Credit: Jennie Vallis/Macmillan Publishers Limited

New research by Xiling Shen and colleagues shows that the hepatic microenvironment causes liver metastases of colorectal cancer in mice to upregulate fructose-bisphosphate aldolase B (ALDOB), an enzyme involved in fructose metabolism, which subsequently fuels the growth of the hepatic metastases. In addition, dietary restriction of fructose has the same suppressive effect on the growth of liver metastases.

Metastatic cancer cells and the primary tumour have been thought to have similar functions. “Hence, we investigated whether metastatic cancer cells needed to adapt to their new microenvironment,” explains Shen. To recapitulate the human disease, the researchers injected human colorectal cancer cells into the colons of immunodeficient mice, where they formed primary tumours that metastasized to the liver and lungs. Metabolic and transcriptomic analyses showed that ALDOB was upregulated in the liver metastases compared with the primary tumour. “Interestingly, the liver is a major metabolic site for fructose,” explains Shen.

Next, the researchers overexpressed or knocked down ALDOB expression in liver metastatic cancer cells in vitro and showed that cancer cell development changed substantially when grown in cell culture medium containing fructose, but not in medium containing glucose. Trace analysis using isotope-labelled fructose revealed that metabolized fructose fuelled the growth of the liver metastases.

Shen and colleagues knocked down ALDOB expression in human colorectal cancer cells and injected the cells into mouse colons. Lack of ALDOB expression decreased the proliferation of cancer cells in the liver and suppressed the development of liver metastases. This inhibition was absent in control cells that expressed ALDOB.

Lack of ALDOB expression ... suppressed the development of liver metastases

Finally, the researchers injected human colorectal cancer cells directly into the colons of mice and then fed them either a regulated high-fructose diet or a regulated diet without fructose. Mice fed the high-fructose diet had increased liver metastases compared with mice fed a diet of no fructose. These findings show that restricting dietary fructose also suppressed the development of liver metastases.

“Our next goal is to understand how fructose promotes tumour growth besides being a carbon source,” concludes Shen.