Ion Transport Protein Linked to Brain Cancer Cell Migration and Invasion

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.

NKCC proteins are membrane transport proteins that transport sodium (Na), potassium (K), and chloride (Cl) ions across the cell membrane. They maintain electroneutrality by moving two positively charged solutes (sodium and potassium) alongside two parts of a negatively charged solute (chloride). NKCC1 is known to regulate cell volume and intracellular chloride concentration and to play an important role in brain tumor-cell invasion.

Researchers at Johns Hopkins University (Baltimore, MD, USA) investigated (1) whether the expression of NKCC1 in human tumors correlated with tumor grade; (2) whether NKCC1 affected cell contractility and migration; (3) whether NKCC1 could have an effect on the interaction between the cells and the cells' adhesion substratum; and (4) whether a signaling mechanism involved in the regulation of NKCC1 by promigratory factors existed in GB cells.

Results published in the May 1, 2012, online edition of the journal PLoS Biology revealed that in addition to its conventional function as an ion transporter, NKCC1 also interacted with the cytoskeleton and affected brain tumor-cell migration by acting as an anchor that transduced contractile forces from the plasma membrane to the extracellular matrix en route to cell migration. Regulation of NKCC1 by a family of unconventional enzymes, the WNK kinases, was an important factor that affected the activity of NKCC1 and determined the invasive ability of brain tumor cells. NKCC1 expression correlated with in vivo glioma aggressiveness, and the transporter activity modulated migration speed and invasiveness of cells derived from various human GBs.

“The biggest challenge in brain cancer is the migration of cancer cells. We cannot control it,” said senior author Dr. Alfredo Quinones-Hinojosa, associate professor of neurosurgery and oncology at Johns Hopkins University. “If we could catch these cells before they take off into other parts of the brain, we could make malignant tumors more manageable, and improve life expectancy and quality of life. This discovery gives us hope and brings us closer to a cure.”

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