Botkjaer et al. Page 1532

The protease urokinase-type plasminogen activator (uPA) is an established prognostic marker and a potential therapeutic target in cancer. To circumvent the specificity problems inherent in inhibitors of the catalytic activity of proteases, we have generated a highly specific uPA-binding 35 nucleotides long 2′-fluoro-pyrimidine RNA molecule. This aptamer inhibits the conversion of the inactive zymogen form to active uPA, the binding of uPA to its cellular receptor uPAR, and uPA-dependent tumor cell dissemination in an in vivo model system. Our results are of general interest for the design of new modalities for inhibition of cancer dissemination.

Rummel et al. Page 1526

Rummel and colleagues address the controversy as to whether the breast microenvironment is genetically stable. Using a panel of microsatellite markers, they evaluated the genetic changes in high-quality, research-grade stromal DNA, compared them to data generated from archival specimens, and found that high-quality specimens harbored significantly fewer alterations than did archived tissues. These data, which demonstrate a lack of genetic changes, support the idea that development and use of therapeutics targeting the breast stroma will provide a new avenue of effective treatment for patients with breast cancer.

Svilar et al. Page 1580

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is highly resistant to chemotherapy. Svilar and colleagues conducted a synthetic lethal siRNA screen in a chemotherapy-resistant GBM cell line with the alkylator temozolomide (TMZ). A comparison with alkylation screens done in Escherichia coli and Saccharomyces cerevisiae suggested that alkylation resistance mechanisms were evolutionarily conserved. Functional analysis showed that high-dose TMZ treatment initiated the formation of reactive oxygen species and revealed an epistatic relationship between UNG and UBE3B in response to TMZ. These studies provide potential new targets to overcome alkylating agent resistance.

Gysin et al. Page 1607

The RAS-activated ERK–MAP kinase pathway is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDA), but the mechanism(s) by which this pathway contributes to the aberrant pathobiology of PDA cells remains obscure. By expression profiling of a panel of PDA cell lines in the absence or presence of pharmacologic pathway blockade, Gysin and colleagues detail the full complexity of mRNAs regulated by this pathway. As expected, mRNAs with protein products that promote the cell division cycle feature prominently. However, surprisingly, many of the antiproliferative effects of RAF–MEK–ERK pathway inhibition can be ascribed to regulatory effects on the c-MYC oncoprotein, a noted master regulator of general mRNA expression within the cell.