The matrix metalloproteases, or MMPs, are a family of zinc-dependent proteolytic enzymes that degrade the extracellular matrix. As such, they are important during cell migration, angiogenesis and wound healing. However, they are also necessary for the invasion and migration of tumor cells. Therefore, MMP expression is often upregulated in invasive metastatic cancers. MMP-19 lacks several structural features present in other MMP subclasses, notably the Asp, Tyr and Gly residues close to the zinc-binding site, the fibronectin-like domain, the transmembrane domain and the furin-activation sequence. On pages 709–716 of this issue, Impola et al. demonstrate yet another unique feature of MMP-19: unlike some of its family members, it is present in normal, proliferating, but not migrating keratinocytes; it disappears from these cells over the course of neoplastic dedifferentiation. Because MMP-19 is induced by TNF-α, because it degrades many basal membrane components, including type IV collage, laminin-1 and nidogen, and because it is present in normal cells, they hypothesize that MMP-19 plays a role in normal tissue remodeling such as that which occurs during wound repair. Because the intrauterine environment may play a role in the development of adult diseases, Leong et al. endeavor to characterize the relationship between birth weight (as a measure of said intrauterine environment) and adult obesity (as a known risk factor for cancer). They collected information on birth weight, adult height and adult weight from randomly selected women aged 50–79 living in the states of Massachusetts, New Hampshire, and Wisconsin via telephone interviews. In their paper on pages 789–791 of this issue, they report their results that both low and high birth weights are associated with higher adult body mass index, and they conclude that fetal experience may influence adult obesity and therefore contribute to cancer risk. Glutathione-S-transferases (GSTs) catalyze the glutathione-dependent detoxification of several chemotherapeutic agents or their metabolites. Therefore, Sweeney et al. hypothesized that polymorphisms resulting in a reduction or elimination of enzymatic activity may modify the effectiveness of chemotherapy and thus predict differences in treatment outcomes. GSTA1 is highly active in the glutathione conjugation of metabolites of cyclophosphamide (CP), a nitrogen mustard chemotherapeutic drug often used in combination chemotherapy for breast cancer. A newly recognized polymorphism, the GSTA1*B allele, reduces hepatic expression of this enzyme. On pages 810–814 of this issue, they report that GSTA1*B/*B homozygotes receiving combination chemotherapy for breast cancer had a longer overall survival during the first 5 years following their diagnosis, probably because their reduced ability to detoxify CP means that they received a higher effective dose. However, after 5 years there was no evidence of a continued survival difference based on genotype. Similar results were reported for patients with the GST1105Val polymorphism who received combination chemotherapy for advanced colorectal cancer. Overall survival among breast cancer patients treated by chemotherapy, by genotype at the GSTA1 proximal promoter polymorphism. Micrometastases are one of the worst problems facing cancer patients who undergo successful resection of their primary tumors, for even if no metastases are detected at the time of surgery, micrometastases may have sprouted and can become manifest years later. The lungs are one of the most common sites for these micrometastases. MMPs play a pivotal role in metastasis by promoting tumor invasion and angiogenesis; thus, a number of inhibitors (MMPIs) have been developed to counteract them. ONO-4817 is a selective spectrum MMPI that inhibits the gelatinases MMP-2 and MMP-9, but not MMP-1, by binding reversibly to the zinc-binding region of these MMPs. On pages 822–828, Yamamoto et al. test its efficacy in combination with a cytotoxic anticancer drug, docetaxel (DOC), against established lung micrometastases. They injected nude mice with either PC14PE6 cells, human non-small-cell lung adenocarcinoma cells, or H226 cells, human squamous cell carcinoma cells, both of which express MMP-1, MMP-2 and/or MMP-9. The mice were then treated with DOC and ONO-4817 after micrometastases had been established. They found that the combination therapy significantly suppressed the tumor burden and prolonged the survival of the mice. Effect of treatment with ONO-4817 and DOC on the survival of nude mice inoculated with PC14PE6 cells. Expression of the RARβ subtype of the retinoic acid receptor (RARβ) is selectively lost in most cultured cancer cell lines and premalignant and malignant lesions, implying that its loss is associated with human cancer development. Its loss also renders the cells resistant to the growth inhibitory effects of retinoic acid treatment. In their report on pages 833–839 of this issue, Teraishi et al. report that recombinant adenovirus-mediated gene transfer of the G1 phase cell cycle inhibitor p21 into H1299 human non-small-cell lung cancer cells and DLD-1 human colorectal cancer cells transcriptionally upregulates RARβ expression, thereby rendering these cells more sensitive to the apoptosis-promoting effects of treatment with all-trans-retinoic acid. Transcriptional activation of the RARβ promoter by Ad5CMV-p21 infection.
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May 1, 2009
Irina G Bogdarina + 2
Open Access
