Reactive Oxygen’s Role in Metastasis

Sara Courtneidge, Ph.D., professor and director of the Tumor Microenvironment Program at Burnham’s NCI-designated Cancer Center, and colleagues have found that inhibiting reactive oxygen reduces invadopodia formation and limits cancer cell invasion. The study was published on September 15 in the journal Science Signaling.

In a companion paper, published in the same issue of Science Signaling, Gary Bokoch, Ph.D., of The Scripps Research Institute, in collaboration with Dr. Courtneidge, found that the proteins Tks4 and Tks5, commonly expressed in cancer cells, are functionally related to p47phox, a protein found in phagocytes that is part of a complex that is instrumental in producing reactive oxygen to mount an immune response.

“Reactive oxygen has a complex cellular role,” said Dr. Courtneidge. “Normal cells use reactive oxygen to signal, grow and move. Immune cells, such as neutrophils, produce reactive oxygen to destroy bacteria. Now we find that reactive oxygen is necessary for invadopodia formation, which allows cancer cells to become metastatic.”

Invadopodia facilitate cancer cell migration by breaking down the extracellular matrix that normally keeps cells in place. In previous research, Dr. Courtneidge discovered that Tks5 is crucial for invadopodia formation. The structural similarities between Tks5 and p47phox, which is part of the NADPH oxidase (Nox) system, led Dr. Courtneidge to consider the role reactive oxygen plays in invadopodia formation.

Using invadopodia-rich mouse fibrosarcoma cells, the Courtneidge laboratory tested a number of antioxidants and found both a marked reduction in invadopodia formation and invasive behavior. In addition, the team inhibited expression of Nox family enzymes with siRNA and had similar results, demonstrating that NADPH oxidases are involved in invadopodia formation. The scientists repeated these experiments with human melanoma, head and neck and breast cancer cell lines and also saw a marked reduction in invadopodia formation.

With the discovery of reactive oxygen’s role in invadopodia formation, researchers have additional possibilities for drug intervention. Future research and drug development may focus on inhibiting NADPH oxidase activity and limiting invadopodia formation to prevent cancer cell migration.

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Burnham Institute for Medical Research is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The institute ranks among the top four institutions nationally for NIH grant funding and among the top 25 organizations worldwide for its research impact. For the past decade (1999-2009), Burnham ranked first worldwide in the fields of biology and biochemistry for the impact of its research publications (defined by citations per publication), according to the Institute for Scientific Information.

Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit public benefit corporation.