Sugar Activates Oncogenes in Tumors

Sugar consumption fueled tumor growth in fruit flies, possibly explaining why people with metabolic syndrome have an increased risk for certain cancers, according to a new study.

Putting Drosophila engineered to express the oncogenes Ras and Src on a high-sugar diet resulted in small, localized tumors growing much larger and metastasizing, reported Ross Cagan, from the Icahn School of Medicine at Mount Sinai in New York City, and colleagues.

The sugary diet caused the flies to develop insulin resistance, but it also promoted tumor cell-specific insulin sensitivity by increasing the activity of the canonical signaling pathway Wingless/Wnt, the researchers wrote in the journal Cell.

"Using our fruit fly model, we discovered how tumors overcome insulin resistance in the body and turn metabolic dysfunction to their advantage," Cagan said in an accompanying statement. "Our study shows that sugar activates oncogenes in the tumor, which then promote insulin sensitivity, meaning that the exorbitant glucose levels in the blood pour into the tumor, having nowhere else to go in the insulin-resistant body."

People with diabetes, obesity, and other metabolic diseases have a higher than average risk for certain malignancies, including breast, liver, colon and pancreatic cancers.

But it has not been clear why these cancers grow so aggressively in insulin-resistant patients, Cagan said.

"How would a tumor thrive in a body that is crippled in its ability to take up insulin and sugar to fuel cells?," Cagan said to MedPage Today. "That has been the mystery."

In earlier research, Cagan's group showed that fruit flies fed a high-sugar diet -- consisting of standard diet supplemented to 1.0 M sucrose -- became diabetic very quickly. They conducted the current study to find out what impact the same diet would have on flies genetically engineered to express tumors.

When young flies that expressed the Ras and Src oncogenes were fed high protein, low-sugar diets, their tumors generally remained very small and localized. But soon after the flies were placed on the calorie-matched, high-sugar diets, the tumors grew and spread.

The sugar acted together with Ras and Src to increase insulin receptors and, in turn, insulin sensitivity in the tumor cells by increasing signaling of the Wingless/Wnt pathway.

"The tumors just went crazy," Cagan said. "When the flies were on a normal diet the tumors could barely be seen, but as soon as the sugar was introduced they were everywhere."

Cagan and colleagues then treated the flies with a three-drug cocktail that included the diabetes drug acarbose, which blocks the conversion of sugar to glucose; the drug pyrvinium, which inhibits Wingless/Wnt signaling; and their own anticancer compound (AD81) that targets Ras/Src and causes cell death.

Each drug had only a modest impact on tumor growth when given alone, but when given together the drugs dramatically reduced tumor size and progression.

More than 90% of the flies given the triple-drug treatment survived to adulthood, compared with none of the flies left untreated, Cagan said.

Cagan's group has begun cellular studies using human tumor samples to determine if sugar has the same impact in people with metabolic disease.

"These results provide a potential explanation for how insulin resistant animals are at increased risk for tumorigenesis, and emphasize the importance of targeting multiple, specific notes to achieve optimal therapeutic value," the researchers wrote.

Source: www.medpagetoday.com