Like microscopic inchworms, cancer cells slink away from tumors to travel and settle elsewhere in the body. Now, researchers have found that new anti-cancer agents break down the looping gait these cells use to migrate, stopping them in their tracks.
The researchers, from Cornell University’s Weill Cornell Medical College and Brookhaven National Laboratory, found that mice implanted with cancer cells and treated with the small molecule macroketone lived a full life without any cancer spread, compared with control animals, which all died of metastasis. When macroketone was given a week after cancer cells were introduced, it still blocked greater than 80 percent of cancer metastasis in mice.
These findings provide an encouraging direction for development of a new class of anti-cancer agents, the first to specifically stop cancer metastasis, which kills more than 90 percent of cancer patients.
Their work started in 2003, after researchers in Japan isolated a natural substance, dubbed migrastatin, that is the basis of many antibiotic drugs. The Japanese researchers noted that migrastatin had a weak inhibitory effect on tumor cell migration. Weill scientists and collaborators at the Memorial Sloan-Kettering Cancer Center then built migrastatin analogues — synthetic and molecularly simpler versions.
In 2005, they showed that several of the new versions, including macroketone, stopped cancer cell metastasis in laboratory animals, but they didn’t know how the agent worked.
In the current study, the researchers used x-ray diffraction at NSLS beamlines X6A and X4C to reveal the mechanism. They found that macroketone targets a protein known as fascin that is critical to cell movement. In order for a cancer cell to leave a primary tumor, fascin bundles actin filaments together like a thick finger. The front edge of this finger creeps forward and pulls along the rear of the cell. Cells crawl away in the same way that an inchworm moves.
Macroketone latches on to individual fascin, preventing the actin fibers from adhering to each other and forming the pushing leading edge. Because individual actin fibers are soft when they are not bundled together, the cell cannot move.
— John Rodgers, Weill Cornell Medical College
L. Chen, S. Yang, J. Jakoncic, J.J. Zhang, X.-Y. Huang, “Migrastatin Analogues Target Fascin to Block Tumour Metastasis,” Nature, 464, 1062 (2010).
a) Structure of fascin shown as a ribbon diagram, viewed from the N-terminal and C-terminal plane. The four domains are colored magenta (1), orange (2), blue (3) and green (4). b) Surface presentation of fascin structure viewed in a. c) View of fascin turned clockwise 90 degrees along the y axis relative to the view in b. d) Overall structure of the complex of fascin and macroketone. The macroketone molecule is shown as a white stick model. e) Macroketone-binding site. Residues involved in interactions with macroketone are shown as surface, and hydrogen bonds are shown as dashed lines.