Research On A Rare Cancer Exposes Possible Route To New Treatments

Research On A Rare Cancer Exposes Possible Route To New Treatments
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Researchers discovered the unusual role of lactate in the metabolism of alveolar soft part sarcoma (ASPS), a rare, aggressive cancer that primarily affects adolescents and young adults. The study also confirmed that a fusion gene is the cancer-causing agent in this disease. The research results were published online in the journal Cancer Cell.
ASPS tumor cells contain a chromosomal translocation - strands of DNA from two chromosomes trade places. The two strands fuse together to create a new gene, ASPSCR1-TFE3 that functions differently than either "parent" gene.
For the study, the researchers activated the ASPSCR1-TFE3 gene in mice. The cancer was completely penetrant; every mouse with the activated fusion gene developed a tumor similar to human ASPS tumors. One surprising finding of the study was the location of the tumors in mice. In humans, most ASPS tumors occur in skeletal muscle, but all the mouse tumors occurred within the skull - not necessarily in brain tissue, but within the environment of the cranium.
The two places where most of the mouse tumors were found, inside the brain and inside the orbit of the eye, had the highest concentrations of lactate. The tissues where ASPS occurs in humans, the skeletal muscles, also have high concentrations of lactate. Most cancer cells generate their energy in a process called glycolysis, in which they rapidly but inefficiently consume glucose. This process creates lactate as a waste product that the cancer cells push out into their surroundings.
In the study, the ASPS tumor cells absorbed lactate from their environment and used it both as a fuel and as a signaling molecule that made the cells behave as if they were in a low-oxygen environment. It's unusual to find a cancer using lactate this way. The ASPS cells grow preferentially where they are bathed in high concentrations of lactate.
Future work in this area could include finding ways to block the cancer cells' uptake of lactate to starve them or render them less aggressive.