Excessive Iron Accelerates F. nucleatum-Positive Colorectal Cancer

Researchers at Japan’s Kumamoto University have described the mechanism through which excessive iron accumulation accelerates cancer progression in Fusobacterium nucleatum-positive colorectal cancer (CRC) and contributes to prognostic variations among patients. The findings, reported in Journal of Clinical Investigation, could support the development of new therapeutic strategies and drugs for the disease.

CRC is the second-leading cause of cancer-related deaths around the world. Though recent studies suggest high levels of intestinal microbes such as F. nucleatum in colorectal tumor tissues may lead to a poor prognosis, the underlying mechanism and reasons for varying outcomes were unclear. The body’s iron levels, which often determine how the immune system responds to infections, has been suggested to play a role.

To explore this theory, researchers from Kumamoto University and Gifu Pharmaceutical University in Japan investigated the relationship between tumor progression and the body’s iron levels in samples of F. nucleatum-positive CRC.   “Focusing on the fact that CRC patients with high systemic iron levels show poor survival rates, we clarified the mechanism through which excess iron accelerates the progression of cancer,” says Kumamoto University’s Prof. Toshiro Moroishi, who co-led the study.

While iron deficiency causes diseases such as anemia, excess iron has often been associated with diseases such as cancer. Previous findings by Moroishi’s team revealed that a disruption of iron homeostasis can alter tissue functions in the body. In the current study, to uncover the link between iron levels and CRC prognosis, they analyzed tumor tissue specimens from 204 patients diagnosed with stage I, II, or III F. nucleatum-positive or F. nucleatum-negative CRC. They also examined iron levels in the tumor tissues and patients’ serum levels of transferrin saturation, an indicator of systemic iron status. This first round of experiments revealed that both high levels of transferrin saturation and iron deposits within the tumor were associated with a worse overall survival (OS) in patients with F. nucleatum-positive CRC.

The rest of the sought to understand how iron affects CRC prognosis. One common link between iron metabolism and cancer progression is the modulation of immune responses, which are mediated by immune cells called macrophages that can both promote and inhibit tumors based on their molecular expression profiles. Hence, the researchers examined the effect of iron and F. nucleatum levels on the molecular expression profiles of macrophages using RNA sequencing. They performed in vitro tests in cultured cells and found that F. nucleatum infection can activate the pro-tumor TLR4/NF-κB signaling pathway in macrophages, thus increasing the production of CCL8, a protein that promotes tumor growth and progression. Together, the results showed that in F. nucleatum-positive CRC, the bacteria transform macrophages into pro-tumor cells expressing CCL8. 

The role of iron in this process, however, remained unclear. To find the final piece of this puzzle, the researchers tested how changes in iron levels affect the increase in CCL8 caused by F. nucleatum. “[We set out to find] if F. nucleatum can still induce CCL8 expression in macrophages if iron is absent,” Moroishi says.  Interestingly, the answer was that it couldn’t; when iron was removed, the production of CCL8 and other pro-tumor signaling molecules in macrophages was reduced considerably, meaning that they could no longer promote tumor development.

“Our research group has clarified that the combination of F. nucleatum infection and high levels of iron in the body accelerates the progression of CRC,” adds Moroishi. “This means that by targeting iron levels, survival rates could potentially be improved in this patient group.”