Cellular Interactions Stimulate Radioresistant Cancer Regrowth

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Person receiving radiation therapy for cancer treatment in linear acelerator
[Source: cunfek/Getty Images]

Many cancer treatment options include radiation therapy and conventional chemotherapies that cause irreversible genomic damage and trigger apoptosis. However, cancers with Ras mutations have a well-known association with cancer cell resistance to radiation therapy, ultimately leading to cancer recurrence.

In new research from the University of Missouri and Yale University, scientists have learned that cell-cell interactions in the tumor microenvironment can influence oncogenic Ras leading to radioresistance. “We show that genotoxic stress-activated p53 acts non-cell autonomously to promote the radioresistance of Ras mutant tumor tissues,” they write in their paper published in Nature.

In many cancers, including lung and colorectal cancers where oncogenic Ras mutations are common, an improved clinical response to genotoxic agents—those that damage cellular DNA, such as radiotherapy—has been observed. However, cellular responses to DNA damage are complex and include activation of cell–cell interactions not fully understood. How these nonautonomous effects influence the response of Ras-driven cancers to genotoxic therapies is largely underexplored as well.

Animal tumor models provide the advantage of interrogating tumor resistance mechanisms at the tissue level, not just the cellular. The team first studied patches of Drosophila eye and human breast and lung tissues containing oncogenic Ras mutations exposed to genotoxic treatment, or therapy like radiation that damages cells’ DNA. They found that many cancer cells with Ras mutations responded by increasing levels of the p53 protein, which orchestrates either DNA repair or triggers apoptosis of damaged cell. If the damage is too extensive the cell will abandon the repair process and trigger its own demise. In this regard, p53 is usually considered as a tumor suppressor protein since its actions were primarily thought to prevent pre-cancerous cells from growing leading to cell death.

Instead, the team discovered that these high p53-expressing Ras clones did not just die. Instead, they released a growth signal, interleukin-6 (IL-6), into the tumor microenvironment. In a cascade effect, IL-6 triggered nearby low p53-expressing cells to activate JAK/STAT cytokines. JAK/STAT signaling is known to support tissue growth by promoting cell survival or cell proliferation.  The result of these interactions?  vigorous tumor regrowth.

“We essentially have a situation where cells that are vulnerable to the treatment are instructing the more robust cells to take over and grow,” said Yves Chabu, an assistant professor in the MU College of Arts and Science. “We find that too much of a normal, not mutated, p53 can signal the surrounding Ras tissues to overgrow.”

To prove the cell-cell effect,  the team tested their lab findings in vivo with mouse xenograft experiments. Animals treated with ruxolitinib, a STAT blocker, had inhibited STAT signaling in areas of high-expressing p53 tissue as well as slower growing mixed tumors.

“In addition to highlighting an emerging role for p53 in cell–cell interactions, our findings provide a possible explanation for the paradoxical resistance of Ras cancers to genotoxic therapies, despite functional p53,” they write. “Stimulation of wild-type p53 cooperates with oncogenic Ras to induce JAK/STAT signaling in the surrounding cells, resulting in nonautonomous growth.”

These research findings also suggest that combining STAT inhibition with radiation therapy may improve clinical outcomes for Ras cancer patients.

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