About a century in the past, Otto Warburg, a German physiologist confirmed that tumor cells eat extra glucose in comparison with wholesome cells to spice up their proliferation.1 This phenomenon underlies a diagnostic imaging method to detect most cancers, the place docs inject radioactive glucose and hint it’s consumption to tumor cells.2
Researchers have since discovered that one other sugar, fructose, promotes the expansion of tumors, however the mechanism has been unclear.3 Fructose and glucose have the identical chemical formulation, however totally different association of the atoms. “Given the position that glucose performs in most cancers metabolism and the way it’s used as such a distinguished gasoline, we have been very considering how fructose may play an identical position,” mentioned Gary Patti, a biochemist and techniques biologist on the Washington College in St. Louis.
Now, in a brand new research Patti and his staff discovered that fructose promotes tumor progress not directly: The liver breaks down fructose into vitamins which can be taken up by tumor cells to gasoline their proliferation.4 The research, revealed in Nature, highlights the advanced metabolic crosstalk between most cancers cells and wholesome tissues, offering potential anticancer therapeutic targets.
Because the small gut and liver metabolize many of the dietary fructose, the staff investigated the impact of this sugar on tumors outdoors of those tissues.5 They uncovered mice that had both breast, cervical, or pores and skin most cancers tumors to high-fructose corn syrup answer, a type of fructose that individuals generally eat. Tumors in mice uncovered to fructose grew sooner in comparison with these in mice on a sugar-free food regimen.
To know how fructose enhances tumor progress, the researchers cultured numerous sorts of most cancers cells in lab dishes. They grew these cells with fructose that had a heavy isotope of carbon which will get included into metabolites. Once they traced the labeled carbon to map the sugar’s destiny, the researchers discovered that the cells metabolized little or no fructose.
This outcome was “completely stunning,” mentioned Patti, who anticipated that most cancers cells would take up and break down fructose to gasoline themselves. The staff questioned if the absence or low exercise of fructose-metabolizing enzymes was chargeable for negligible breakdown of the sugar. Positive sufficient, biochemical assays revealed that cultured most cancers cells lacked the enzymes ketohexokinase-c and aldolase-b required to course of fructose.
Primarily based on these information, Patti hypothesized that tissues that categorical the enzymes, such because the liver, break down fructose into gasoline for the most cancers cells. On rising wholesome liver cells with labeled sugar, the staff might hint its uptake into the cells.
Subsequent, the staff wished to find out whether or not liver cells break down fructose into molecules that most cancers cells elsewhere within the physique might make the most of. The researchers cultured wholesome liver cells and cervical most cancers cells in a dish separated by a membrane. In comparison with most cancers cells grown with out liver cells, these co-cultured with liver cells proliferated a lot sooner within the presence of fructose. Proliferation in co-cultured cells decreased on therapy with an inhibitor of ketohexokinase, indicating that fructose metabolism in liver cells helps progress of most cancers cells.
When the researchers profiled metabolites secreted by liver cells and people taken up by most cancers cells, they discovered that most cancers cells take up lipids, particularly lysophosphatidylcholines (LPCs), secreted from liver cells.
The researchers subsequent investigated whether or not dietary fructose elevated LPCs in vivo. On evaluating circulating lipid profiles within the sera of mice on sugar-free and fructose-rich diets, they noticed elevated LPC ranges within the latter group.
Exposing mice to labeled fructose and tracing it to LPCs of their sera helped Patti and his staff affirm that the elevated serum LPCs originated from dietary fructose. Tracing the destiny of the labeled LPCs helped the researchers perceive how tumor cells processed them. They discovered that phosphatidylcholines (PCs)—key constructing blocks of cell membranes—in tumor cells contained the labeled carbon, indicating that tumors convert LPCs to PCs.
“I feel [this study is] really very effectively thought out, and it’s very attention-grabbing,” mentioned Kayvan Keshari, a biochemist and bioengineer at Memorial Sloan Kettering Most cancers Heart, who was not related to the research. “[These results] counsel a really attention-grabbing mechanism for a way tumors in vivo could use vitamins coming from host,” he mentioned.
Nevertheless, he didn’t discover the outcomes significantly stunning, as a result of researchers are more and more displaying that different cells convert vitamins into usable molecules for most cancers cells. The subsequent steps ought to be to see if the identical mechanism takes place in people, he added.
“We’d like extra information and extra experiments in people to validate [the results],” agreed Patti. However this is a vital first step, as a result of this research reveals that focusing on metabolism in wholesome tissues may restrict tumor development, he added. “That opens up loads of potential therapeutic home windows.”
