New Study Links the Keto Diet to Cancer Metastasis

The ketogenic diet — a high-fat, low-carbohydrate diet purported to have benefits for people with cancer — may increase the risk of tumor metastasis, according to a new study by researchers at the Herbert Irving Comprehensive Cancer Center (HICCC). The researchers, led by Wei Gu, PhD, found that in a mouse model of breast cancer, mice fed with a ketogenic diet experienced significantly more lung metastases compared to those on a control diet.

“Our lab studies how metabolic stress regulates tumor growth and metastasis,” says Gu, professor of pathology and cell biology at Columbia University and member of the Cancer Genomics and Epigenomics program at the HICCC. “How the ketogenic diet affects tumor growth has been reported by several groups, but we wanted to look at how it affects tumor metastasis, and we got a very surprising result.”

The keto diet and cancer: what we know

Originally used in clinical settings to reduce seizures in children with epilepsy, the ketogenic diet has become popular in recent years for weight loss and other health benefits. It is characterized by a very low intake of carbohydrates, putting the body into a metabolic state called ketosis. Normally, the body breaks down carbohydrates into glucose to fuel our cells. In ketosis, the body burns fat for energy instead of glucose.

Previous research has shown that the ketogenic diet may slow tumor growth, since the lack of glucose causes cancer cells to be deprived of energy. For example, a recent clinical trial found that patients with breast cancer who followed a ketogenic diet for 12 weeks had a better response to chemotherapy, such as reduced tumor size and downstaging, compared to those in a control diet group. However, its effects on metastatic progression — a major cause of cancer-related mortality — remain unclear.

An unexpected result on tumor metastasis 

Gu and his colleagues fed mice either a carbohydrate-free ketogenic diet or control diet for 7 weeks, tracking the size and weight of their primary tumors. As expected, they observed a noticeable reduction in primary tumor growth in the ketogenic group compared to the control group. However, fluorescence imaging of the lungs revealed that mice on the ketogenic diet had accumulated a much larger number of metastatic nodules.

“We did indeed see that the ketogenic diet suppressed tumor growth — but we also saw, surprisingly, that it promoted tumor metastasis,” says Gu. “That was really a shock to us.”

The culprit: glucose starvation and sugar-hungry cancer cells

Upon further investigation, the researchers found that the ketogenic diet-induced metastasis is dependent on a protein called BACH1. Prior work has linked BACH1 to enhanced metastatic potential in breast and lung cancers. Gu and his colleagues leveraged RNA sequencing analysis to determine that glucose starvation leads to an up-regulation in BACH1-modulated pro-metastatic genes.

"The cancer cells detect that this place deprived of glucose is not nutritionally comfortable, so they want to escape. They don’t want to stay in the wrong place,” Gu says. “The consequence of that is metastasis.

While a large body of work points to the impact of diet and metabolism, including such conditions as diabetes and obesity, on cancer development and progression, the mechanism of impact remains unclear.

“The findings from Gu’s laboratory provide some the first insights about the effects of diet, in this case a ketogenic diet and cancer metastasis,” says Anthony Ferrante, Jr., MD, PhD, the Tilden-Weger-Bieler Professor of Medicine at Columbia’s Vagelos College of Physicians and Surgeons (VP&S). “These results point to a specific pathway and most importantly provide a framework for testing the role of ketogenic diet in human cancers,” adds Ferrante, who is also co-director of the Naomi Berrie Diabetes Center, a close collaborator with the HICCC in developing research in the area of diet, systemic metabolism, and cancer.

When knocking out BACH1 in breast cancer cells, later injected into mice, those cells lost the metastatic boost normally induced by the ketogenic diet. The researchers are currently exploring the possibility of using compounds that suppress BACH1 to block metastasis. Future clinical trials could explore the benefits of combining the ketogenic diet and BACH1 inhibition, in order to preserve the growth-repressive effect of glucose starvation while eliminating the increased risk of metastasis.

“Our study used an experimental system and did not test the keto diet in humans,” says Gu, “Because so many people are interested in the ketogenic diet for cancer, we should continue to research its potential risks as well as its benefits.”