Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener in beverages and ultra-processed foods. In terms of its chemical structure, fructose is similar to glucose. They are both common types of sugar, with the same chemical formula, but they differ in how the body metabolizes them. Glucose is processed throughout the whole body, while fructose is almost entirely metabolized by the small intestine and liver. Prior to the 1960s, people consumed relatively little fructose compared with today’s numbers. A century ago, an average person consumed just 5-10 pounds of fructose per year. To put it in familiar terms, that is roughly equal to the weight of a gallon of milk. In the 21st century, that number has increased to be as high as the equivalent of 15 gallons of milk.
New research from Washington University in St. Louis shows that dietary fructose promotes tumor growth in animal models of melanoma, breast cancer and cervical cancer. However, fructose does not directly fuel tumors, according to a new study published in the journal Nature. Instead, looks like that the liver converts fructose into usable nutrients for cancer cells, a compelling finding that could open up new avenues for care and treatment of many different types of cancer. Original expectation from the scientist were that tumor cells metabolize fructose just like glucose, directly utilizing its skeleton to build new cellular components such as DNA bases (nucleosides). This could make sense, since if fructose is firslty converted into glucose, this undergo catobolism through glycolysis to produce acetyl-coenzyme A (acetil-CoA).
This in turn may be used in mitochondrial Krebs cycle to produce energy directly; on the other hand, acetil-CoA molecular condensation driven by fatty acid synthase (FAS) generates long-chain fatty acids. Using metabolomics the researchers concluded that one way in which high levels of fructose consumption promote tumor growth is by increasing the availability of circulating lipids in the blood. These lipids are building blocks for the cell membrane, intermediates for signaling molecules and energy substrates as well and cancer cells need them to grow. Prostate cancer, for example is well known to use free fatty acid to sustain its energy requirements for cell proliferation, by mean of beta-oxidation again to produce ATP in mitochondria.
Scientists have long recognized that cancer cells have a strong affinity for glucose, a simple sugar that is the body’s preferred carbohydrate-based energy source. Given the rapid rise in the consumption of dietary fructose over recent decades, the WashU researchers wanted to know more about how fructose impacts the growth of tumors. Led by Drs. Patti and Fowle-Grider began their investigation by feeding tumor-bearing animals a diet rich in fructose, then measuring how quickly their tumors grew. The researchers found that added fructose promoted tumor growth without changing body weight, fasting glucose or fasting insulin levels. In some cases, the growth rate of the tumors accelerated by two-fold or even higher.But the next step in their experiments initially stumped them.
When scientists turned into in vitro experiments with cancer cells, these did not respond. In most cases they grew almost as slowly as if we gave them no sugar at all. This is where researchers focused their investigation with metabolomics, whiche led them to discover that a variety of lipid species, including lysophosphatidyl-cholines (LPCs) lied behind the effects of fructose: in vitro cultured liver cells that were fed fructose release LPCs, which in turn, go to feed tumors. A defining characteristic of cancer is uncontrolled proliferation of malignant cells. Each time cell divide, they must replicate their contents, and membranes are of course included. While lipids can be synthesized from scratch, it is much easier for cancer cells to simply take lipids up from their surrounding environment.
Compared to triglycerides, lisophosphatidyl-cholines are far more soluble in water: they, indeed, are composed of a fatty moiety (the fatty acid acid itself) esterified with a polar head of phosphate and a positively charged choline residue. Such a combination in organic chemistry is called “amphipatic”, meaning simultaneously soluble in water and solvent, like a soap. In addition, there are membrane receptors wihich are endogenously activated by liso-phospholipids like LPCs. Among these the GPR4 and GPR132. The first is abundantly expressed in macrophages, which may infiltrate tumors and regulate the immune response. GPR132 is also activated by tissutal acidosis, which is common in peri-tumoral and intra-tumoral environment. This aspect has not been investigated by the authors, but since LPCs are abundantly present in tissues and bloodstream, they have been deemed as possible activators of costitutively active GPCRs.
Beside, if LPCs are converted into lisophosphatidic acid (LPA), this may work not only as a building block for new phospholipids, but may use other G protein-coupled surface receptors (LPAR1-4) to enhance the growth response triggered by growth factors (e.g. EGF and FGF2) in cancer cells. Therefore, aside from dietary intervention, the study authors said that this research could help develop a way to prevent fructose from driving tumor growth therapeutically by means of drugs.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Fowle-Grider R et al. Nature 2024; in press.
Wang Y et al. Trends Cell Biol. 2023; 33:1014.
Jeong S et al. Cell Metab. 2021; 33:145–159.
Liang RJ et al. Cancer Metab. 2021; 9(21).
