Fusobacterium nucleatum in the gut can stop chemotherapy from causing apoptosis
Researchers from Michigan Medicine and China have discovered that a type of bacterium is associated with the recurrence of colorectal cancer and poor outcomes. They found that Fusobacterium nucleatum in the gut can stop chemotherapy from causing apoptosis. Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death worldwide. The two most widely used drugs to treat colorectal cancer act to either inhibit enzyme activity of cancer cells or arrest tumour cell growth, Fusobacterium nucleatum can make them ineffective.
"We treat patients with chemotherapy so that it will ultimately induce tumour cell apoptosis,” said Dr Weiping Zou, professor of surgery at Michigan Medicine. “But some cancer cells have a way to avoid apoptosis that is induced by chemotherapy. Those cells escape from the apoptosis process by activating a cell-survival mechanism called autophagy. That mechanism protects cancer cells from destructing."
This collaborative study between Michigan Medicine and China, ‘Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy’, published in Cell, was led by two teams, Dr Zou, at Michigan Medicine, and Dr Jing-Yuan Fang, from Renji Hospital, Shanghai Jiao Tong University School of Medicine.
"Once autophagy is active, the cancer becomes resistant to chemotherapy. Then Fusobacterium nucleatum keeps autophagy turned on. That's how the tumour cells may be able to avoid the induced apoptosis," added Zou. "Typically, autophagy can be turned on or off. However, the bacterium prevents the expression of two microRNAs so that autophagy doesn't turn off. The loss of these microRNAs keeps the autophagy turned in the 'on' position.”
The idea to check the role of the bacterium associated with innate immune signalling in chemotherapy resistance was linked to earlier work done by this researcher team. Their study was published in Cell in 2016. In the previous research, they studied adaptive immunity, specifically the impact of T cells on chemoresistance. They found that adaptive immunity is reversely associated with resistance of cisplatin, the drug used for ovarian cancer. This means if you have a strong T cell immunity, then the cancer cells are more sensitive to chemotherapy.
In the current study in Cell, they researched whether bacterium-mediated innate immune signalling regulates chemotherapy resistance in colon cancer.
The innate immune system refers to the front-line defenders—the cells and molecular mechanisms that attack pathogens. The adaptive immune system refers to the body's response to specific antigens, such as foreign substances from bacteria or tumour-associated antigens from tumour cells.
Adaptive immunity is mediated by T cell signalling. Innate immunity is mediated by innate signalling including proteins called Toll-like receptors (TLR).
"We knew that the body uses both systems, adaptive and innate, to fight cancer and infectious pathogens. That gave us the inspiration to look further at bacterium associated with innate immune signalling,” said Dr Zou. "The results of the research were a surprise. We did not expect bacterium to contribute to chemoresistance.”
There are other factors that are unknown about F nucleatum. For example, what would happen if the bacterium were reduced or blocked? Would other prevalent bacterium create a similar problem with chemoresistance?
"Right now, we don't have a specific approach to selectively treat or control Fusobacterium nucleatum. Also, we don't know if an abundance of this bacterium is found in any other types of cancer chemoresistance," concluded Zou. "Still, based on our studies, we think that if we deal with this bacterium, we may be able to delay and prevent chemoresistance in colorectal cancer."