Low Vitamin C speeds up leukaemia in mice – Expert Reaction

US researchers have uncovered a reason why low vitamin C may speed up the development of leukaemia in mice. 

Unlike humans, mice can make vitamin C in their bodies, but the researchers genetically engineered mice so they couldn’t any longer — making them reliant on vitamin C from food. These mice had higher rates of leukaemia, and reduced activity of a gene that usually suppresses tumour development, but when the scientists fed the mice additional vitamin C, their leukaemia slowed.

More information about the research is available on scimex.org for registered journalists. The SMC gathered expert reaction to the study, please feel free to use these comments in your reporting. 

Professor Margreet Vissers, principal investigator, Centre for Free Radical Research, University of Otago, comments:

“Whether vitamin C (ascorbate) has a role to play in cancer prevention and in the treatment of established cancers has been a controversial topic for some decades. One of the main reasons for the controversy has been the lack of a plausible mechanism of action, but in the past decade new functions for vitamin C have been identified that could influence cancer cell growth.

Since the 1960s it has been known that vitamin C is essential to maintain activity of the enzyme responsible for the stabilisation of collagen and that acute vitamin C deficiency leads to many problems associated with connective tissue dysfunction (skin, blood vessels). In recent years, many more related enzymes have been identified that also need vitamin C for activity.

These enzymes all carry out a similar reaction, but have different cellular functions, including the regulation of cell metabolism (the hypoxic response and related energy production) and the control of gene expression through the modification of epigenetic marks by enzymes known as the Tet enzymes. These functions can influence the development of cancers, and the growth and survival of established tumours.

“This new publication from Sean Morrison and colleagues from Texas and Utah, describes what may become a landmark study that has demonstrated a unique requirement for very high levels of vitamin C in bone marrow stem cells. These cells were shown to concentrate the vitamin to extraordinarily high levels, suggesting an essential need. Inside the cells, vitamin C supports the activity of the Tet enzymes that modify the DNA and control gene expression.

Using a mouse model that, like humans, has lost the ability to synthesise vitamin C, the researchers have shown that the activity of the Tet enzymes in bone marrow stem cells was decreased and gene expression was changed. It appears that the Tet enzymes normally limit the number and function of bone marrow stem cells and that low vitamin C levels thereby increased stem cell numbers and activity and promoted the development of leukaemia. The study has used elegant methods to identify these very complex changes in bone marrow stem cells.

“The paper describes a proof of concept model that adds to our understanding of a potential way in which vitamin C could both prevent cancers such as leukaemia and slow the progression of such a disease. The implications for future cancer therapies are exciting, and studies such as these will inform the human clinical studies that will determine whether a similar mechanism could apply to human cancers.”

Associate Professor Gabi Dachs, cancer researcher, University of Otago Christchurch, comments:

“The paper provides compelling evidence (in mice) that inadequate amounts of vitamin C in the diet can lead to an increased risk of leukaemia.

“The authors set out to measure metabolites (chemicals that a cell produces or requires to sustain life) in specific sets of bone marrow cells from mice, and found that stem cells, in particular, had very high levels of vitamin C.

“We know that vitamin C levels vary greatly between different organs and tissues of the body, and it is believed that this reflects the vitamin C requirement of each tissue. The study also looked at bone marrow cells from 12 (human) individuals and found a similar pattern, ie notably higher levels of vitamin C in the bone marrow stem cells.

“To further study the role of the vitamin in the mice, they needed to use a genetic knockout mouse, which similar to humans, is unable to produce its own vitamin C. Indeed, humans and apes are among a handful of animals that cannot synthesise vitamin C and require it from their diet every day; all other animals make their own, and in fact have been shown to increase their vitamin C production when under stress or ill.

“Using these specific mice, the authors could reduce the amount of vitamin C in the bone marrow by providing the animals with inadequate amounts of vitamin C in the diet. This reduction in vitamin C actually increased the number and function of the stem cells, and the authors identified the enzyme that is involved.

“This enzyme, Tet2, is a known tumour-suppressor and requires vitamin C for its activity. The authors further investigated what effect vitamin C deficiency had in the presence of a common precancerous mutation, and found that this combination resulted in overt leukaemia and a significant reduction in mouse survival, both of which were partially reversible by increasing vitamin C supply.

“The vitamin C levels in the deficient mice were similar to those measured in about 1/20 healthy adults in the US, and there is no reason to believe that healthy NZ adults would have higher levels. Indeed, the daily recommended intake for vitamin C in NZ is among the lowest world-wide.

“Although this study is vital for our understanding of the numerous functions of vitamin C in cancer, it needs to be emphasised that it was a mechanistic study in mice, and although human samples were tested for their levels of vitamin C, 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.”

Associate Professor Patries Herst, radiation therapy scientist, University of Otago, comments:

“This very elegant study in top scientific journal, Nature, shows that seriously depleted levels of vitamin C increase the number and turnover rate of stem cells in the blood forming system (HSCs) in a special breed of mice. These mice need vitamin C in their diet just like humans do. Mice that are 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.

