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Recalculating

January 16, 2013

mouse tongue epithelium showing the normal distribution of mTOR activity For millions of motorists, GPS (or Global Positioning System) has become an everyday necessity.  So has the robotic update “recalculating” that has rescued many a gas tank from snap decisions that at the time seemed like logical navigational maneuvers.
 

For scientists, roughly the same interactive dynamic exists in the laboratory.  Their GPS system is often a literature or database search that guides the way ahead to a working hypothesis.  When their initial experiments show the hypothesis is problematic, the recalculating feature kicks in and redirects the research toward an alternative route that can lead to a far more clinically relevant endpoint.

A fantastic example is a recent article that NIDCR scientists and their NIH colleagues published in the journal Cell Stem Cell about a protein called mTOR.  The scientists had helped to build the case that mTOR is frequently activated in epithelial, or skin, cells extracted from head and neck squamous cell carcinomas, or HNSCC.  This discovery raised an intriguing therapeutic possibility.  Since almost 80 percent of patients with HNSCC will receive radiation therapy, what if the tumor cells were pretreated with the mTOR-inhibiting chemotherapy drug rapamycin?  Would the drug sensitize the tumor cells and potentially allow oncologists to reduce the level of radiation needed to kill them?

The scientific literature, like GPS, indicated this one-two punch would be an effective route to take.  Laboratory studies already have shown it to be so using tumor cells cultured from three other cancers (glioblastoma multiforme, non-small cell lung cancer, and soft tissue sarcoma).

And so the scientists established a panel of two standard HNSCC-derived cell lines and included colonies of normal oral mucosa, or skin, cells as a control.  They introduced the mTOR inhibitor to the cell lines followed by sublethal levels of ionizing radiation.   In the HNSCC cells, a subtle effect was seen in the size and survival of the colonies.  But it was extremely limited.

They turned to the colonies of normal oral mucosal cells, assuming they had withered and died from the combination of rapamycin and radiation.  To their complete surprise, the colonies had grown significantly and were more efficient at forming new colonies.  The implication being, rapamycin protects them from the effects of the radiation.  More importantly, since each colony would have to arise from a single surviving progenitor cell, rapamycin also protects oral mucosal stem cells from radiation. 

Recalculating. 

The scientists began thinking in a new direction.  Maybe rapamycin has the potential to protect HNSCC patients treated with radiation from developing a painful side effect called oral mucositis.  The condition occurs because oral mucosal cells near the tumor absorb energy from the radiation beam and die.  Among the collateral damage are the stem cells that naturally repopulate damaged tissue with healthy new cells.  Without functioning stem cells, the wounds can be extremely slow to heal, and patients are at great risk of developing secondary infections and often have difficulty chewing and swallowing.

Follow-up animal studies confirmed their cell-culture surprise, including the survival of the stem cells.  The researchers also drilled down deeper into the cell biology.  They found rapamycin likely protects against oxidative damage (which can cause cell senescence and death) via increased expression of the protein MnSOD, a mitochondrial enzyme that has been linked to radiation resistance.


  • Iglesias-Bartolome R, Patel V, Cotrim A, Leelahavanichkul K, Molinolo AA, Mitchell JB, Gutkind JS.  mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis, Cell Stem Cell 2012 Sep 7:11(3):401-14

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This page last updated: February 26, 2014