By unraveling a complicated tangle of intercellular signaling pathways a team of cancer biologists has identified one that is intimately linked with the ability of brain cancer cells to resist chemotherapy and to migrate away from the site of the original tumor.

Glioblastoma multiforme (GBM) is an aggressive brain tumor, fatal within one year from diagnosis in most patients, despite intensive treatment with surgery, radiation, and chemotherapy. The migratory and microscopically invasive nature of GBM as well as its resistance to chemotherapy renders conventional therapies inadequate in its treatment.

Investigators at the University of Colorado School of Medicine (Denver, USA) have been studying for the last several years molecular signaling pathways linked to the ability of GBM to survive chemotherapy and to migrate away from the site of the original tumor.

In a paper published in the December 19, 2011, online edition of the journal Nature: Oncogene they reported finding a role for the Mer receptor tyrosine kinase (RTK) in brain tumor migration and showed that Mer inhibition profoundly impeded GBM migration and altered cellular morphology.

Mer along with Tyro-3 and Axl constitute the TAM family of receptor tyrosine kinases characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates a mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer.

In the current study, the investigators showed that inhibition of Mer RTK with a newly developed monoclonal antibody blocked GBM migration due to altered signaling through focal adhesion kinase (FAK) and RhoA GTPase and a transformation of cytoskeletal organization.

“I thought, aha, I have this great way to treat this cancer, but needed to check that we were not going to cause other problems. We wondered if turning off TAM family signaling would make brain cancer cells crawl away to a new spot where they might make new problems,” said senior author Dr. Amy Keating, assistant professor of pediatrics at the University of Colorado School of Medicine. “This represents a new targeted therapy, offering a potential new direction that nobody has tried before.”

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