Why does vitamin C protect us from cancer?

For some time, it has been known that people with lower levels of ascorbate (vitamin C) are at increased risk of cancer. Now, US researchers think they finally know why this is — and it all comes down to our stem cells.

While epidemiological data has shown that people with low ascorbate levels have a higher risk of cancer — and that people with leukaemia tend to have lower ascorbate levels than healthy individuals — the molecular underpinnings of these associations have until now been unclear. Furthermore, the relationship between levels of metabolites such as ascorbate, stem cell function, tissue regeneration and tumour suppression has been typically difficult to study — a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare.

Researchers from the Children’s Medical Center Research Institute at UT Southwestern, led by Sean Morrison, developed a highly sensitive metabolomics technique for analysing the metabolic profiles of rare cell populations isolated from tissues and used it to study human and mouse haematopoietic stem cells (HSCs). They discovered that every type of blood-forming cell in the bone marrow had distinct metabolic signatures, taking up and using nutrients in their own way — with stem cells found to soak up unusually high levels of ascorbate.

To determine if ascorbate was important for stem cell function, the researchers used mice that lacked gulonolactone oxidase (Gulo) — a key enzyme that most mammals, including mice but not humans, use to synthesise their own ascorbate. Loss of the enzyme required the Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave the scientists strict control over ascorbate intake by the mice and allowed them to mimic levels seen in approximately the 5% of otherwise healthy humans with vitamin C deficiency.

At these levels, the researchers expected depletion of ascorbate might lead to loss of stem cell function, but they were surprised to find the opposite was true — stem cells actually gained function. Mice fed a diet with only 10% of normal vitamin C levels for 3–6 months produced more HSCs and more white blood cells than their littermates that were fed a normal vitamin C diet. However, this gain came at a cost — and that cost was increased instances of leukaemia.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said Dr Michalis Agathocleous, lead author of the study. “The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off. So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukaemia.”

This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, with the inactivation of Tet2 through mutation typically serving as one of the first stages in the formation of leukaemia. The scientists found that ascorbate depletion can limit Tet2 function in tissues in a similar way, thus increasing the risk of leukaemia.

There was some good news for the mice, however — once they developed leukaemia, increasing their vitamin C to normal healthy levels suppressed the cancer’s development and prolonged their survival.

The study findings, published in the journal Nature, have implications for older human patients with a common precancerous condition known as clonal haematopoiesis, which puts patients at a higher risk of developing leukaemia and other diseases. As noted by Dr Morrison, “One of the most common mutations in patients with clonal haematopoiesis is a loss of one copy of Tet2.

“Our results suggest patients with clonal haematopoiesis and a Tet2 mutation should be particularly careful to get 100% of their daily vitamin C requirement,” he continued. “Because these patients only have one good copy of Tet2 left, they need to maximise the residual Tet2 tumour-suppressor activity to protect themselves from cancer.”

Monash University’s Associate Professor David Curtis, who was not involved in the research, has meanwhile gone one step further, suggesting that the study has “direct implications for a broad range of blood cancers where loss of Tet2 activity is an important cause”.

“Vitamin C supplementation might even benefit the one in 50 healthy elderly Australians who have loss of Tet2 activity, putting them at a high risk of death from leukaemia as well as heart disease,” said Associate Professor Curtis, who is director of Blood Cancer Research at the Australian Centre for Blood Diseases.

Commentary has also come from Dr Gabi Dachs, an associate professor at the University of Otago, Christchurch, who made sure to emphasise that this was “a mechanistic study in mice” and that “no patient studies were carried out”.

“Especially, we do not know whether increasing vitamin C intake in leukaemia patients would make any difference to their cancer progression, and well designed and controlled human clinical trials are needed to address this issue,” Dr Dachs said.

The researchers intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.