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Fructose metabolism in liver proliferates metastatic cancer growth

Metastatic cancer cells originating from colorectal cancer can reprogram their metabolism to create an enzyme that feeds on fructose in the liver, which increases proliferation, according to a recently published study.

“Intrahepatic implantation indicates that the liver environment causes [colorectal cancer (CRC)] cells to upregulate [aldolase B (ALDOB)],” Pengcheng Bu, MD, from Duke University, North Carolina, and colleagues wrote. “Metabolomics and C-labeled fructose tracing studies indicate that ALDOB promotes fructose metabolism to fuel glycolysis, gluconeogenesis and the pentose phosphate pathway. ALDOB knockdown or dietary fructose restriction suppresses growth of CRC liver metastases, but not primary tumors or lung metastases, highlighting the importance of tumor microenvironment.”

Bu and colleagues identified 90 matched samples from 30 patients with stage 4 colorectal cancer as well as 186 primary tumor samples, 47 liver metastatic samples and 20 lung metastatic samples without matching.

“Among the altered metabolic pathways, we considered fructose metabolism to be quite unique,” the researchers wrote. “While the intestine may be a major site of fructose metabolism at low doses of fructose, at high doses, the liver is likely the major site of fructose metabolism.”

ALDOB was among the top metabolic genes in the matched samples and the metabolites involved with ALDOB were significantly upregulated in liver metastases.

Analysis of the unmatched samples confirmed that ALDOB was significantly upregulated in liver metastasis but not in lung metastasis.

The researchers hypothesize that products of ALDOB-mediated reaction could contribute to glucose, glycogen, lactate and lipid synthesis, all of which are essential for sustaining highly proliferative cells.

According to Bu and colleagues, CRC cells may have to adjust to the metabolic environment in the liver after they migrate from the colon.

“We show that metastatic CRC cells are capable of adjusting to nutrient changes in their colonized organ,” the researchers concluded. “Metastatic CRC cells upregulate ALDOB in the liver, which promote fructose metabolism to boost the central carbon metabolism. Silencing of ALDOB or dietary fructose restriction suppresses CRC liver metastasis. Targeting fructose metabolism presents a potentially interesting strategy to treat CRC liver metastasis.” – by Talitha Bennett

Disclosure: Healio.com/Hepatology was unable to determine relevant financial disclosures at the time of publication.