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View the Table of Contents for the July 1 issue of Cancer Research.
Rosek et al. Page 5488
To evaluate the risk of colorectal cancer associated with germline variation in caudal-type homeobox gene CDX2 (13q12-13), Rozek et al. investigated single nucleotide polymorphisms and CDX2 expression patterns in a population-based sample of Ashkenazi Jewish cases and controls. No SNP or haplotype of SNPs identified in this study was associated with colorectal cancer or CDX2 expression patterns. The authors noted CDX2 underexpression in right-sided, poorly differentiated tumors, consistent with previous reports, and reduced CDX2 expression in microsatellite instable tumors regardless of tumor location. While germline variation is unlikely to be associated with risk of colorectal cancer in this population, multivariate analyses demonstrate that microsatellite instability was more strongly related to CDX2 expression than tumor location.
Ponti et al. Page 5506
Breast cancer-initiating cells (BC-ICs) have recently been prospectively identified in breast carcinoma as CD44+/CD24-/low stem-like cells, which exclusively retain tumorigenic activity. In this study, Ponti et al. provided evidence that cells isolated from human breast cancers and propagated in vitro as non-adherent mammospheres display stem/progenitor cell properties. Mammosphere cultures encompass undifferentiated, self-renewing CD44+/CD24- cells capable of differentiating along distinct mammary epithelial lineages that are tumorigenic in mice when injected at low concentrations (103 cells). These BC-IC–generated cells overexpress neoangiogenic and cytoprotective factors and the putative stem cell marker Oct-4. Long-term cultures of BC-ICs represent a suitable in vitro model to develop novel diagnostic and therapeutic approaches.
Vizan et al. Page 5512
K-ras codon mutations induce tumors with distinctively different survival strategies. Codon 12 mutations induce slow growing, apoptosis-resistant tumors, while codon 13 mutations produce rapidly proliferating apoptosis-sensitive malignant cells. Vizan et al. report two distinct stable isotope-based dynamic metabolic profiles (SIDMAP) of human fibroblasts. Codon 12 mutations increase anaerobic glycolysis (Warburg effect) and glucose oxidation, while codon 13 mutations shift glucose carbons toward non-oxidative nucleic acid synthesis and anabolic glucose use in the TCA cycle. This is the first report of identifying robust metabolic network changes using the [1,2-13C2]-D-glucose tracer which allows detailed measurements of K-ras transformation-altered system properties of the metabolic network. This new tracer-based metabolomics technology allows scientists to navigate within the complex metabolic network of any in vitro or in vivo system in order to delineate gene, drug, and nutrient interactions with metabolite fluxes, molecule synthesis patterns, and phenotype.
Zhao et al. Page 5561
The lung cancer genome undergoes numerous genetic alterations, including changes in chromosomal copy number. Zhao et al. examined genome-wide copy number alterations using high density single nucleotide polymorphism (SNP) arrays, producing a high resolution map of the lung cancer genome across subtypes. In addition to previously characterized loci, this study identified regions of loss (9p23 and 3q25) and gain (8q12-13, 12p11 and 22q11), which may harbor novel tumor suppressor genes and oncogenes. The genes within these loci are potential new therapeutic targets for lung cancer.
Ma et al. Page 5730
The PTEN tumor suppressor gene is frequently inactivated in prostate cancer. Ma et al. describe a novel mouse model of prostate cancer based on targeted inactivation of Pten. In the model, the human prostate specific PSA promoter is utilized to drive Cre expression. Pten is inactivated by Cre-induced deletion of exon 5. Monoallelic inactivation of Pten had no effect on prostate morphology. Biallelic inactivation of Pten shows the consecutive steps of prostate cancer development, including hyperplasia, PIN lesions, adenocarcinoma and undifferentiated carcinoma. Pten inactivation not only induces increased cell proliferation, but also enhanced apoptosis in the prostate.