About a century ago, Otto Warburg, a German physiologist showed that tumor cells consume more glucose compared to healthy cells to boost their proliferation.1 This phenomenon underlies a diagnostic imaging technique to detect cancer, where doctors inject radioactive glucose and trace it’s consumption to tumor cells.2
Researchers have since found that another sugar, fructose, promotes the growth of tumors, but the mechanism has been unclear.3 Fructose and glucose have the same chemical formula, but different arrangement of the atoms. “Given the role that glucose plays in cancer metabolism and how it’s used as such a prominent fuel, we were very interested in how fructose might play a similar role,” said Gary Patti, a biochemist and systems biologist at the Washington University in St. Louis.
Now, in a new study Patti and his team found that fructose promotes tumor growth indirectly: The liver breaks down fructose into nutrients that are taken up by tumor cells to fuel their proliferation.4 The study, published in Nature, highlights the complex metabolic crosstalk between cancer cells and healthy tissues, providing potential anticancer therapeutic targets.
As the small intestine and liver metabolize most of the dietary fructose, the team investigated the effect of this sugar on tumors outside of these tissues.5 They exposed mice that had either breast, cervical, or skin cancer tumors to high-fructose corn syrup solution, a form of fructose that people commonly consume. Tumors in mice exposed to fructose grew faster compared to those in mice on a sugar-free diet.
To understand how fructose enhances tumor growth, the researchers cultured various types of cancer cells in lab dishes. They grew these cells with fructose that had a heavy isotope of carbon which gets incorporated into metabolites. When they traced the labeled carbon to map the sugar’s fate, the researchers found that the cells metabolized very little fructose.
This result was “totally surprising,” said Patti, who expected that cancer cells would take up and break down fructose to fuel themselves. The team wondered if the absence or low activity of fructose-metabolizing enzymes was responsible for negligible breakdown of the sugar. Sure enough, biochemical assays revealed that cultured cancer cells lacked the enzymes ketohexokinase-c and aldolase-b required to process fructose.
Based on these data, Patti hypothesized that tissues that express the enzymes, such as the liver, break down fructose into fuel for the cancer cells. On growing healthy liver cells with labeled sugar, the team could trace its uptake into the cells.
Next, the team wanted to determine whether liver cells break down fructose into molecules that cancer cells elsewhere in the body could utilize. The researchers cultured healthy liver cells and cervical cancer cells in a dish separated by a membrane. Compared to cancer cells grown without liver cells, those co-cultured with liver cells proliferated much faster in the presence of fructose. Proliferation in co-cultured cells reduced on treatment with an inhibitor of ketohexokinase, indicating that fructose metabolism in liver cells supports growth of cancer cells.
When the researchers profiled metabolites secreted by liver cells and those taken up by cancer cells, they found that cancer cells take up lipids, specifically lysophosphatidylcholines (LPCs), secreted from liver cells.
The researchers next investigated whether dietary fructose increased LPCs in vivo. On comparing circulating lipid profiles in the sera of mice on sugar-free and fructose-rich diets, they observed elevated LPC levels in the latter group.
Exposing mice to labeled fructose and tracing it to LPCs in their sera helped Patti and his team confirm that the elevated serum LPCs originated from dietary fructose. Tracing the fate of the labeled LPCs helped the researchers understand how tumor cells processed them. They found that phosphatidylcholines (PCs)—key building blocks of cell membranes—in tumor cells contained the labeled carbon, indicating that tumors convert LPCs to PCs.
“I think [this study is] actually very well thought out, and it’s very interesting,” said Kayvan Keshari, a biochemist and bioengineer at Memorial Sloan Kettering Cancer Center, who was not associated with the study. “[These results] suggest a very interesting mechanism for how tumors in vivo may use nutrients coming from host,” he said.
However, he did not find the results particularly surprising, because researchers are increasingly showing that other cells convert nutrients into usable molecules for cancer cells. The next steps should be to see if the same mechanism takes place in humans, he added.
“We need additional data and additional experiments in humans to validate [the results],” agreed Patti. But this is an important first step, because this study shows that targeting metabolism in healthy tissues might limit tumor progression, he added. “That opens up a lot of potential therapeutic windows.”
