Reining in metastatic cells
Surgical removal of a primary tumor is normally followed by radiation and/or drug therapy to eliminate malignant cells that are motile and could induce new tumors in other tissues. As yet, there are no targeted therapies for the inhibition of metastasis, largely because the processes that enable tumor cells to migrate to other organs are poorly understood. Under the auspices of a DFG-granted research group (FOR 1406) an international collaboration led by Professor Angelika Vollmar at LMU has now discovered a new mechanism that is essential for metastasis, and vulnerable to inhibition.
The team found that a complex natural product synthesized by myxobacteria is able to inhibit the migration of rogue tumor cells into the bloodstream. “We have shown that this so called archazolid very effectively prevents the migration of highly invasive tumor cells,” says Vollmar, who holds the Chair of Pharnaceutical Biology at LMU. In a mouse model archazolid significantly decreased the dissemination of breast cancer cells to the lung. The agent apparently acts by blocking the signaling pathways that regulate the motility of metastatic cells.
Proton pump essential for cell motility
Archazolid was already known to interact specifically with a protein called V-ATPase, which acts as a proton pump. It is found on the cell membrane and on vesicles that are involved in uptake, intracellular transport and degradation of signal molecules that bind to cell-surface receptors. The new findings now demonstrate that V-ATPase is also required for the directed migration of tumor cells – identifying it as a possible target for an anti-metastatic drug.
The application of archazolid has thus led to the discovery of a functional link between the V-ATPase and the invasive behavior of metastatic tumor cells. “The proton pump therefore represents a promising target for the development of therapeutic agents for the inhibition of metastasis,” says Vollmar. (Cancer Res., Published online September 17, 2012) bedo