Two new studies from investigators at the Fred Hutchinson Cancer Center have revealed how bacteria infiltrate tumours and how they could be helping tumours progress and spread. The team also showed that the different microbial players in a tumour’s microbiota (the full collection of microbes it carries) could influence how a cancer responds to treatment.
The two papers, one published in Cell Reports and the other published in Nature, focus on an oral bacterium called Fusobacterium nucleatum, which has been linked to colorectal cancer. F. nucleatum is an anaerobic commensal and a periodontal pathogen associated with a wide spectrum of human diseases.
In relation to cancer, Fusobacterium species are recovered in higher quantities in certain types of colon tumours compared with the colons of healthy individuals. F. nucleatum creates a pro-inflammatory environment which is conducive to tumour growth through the recruitment of tumour-infiltrating immune cells. This suggests direct and specific carcinogenesis.
In the first research study, F. nucleatum is established as the dominant bacterial species in colorectal cancer tissue. This tissue is associated with cancer progression and poorer patient prognosis.
Based on a small-molecule inhibitor screen of 1,846 bioactive compounds against a F. nucleatum isolate, the researchers found that 15 percent of inhibitors are antineoplastic agents including fluoropyrimidines.
An assessment of these findings revealed that 5-fluorouracil (5-FU), a first-line colorectal cancer chemotherapeutic, is a potent inhibitor of F. nucleatum isolates.
As well as being potent against these undesirable microbes, 5-fluorouracil may also enable beneficial microbes to function. The researchers identified members of the intratumoral microbiota, including Escherichia coli, that are resistant to 5-fluorouracil. These E. coli isolates can modify 5-fluorouracil and relieve 5-fluorouracil toxicity toward otherwise-sensitive F. nucleatum and human colorectal cancer epithelial cells.
This study is titled “The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota.”
The second study further confirms the role of F. nucleatum. This demonstrates that cancer cells that are infected with bacteria invade their surrounding environment as single cells and recruit myeloid cells to bacterial regions. This was based on 16S rRNA gene sequencing on 44 pieces of tissue from the tumours of eleven patients.
Collectively, these data reveal that the distribution of the microbiota within a tumour is not random; instead, it is highly organized in microniches with immune and epithelial cell functions that promote cancer progression.
Gaining this understanding is important because a high burden of F. nucleatum in the tumours of patients with colorectal cancer is associated with resistance to chemotherapy, disease recurrence, metastasis, and poorer survival. This means that ne treatment options need to be explored, and this could be influenced by altering the microbial balance. The second research study is titled “Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer.”
