Fructose is a naturally occurring sugar found in fruits, honey, and other foods. It is also a major component of high-fructose corn syrup and corn syrup, commonly used in many beverages and desserts. While fructose shares the same molecular formula as glucose, their structures and metabolic pathways differ. Once ingested, some fructose is absorbed in the small intestine, while the excess is metabolized in the liver and converted into other compounds.

Excessive fructose consumption has been linked to insulin resistance and obesity, and it may also have connections to cancer development. One widely discussed theory suggests that fructose is associated with accelerated tumor growth. Studies have shown that high levels of fructose can promote the progression of various cancers. For example, certain cancerous tissues exhibit elevated levels of fructose transport proteins, enabling them to absorb more fructose.

However, this theory faces two unresolved challenges:

1. Unlike the abundant availability of glucose, fructose levels in the circulatory system are quite limited, making it difficult for cancer cells to access.
2. Structurally, fructose contains a ketone group, but many cancer cells lack ketohexokinase-C (KHK-C), an enzyme necessary to efficiently utilize fructose.

A New Study Reveals How Fructose Promotes Cancer

Today, a groundbreaking paper in Nature unveils a novel mechanism by which fructose contributes to cancer progression. The study reveals that cancer cells do not metabolize fructose directly. Instead, they rely on a byproduct of fructose metabolism in the liver—lysophosphatidylcholine (LPC)—to maintain cell membrane function and support tumor nutrition. This indirect utilization represents a non-autonomous metabolic pathway through which fructose drives cancer development.

The researchers used various models, including zebrafish, mice, and specialized cell combinations, to investigate the connection between fructose and cancer mechanisms. They first developed melanoma models in zebrafish. Remarkably, tumors grew more significantly in zebrafish exposed to fructose-enriched water compared to those in regular water. Similarly, in mouse tumor models, increasing dietary fructose intake to levels resembling a Western diet accelerated tumor progression.

However, cellular experiments painted a different picture. Adding fructose directly to cancer cell cultures had little impact on their growth compared to control groups. This finding suggested that fructose itself does not directly promote cancer. Instead, it is more likely that fructose metabolites produced within the body are utilized by cancer cells.

This led researchers to focus on the liver, a key organ in fructose metabolism.

They found that liver cells and cancer cells differ significantly in their expression of ketohexokinase-C (KHK-C), an enzyme critical for fructose metabolism. Liver cells, which express high levels of KHK-C, efficiently convert fructose into various lipid molecules.

Among these, LPC stands out because, unlike most lipids, it dissolves in blood and can be continuously absorbed by cancer cells.

The study also showed that mice consuming high-fructose corn syrup experienced a sevenfold increase in serum LPC levels, providing further evidence of the link between dietary fructose, liver metabolism, and cancer progression.

The authors employed two approaches to validate their hypothesis. First, they directly inhibited KHK-C in the livers of mice, blocking fructose metabolism. As a result, tumor growth slowed significantly. In the second approach, they directly injected LPC into the mice. Even without supplemental fructose, tumors progressed noticeably faster. Theoretically, LPC provides molecules essential for cell membrane synthesis, enabling cancer cells to maintain rapid division and proliferation.

The researchers noted that they aim to explore the connection between increased fructose intake and cancer incidence in humans further. For example, the increasing prevalence of cancer among younger populations might correlate with the high fructose consumption common among young people. However, the extent of this link requires more extensive future research.

Interestingly, some studies have presented findings that differ from this research. For instance, a paper published last year in Cell Metabolism suggested that fructose could stimulate anti-tumor CD8+ T cell responses by influencing adipocyte metabolism, potentially exerting an anti-cancer effect. The authors of that study speculated that the discrepancies in results might stem from differences in the models used across studies. As such, the relationship between fructose and cancer requires careful consideration of various scenarios and contexts, warranting further nuanced investigations by scientists in the future.