Liver conversion of fructose fuels cancer growth by supplying lipids for tumor proliferation

Research uncovers how cancer cells exploit fructose as an alternative fuel for growth, revealing a surprising metabolic process

In a recent study published in Nature, researchers from Washington University investigated how dietary fructose indirectly promotes tumor growth through metabolic mechanisms involving the liver.

The findings demonstrated that cancer cells lacking the ability to metabolize fructose directly benefit from the lipids produced by the liver after fructose metabolism. This process revealed a novel inter-organ nutrient transfer that is critical to tumor development and suggested potential therapeutic targets.

Background

Cancer cells are known to use glucose extensively for energy and growth in a phenomenon termed the Warburg effect. Recent research has highlighted the potential role of fructose in tumor growth. Fructose is a naturally occurring sugar that is metabolized differently from glucose and is processed primarily by the liver. Elevated dietary fructose consumption, linked to the increasing prevalence of high-fructose corn syrup in processed foods, raises numerous concerns about its impact on health, including cancer progression.

Unlike glucose, fructose metabolism requires specific enzymes that are not commonly found in most cancer cells, suggesting that fructose plays an indirect role in tumor development. The metabolic crosstalk between normal organs and tumors, such as nutrient exchange between the liver and cancer cells, is emerging as a crucial factor in cancer biology. However, the precise mechanisms through which fructose supports tumor growth remain unclear, necessitating further exploration of inter-organ interactions in cancer metabolism.

About the study

The present study utilized various experimental systems, including zebrafish and murine models, to explore how dietary fructose influences tumor growth. Zebrafish engineered with melanoma-associated mutations and mice implanted with cancer cells were used to monitor tumor growth under high-fructose diets.

The researchers also conducted in vitro experiments where cancer cell lines were cultured with labeled fructose to assess their ability to metabolize the sugar. Additionally, co-culture experiments were also performed where cancer cells were paired with liver cells to evaluate the role of hepatic metabolism in supporting tumor growth.

The study used several analytical techniques, including liquid chromatography-mass spectrometry (LC-MS), to identify key metabolites derived from fructose in the liver and track their uptake by cancer cells. The researchers also inhibited ketohexokinase-C (KHK-C), an enzyme critical for fructose metabolism in the liver, to observe changes in tumor progression.

Additionally, lipid profiling revealed an increase in lysophosphatidylcholines (LPCs), a class of lipids that cancer cells use to build membranes. Mice that were directly treated with LPCs or genetically modified to enhance LPC production showed accelerated tumor growth. Conversely, suppressing LPC utilization in cancer cells significantly reduced their proliferation and tumor size.

The study also included comparative assessments of the metabolic pathways of glucose and fructose to highlight the distinct but indirect role of fructose in tumor growth. Overall, the study combined genetic, biochemical, and dietary interventions to detect how the liver converts fructose into metabolites that indirectly fuel tumor growth while providing a comprehensive understanding of inter-organ metabolic interactions.

Major findings

The researchers observed that dietary fructose indirectly enhances tumor growth through metabolites produced by the liver. While cancer cells do not metabolize fructose effectively due to the lack of essential enzymes such as KHK-C, the liver processes fructose into lipids, including LPCs. These LPCs enter the bloodstream and are absorbed by tumor cells, which convert them into phosphatidylcholines, crucial for building cellular membranes during cancer cell proliferation.

Using zebrafish and mouse models, the researchers also demonstrated that high-fructose diets resulted in faster tumor growth compared to control diets. The fructose-fed mice did not exhibit weight gain or metabolic disruptions, which further highlighted the specific tumor-promoting effects of fructose.

Furthermore, the inhibition of KHK-C reduced the circulating LPC levels and significantly impeded tumor growth, confirming that the enzyme plays an important role in fructose metabolism and nutrient transfer.

Moreover, the lipid analyses revealed that LPCs, particularly those containing 18:1 fatty acid chains, were heavily utilized by tumors. Supplementing these lipids directly increased tumor growth in animal models.

Conversely, silencing lysophosphatidylcholine acyltransferase 1 (LPCAT1), which converts LPCs into phosphatidylcholines, inhibited cancer cell proliferation and tumor expansion. These experiments confirmed that dietary fructose elevates serum LPC levels, reinforcing their role as intermediaries in the fructose-tumor growth pathway.

Conclusions

Overall, the study revealed a critical link between dietary fructose, liver metabolism, and tumor growth. The results showed that fructose indirectly supports cancer proliferation by increasing circulating LPCs, which tumors use for membrane biosynthesis.

The findings also suggested that fructose promotes an inter-organ metabolic mechanism where liver-derived lipids support tumor growth, independent of direct fructose metabolism by cancer cells.

This discovery emphasized the importance of inter-organ nutrient transfer in cancer progression and suggested that targeting fructose metabolism or its lipid intermediates could present new strategies to inhibit tumor growth without directly affecting systemic metabolism.