Spotlight

Abstract

Cheng et al., pp.345–353 Prolonged exposure to estrogens can induce tumors in laboratory animals and has been associated with breast and uterine cancers in humans. The proliferative effect of estrogen on breast epithelium is part of the mechanism. In addition, recently surfaced evidence demonstrated that estrogen metabolites can cause DNA damage and mutations, an important step in tumor initiation. Oxidation of two catechol estrogen (CE) metabolites, 4-hydroxyestradiol and 4-hydroxyestrone, generates quinone intermediates. They can react with purine bases to form DNA adducts that generate highly mutagenic apurinic sites; CEs can also generate oxygen radicals and DNA double strand breaks (DSB). Cheng et al. examined whether breast tumorigenesis is linked to inherited variants in five genes that are involved in detoxifying pathways of estrogen metabolites. Women harboring a greater number of high-risk genotypes of CE-metabolizing genes faced an increased risk of breast cancer. This trend was more pronounced in women who had never been pregnant or older at their first full-term pregnancy and therefore at greater risk for breast cancer. Cheng also examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes. They found that a joint effect was significantly associated with breast cancer development. This study supports the hypotheses that increased estrogen exposure confers a higher risk of breast cancer, in part caused by DSB in DNA. Brennetot et al., pp.446–450 High-frequency microsatellite instability (MSI-H) is due to either insertion or deletion of repetitive sequences during DNA replication and failure of the mismatch repair system (MMR) to correct these errors. As a consequence, MMR-deficient tumors accumulate thousands of small mutations genome-wide. Almost all tumors from patients with human non-polyposis colorectal cancer (HNPCC) are MMR deficient, as are 10–15% of sporadic colorectal, gastric and endometrial cancers.2 Allelic profiles of BAT-26 and BAT-25 obtained by independent fluorescent PCR of these markers. MSI-H tumors differ from microsatellite-stable (MSS) tumors in molecular and in clinicopathological attributes. Generally, patients with MSI-H tumors are reported to have a better clinical outcome than patients with MMR-proficient tumors. Hence, screening of all human tumors where the MSI phenotype is frequent would not only allow the treatment to be custom-tailored but also assist in the diagnosis of ambiguous HNPCC cases. The present study demonstrates that together the markers BAT-25 and BAT-26, two mononucleotide repeats widely used as part of a larger set of markers, are sensitive enough to establish the MSI status of human tumors. Furthermore, they can detect instability when the tumor cell content of a sample is as low as 5–10%. This observation is very important in the context of proposed regular MSI screening for all colorectal, gastric and endometrial cancers. Not only might fewer markers than the routinely suggested panel of five suffice to reliably establish the microsatellite status of tumors, the labor-intensive and time-consuming process of enriching tumor cells in contaminated samples may only be required in a small subset of biopsies. Merchan et al., pp.490–498 Most angiogenesis inhibitors were developed intentionally to interrupt new blood vessel formation. In an unexpected twist, the antiangiogenic activity of several cytotoxic agents was discovered accidentally, among them the widely used chemotherapeutic paclitaxel. In addition to its well-known microtubule-interfering effect, paclitaxel inhibits endothelial cell (EC) migration, invasion, capillary tube formation and proliferation at low concentrations in vitro. In vivo, it significantly reduces microvessel density and decreases vascular endothelial growth factor (VEGF) production. While paclitaxel's effects on ECs are well studied and clinical trials investigating its antiangiogenic potential are underway, the underlying mechanism has not yet been elucidated. Based on the latest results by Merchan et al. it appears that an approximately fivefold increased ability of human ECs to accumulate the drug when compared to other cell types is responsible for the enhanced sensitivity of ECs. However, at the same time low concentrations of paclitaxel upregulate the expression of Cox-2, an enzyme also known for its angiogenesis-stimulating activity. Combined treatment with the specific Cox-2 inhibitor celecoxib resolved the undesirable dichotomy and resulted in more pronounced antiendothelial effects than applying either compound alone. These findings could be extended to a clinical setting, where four patients with prostate cancer or malignant melanoma were treated with prolonged intravenous infusions of paclitaxel and celecoxib. The potent antiangiogenic activity observed in plasma specimens suggests that a combination treatment may be an attractive strategy to capitalize on the intrinsic antiangiogenic and cytotoxic effects of each agent alone.