypoxia-induced Snail activation and subsequent EMT and cell migration. These findings identify snail as a HIF target gene and provide new mechanistic insights into hypoxia-induced EMT.