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Colorectal Cancer-Associated Microbes Persist in Metastases, Suggest New Treatments

NEW YORK (GenomeWeb) – Bacteria sometimes found in association with colorectal cancer (CRC) tissue often turn up at CRC metastases in other parts of the body, new research suggests, and may be beneficial to tumor growth or progression. In addition, results in mice suggest that antibiotics may be helpful to treat certain microbe-positive colorectal tumors.

Researchers at the Dana-Farber Cancer Center, the Broad Institute, Brigham and Women's Hospital, and elsewhere used qPCR, bacterial genome sequencing, RNA sequencing, 16S ribosomal RNA sequencing, tumor xenograft experiments, and other strategies to show that Fusobacterium and other microbes can accompany primary tumors to metastatic sites, potentially boosting tumor growth and boding poorly for patient outcomes. Their results appeared online last week in Science.

"[C]olonization of human colorectal cancers with Fusobacterium and its associated microbiome, including Bacteroides, Selenomonas, and Prevotella species, is maintained in distal metastases, demonstrating microbiome stability between paired primary-metastatic tumors," corresponding author Matthew Meyerson, director of cancer genomics at Dana-Farber and the Broad, and his colleagues wrote.

There have been several past hints that Fusobacterium and other bugs might be more common in and around CRCs. In a paper published in Genome Medicine in 2015, for example, the University of Minnesota's Ran Blekham and colleagues described enhanced microbial diversity in the microenvironment of primary CRC tumors, along with a rise in potentially pathogenic bacteria from the Fusobacterium and Providencia genera.

Prior to that, a University of Michigan team reporting in Cancer Prevention Research saw gut microbial differences between 30 healthy individuals, 30 individuals with pre-cancerous adenomatous polyps, and 30 colorectal carcinoma patients, including over-representation of Fusobacterium and other bugs in the carcinoma cohort.

That research group proposed incorporating gut microbiome information into CRC screening protocols, while authors of the latest analysis noted that high levels of F. nucleatum, in particular, have been implicated in advanced CRC disease, poorer tumor infiltration by immune T cells, and worse CRC outcomes.

To explore this potential relationship further, the researchers brought together data from five cohorts, including 430 fresh-frozen colon carcinoma tumors and more than 200 liver cancer (hepatocellular carcinoma) tumors tested for the Cancer Genome Atlas project.

The remaining sample sets contained fresh frozen or formalin-fixed, paraffin-embedded (FFPE) colon cancers, paired with corresponding metastatic tumors, fresh frozen CRCs with accompanying recurrence data, and additional primary CRC tumor samples used to develop tumor xenografts. 

Using qPCR, the team identified Fusobacterium genetic material in nine of 11 primary tumors from one of the fresh frozen sets, culturing the microbe from nine of those tumors. Although several metastatic samples were too small to attempt culturing, qPCR pointed to the presence of Fusobacterium DNA in metastatic tumors from seven of the individuals with Fusobacterium-positive primary tumors.

With the help of whole-genome sequencing on samples from two individuals, the researchers saw more than 99.9 percent sequence identity between Fusobacterium strains in each person's tumors, suggesting microbes may piggyback to metastatic sites.

Their RNA sequencing analysis of 10 primary CRC-metastatic tumor pairs similarly pointed to concordance between the Fusobacterium species at each site, highlighting similarities between some broader microbiome features at primary and metastatic tumors in each individual.

In particular, the team noted that the Fusobacterium-positive tumor pairs tended to contain F. nucleatum, F. necrophorum, and bacterial species from the Bacteroides, Prevotella, and Selenomonas genera. But these microbial collections typically did not occur in metastatic tumors missing Fusobacterium.

Those initial findings were bolstered by 16S ribosomal RNA sequencing experiments revealing comparable Fusobacterium levels in matched primary and metastatic tumors. And the researchers' qPCR analyses of 101 FFPR tumor pairs picked up Fusobacterium DNA in 43 percent of primary tumors and 45 percent of matched metastases.

The team's follow-up experiments supported ties between primary and metastatic Fusobacterium. It found that Fusobacterium was rare in liver cancer, for example, but linked to poor patient outcomes in individuals with CRC, particularly when the primary tumor turned up at cecum or ascending colon sites.

The microbes in human tumor samples could be carried over to tumor xenografts in mice as well, the researcher's reported, where the presence of F. nucleatum and related microbes coincided with enhanced tumor growth — an effect they reversed with an antibiotic that's active against Fusobacterium.

"Our results provide a strong foundation for pursuing targeted approaches for colorectal cancer treatment directed against Fusobacterium and other key constituents of the cancer microbiota," the authors concluded.