My thesis advisor would describe some new results—disparagingly—as “not hypothesis driven.” Instead, the researchers who are reporting these results thought to themselves: hmmm, tumor cells really like glucose. (Yes, all cells really like glucose, but tumor cells really really like it.) Wonder if they like all sugars? They soon grew some osteosarcoma cells in the presence of different sugars and found that one sugar significantly impeded cell growth.

Despite the lack of a hypothesis, at least this is a Nature paper, so it is incredibly comprehensive. The authors followed up on many ramifications of their initial findings and did an inordinate number of experiments to bolster each of their assertions.

Mano a mannose

The authors compared the tumor cells' growth on a variety of sugars: glucose, fructose, frucose, galactose, and mannose. Out of everything they tested, mannose was the only one that seemed to slow the cells down.

So they examined the mechanism by which mannose might limit tumor cell growth. They initially thought that mannose might interfere with glucose uptake, since the two sugars use the same transporter to get into cells. But no, that wasn’t it. The researchers next measured the levels of various products of glucose metabolism and concluded that mannose inhibits key enzymes involved in essential metabolic pathways, all of which rely on glucose.

One of the pathways that's inhibited is the tricarboxylic acid cycle, or Krebs cycle, which is how cells generate energy through aerobic respiration. Another is the pentose phosphate pathway, an additional energy-producing metabolic pathway that also generates some of the nucleotides used to build genetic material. There is also glycolysis, in which glucose is broken down to produce energy. The last pathway is glycan synthesis, in which sugars are modified so that they can be attached to proteins. Basically, mannose just gums up much of the cellular works.

Many researchers would stop here, and that would be the complete report: Mannose Slows Tumor Cell Growth by Interfering with Glucose Metabolism. That could be a totally legitimate paper, but not for these folks. Once they figured out how mannose slowed growth, they decided to check if it could help chemotherapeutic agents. Although on its own it did not kill tumor cells in culture, the team found that it dramatically enhanced cell death by two different chemotherapy drugs, cisplatin and doxorubicin.

Boosting chemo

How did it do that? A whole additional series of experiments revealed that mannose + drug worked by inducing programmed cell death (called apoptosis). And how did it do that? Specifically, it altered the levels of three proteins that regulate a cell death pathway, which they do by controlling how easily things can get into and out of the mitochondria. Further experimentation indicated that fewer of these proteins are made in the presence of mannose + drug.

The authors “were keen to find out” (they’re in the UK) if these effects that they’d seen in tissue culture dishes could be recapitulated in vivo. They fed mannose to mice with tumors, and it slowed tumor growth and enhanced chemotherapy in the mice, too. It did not cause weight gain or otherwise impact the health of the mice.

Then they went on to probe why some tumor cells are more sensitive to mannose than others. The researchers found that mannose sensitivity was inversely proportional to the levels of an enzyme that helps metabolize mannose. Knocking down the enzyme in tumor cell lines made any cell sensitive to mannose. The researchers looked at a panel of human cancers—ovarian, renal, breast, prostate, colorectal—and saw that the enzyme varied among them, but had no prognostic significance (probably because there’s usually not that much mannose around, especially relative to glucose). Colorectal tumors tend to have especially low levels so might be good candidates for initial treatments with the sugar.

Candy bars are still not good for you. But mannose might be a safe way to enhance the treatment of some cancers. And it won't need FDA approval, although we'll want further evidence before using it clinically.

Nature, 2018. DOI: 10.1038/s41586-018-0729-3 (About DOIs).