Fluorescent Compounds Make Tumors Glow

A series of novel imaging agents could light up tumors as they begin to form – before they turn deadly – and signal their transition to aggressive cancers.

The compounds – fluorescent inhibitors of the enzyme cyclooxygenase-2 (COX-2) – could have broad applications for detecting tumors earlier, monitoring a tumor’s transition from pre-malignancy to more aggressive growth, and defining tumor margins during surgical removal.

“We’re very excited about these new agents and are moving forward to develop them for human clinical trials,” said Lawrence Marnett, Ph.D., the leader of the Vanderbilt University team that developed the compounds, which are described in the May 1 issue of Cancer Research.

COX-2 is an attractive target for molecular imaging. It’s not found in most normal tissues, and then it is “turned on” in inflammatory lesions and tumors, Marnett explained.

“COX-2 is expressed at the earliest stages of pre-malignancy – in pre-malignant lesions, but not in surrounding normal tissue – and as a tumor grows and becomes increasingly malignant, COX-2 levels go up,” Marnett said.

Compounds that bind selectively to COX-2 – and carry a fluorescent marker – should act as “beacons” for tumor cells and for inflammation.

Marnett and his colleagues previously demonstrated that fluorescent COX-2 inhibitors – which they have now dubbed “fluorocoxibs” – were useful probes for protein binding, but their early molecules were not appropriate for cellular or in vivo imaging.

“It was a real challenge to make a compound that is COX-2 selective (doesn’t bind to the related COX-1 enzyme), has desirable fluorescence properties, and gets to the tissue in vivo,” Marnett said.

To develop such compounds, Jashim Uddin, Ph.D., research assistant professor of Biochemistry, started with the “core” chemical structure of the anti-inflammatory medicines indomethacin and celecoxib. He then tethered various fluorescent parts to the core structure, ultimately synthesizing more than 200 compounds. The group tested each compound for its interaction with purified COX-2 and COX-1 proteins and then assessed promising compounds for COX-2 selectivity and fluorescence in cultured cells and in animals. Two compounds made the cut. Read more

Skeleton Key For Cancer Metastasis

Cancer cells need all three of their cytoskeletons – actin, microtubules, and intermediate filaments – to metastasize, according to a study published online on April 26 in the Journal of Cell Biology.

A cancer cell in an epithelial layer is trapped unless it can force through the basement membrane, which cordons off the tissue. Tumor cells start to dissolve the basement membrane with enzymes that build up within extensions called invadopodia. How the different components of the cytoskeleton collaborate to spring the cell remains unclear. To find out, Danijela Vignjevic and colleagues (Institut Curie) followed cancer cells as they started their breakout.

They found that a tumor cell escapes in three stages. First, stumpy protrusions dig into the basement membrane. These structures then elongate into “mature” invadopodia. Finally, the rest of the cell follows. In culture, crawling cells produce extensions that carry either bundles of actin or an actin mesh. In the cancer cells, both forms of actin were necessary for invadopodia to form and grow. However, microtubules and intermediate filaments were only essential for invadopodia to lengthen. Read more

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