aA century ago, German physiologist Otto Warburg showed that tumor cells consume energy. more glucose Promotes proliferation compared to healthy cells.1 The root of this phenomenon is Image diagnosis A technology to detect cancer in which doctors inject radioactive glucose and track the amount consumed by tumor cells.2
Researchers have since discovered other sugars. fructosepromotes tumor growth, but the mechanism is unknown.3 Fructose and glucose have the same chemical formula, but the arrangement of the atoms is different. “Given the role that glucose plays in cancer metabolism and how it is used as such a prominent fuel, we are very interested in how fructose could play a similar role. ” he said. Gary Pattya biochemist and systems biologist at Washington University in St. Louis.
Now, in a new study, Patti and his team have discovered: Fructose indirectly promotes tumor growth: The liver breaks down fructose into nutrients that are taken up by tumor cells to promote growth.4 This research naturehighlights the complex metabolic crosstalk between cancer cells and healthy tissues and provides potential anticancer therapeutic targets.
as small intestine and liver Because they metabolize most of the dietary fructose, the research team investigated the effects of this sugar on tumors outside these tissues.5 Researchers exposed mice with either breast, cervical, or skin cancer to a high-fructose corn syrup solution, a type of fructose commonly consumed by people. Tumors in mice exposed to fructose grew faster compared to tumors in mice fed a sugar-free diet.
To understand how fructose promotes tumor growth, researchers cultured different types of cancer cells in laboratory dishes. They grew these cells using fructose, which has a heavy isotope of carbon that is incorporated into metabolites. By tracking the labeled carbons to map the sugar’s fate, the researchers found that cells metabolized very little fructose.
The results were “absolutely surprising,” said Patti, who had expected cancer cells to take up and break down fructose as fuel for themselves. The researchers suspected that the absence or low activity of fructose-metabolizing enzymes might be responsible for the negligible breakdown of the sugar. Sure enough, biochemical assays revealed that the cultured cancer cells lacked the enzymes ketohexokinase-c and aldolase-b, which are required to process fructose.
Based on these data, Patti hypothesized that tissues that express the enzyme, such as the liver, break down fructose to fuel cancer cells. By growing healthy liver cells with labeled sugars, the researchers were able to track the uptake of sugar into the cells.
Next, the researchers wanted to see whether liver cells break down fructose into molecules that can be used by cancer cells elsewhere in the body. The researchers cultured healthy liver cells and cervical cancer cells in a dish separated by a membrane. Compared to cancer cells grown without hepatocytes, cancer cells co-cultured with hepatocytes grew much faster in the presence of fructose. Treatment with a ketohexokinase inhibitor reduced proliferation of co-cultured cells, indicating that hepatocyte fructose metabolism supports cancer cell proliferation.
Researchers profiled metabolites secreted by liver cells and taken up by cancer cells and found that cancer cells take up lipids secreted by liver cells, particularly lysophosphatidylcholine (LPC). .
The researchers next investigated whether dietary fructose increases LPC in vivo. When we compared circulating lipid profiles in the serum of mice fed sugar-free and fructose-rich diets, we observed increased LPC levels in the latter group.
Exposing mice to labeled fructose and tracking it to serum LPC helped Patti and his team confirm that the rise in serum LPC was derived from dietary fructose. Tracking the fate of labeled LPCs has helped researchers understand how tumor cells process them. They found that phosphatidylcholine (PC) in tumor cells, an important component of cell membranes, contained labeled carbon and showed that tumors convert LPC to PC.
“I think [this study is] It’s actually very well thought out and very interesting.” Kayvan Keshariis a biochemist and bioengineer at Memorial Sloan Kettering Cancer Center but was not involved in the study. “[These results] “This suggests a very interesting mechanism for how tumors use nutrients coming from the host in vivo,” he said.
But he thought the results were not particularly surprising, since researchers have shown that other cells convert nutrients into molecules that can be used by cancer cells. The next step is to see if the same mechanism occurs in humans, he added.
“Additional data and additional human experiments are needed to confirm.” [the results]” Patty agreed. But he added that this study is an important first step because it shows that targeting metabolism in healthy tissue may limit tumor progression. “This opens up many treatment possibilities.”