“Although this may seem trivial, the authors also showed that high HSC numbers decreased the activity of an enzyme (Tet2) which, at normal activity levels, prevents the development of an early stage of leukemia. Mice fed low vitamin C diets not only had more HSCs, they also had lower Tet2 activity and an increased chance of developing leukemia, albeit in the presence of additional mutations.

“Depleted vitamin C levels had the same effects as Tet2 inactivation through mutation. Adding vitamin C to the mices’ diet decreased HSC numbers, increased Tet2 activity and normalised the chance of developing leukemias.

“Once these mice had developed leukemia, adding vitamin C to normal healthy levels prolonged their survival.”

What are the implications of this research for humans?

“Although results from animal models need to be interpreted with caution (mice are not humans), the Gulo-/- model does mimic the inability of human cells to produce vitamin C. The authors also showed that HSCs in the bone marrow of both mice and humans take up a lot of vitamin C through specific vitamin C transporters in the membrane of the HSCs. An estimated 5% of the human population would have similarly low levels of vitamin C as these mice.

“The development of any cancer, including blood cancers, requires the accumulation of a number of mutations. Extremely low levels of vitamin C in the body mimic the effects of a Tet2 inactivating mutation. However, this could only progress to leukemia if other mutations are present.

“Vitamin C is an essential micro-nutrient with a very important role as an anti-oxidant, in the production of collagen, neurotransmitters and hormones. It is important to point out that this research compares healthy vitamin C levels with depleted vitamin C levels in mice and must not be confused with pharmacological doses of vitamin C where extremely high doses of vitamin C  are administered intravenously.”

The Australian Science Media Centre also gathered the following comments.

Associate Professor David Curtis is Director of Blood Cancer Research at the Australian Centre for Blood Diseases, Monash University

“Ever since the Nobel Prize winning discovery of vitamin C in 1937, scientists have explored its anti-cancer properties. Low vitamin C levels are linked to higher death rates from cancer and early clinical trials using massive intravenous doses of vitamin C showed some remarkable benefits. But these and other reports were silenced by more carefully designed, yet flawed, trials in the late 70s.

Now, work led by Sean Morrison will help to reignite the hope that vitamin C can help cancer patients.

Humans can only source vitamin C from their diet while other animals, including mice, can make their own using a liver enzyme known as GULO. This difference has made animal studies of vitamin C supplementation problematic.

Using genetically-modified mice lacking GULO, the Morrison group cleverly showed that vitamin C deficiency, similar to levels seen in 5 per cent of humans, promotes the development of leukaemia by reducing the activity of an enzyme called Tet2. Most dramatically, vitamin C supplements were able to slow the progression of leukaemia in these mice.

This discovery, which has been confirmed by an independent group*, 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 1 in 50 healthy elderly Australians who have loss of Tet2activity, putting them at a high risk of death from leukaemia as well as heart disease.

With this improved understanding, the time is ripe for new clinical trials of vitamin C supplements in cancer.”

Associate Professor Steven Lane is Group Leader of the Gordon and Jessie Gilmour Leukaemia Research Lab at QIMR Berghofer Medical Research Institute

“Since the times of Captain Cook, it has been widely known that dietary intake of fresh fruit and produce is essential to prevent scurvy, the disease associated with vitamin C deficiency.

A new study from Sean Morrison and colleagues in the prestigious journal Nature examines the effect of severe vitamin C deficiency on blood production and leukaemia. They find that vitamin C controls a number of important pathways within blood cells, and these pathways are important to fine tune, to slow down and control the orderly production of blood cells.

Leukaemia is the classical disease where the control of blood production goes awry. Too many blood cells build up in the blood, bone marrow and other organs. We know that most leukaemia is actually caused by genetic changes within blood cells that you pick up throughout life and these genetic changes cause the blood cell to grow uncontrollably and/or prevent the blood cells from dying.

The authors use clever techniques to remove vitamin C from the leukaemia cells, and in this context, the leukaemia cells are able to grow faster and be more aggressive in the body. They summarise by stressing the importance of treating vitamin C deficiency in patients with leukaemia and other blood cancers.

This paper is very interesting and uncovers a new pathway related to our metabolism that might be important in the origin and treatment of cancers. Most of us accept the link between dietary intake and diseases such as heart attacks and cancer, but these results show us how finely balanced the human body really can be.

So the obvious question is – should patients start supplementing their diets with high levels of vitamin C based on this work?

Clearly such a recommendation is premature. True vitamin C deficiency is exceedingly rare in an privileged developed nation such as Australia. Furthermore, nutritional review and support by dietitians is an essential part of inpatient clinical management of patients with leukaemia, and other cancers.

There is no suggestion from this article that supplementing chemotherapy or other treatments with vitamin C has any beneficial effect to individual patients with leukaemia.

Rather, this work reinforces the general advice that a healthy, balanced diet containing the recommended intake of essential minerals and vitamins is the best way to keep your body functioning normally, and to recover after life changing diseases such as cancer.”