The work used metabolomic technologies to find molecular evidence suggesting a vicious circle in which cancerous changes in colon cells promote the growth of bacterial conglomerations called biofilms, and biofilms in turn promote cancer development.
On the whole, the findings suggest that removing bacterial biofilms could be a key strategy for preventing and treating colon cancers, which currently kill about 50,000 Americans per year. The study also revealed an apparent metabolic marker of biofilm-associated colon cancers.
Metabolites are small molecules in blood and tissues that are products of the myriad metabolic processes in cells. More than 10,000 distinct metabolites normally can be found in humans.
The team began the search with an "unbiased screen," a wide-net technique--using advanced liquid chromatography and mass spectrometry and their XCMS metabolomic cloud-based platform--that registered the levels of thousands of metabolites in a set of colon tissue samples from patients at Johns Hopkins and at the Karolinska Institute in Sweden.
The data showed that polyamines were important in general and one metabolite--N1, N12-diacetylspermine--was particularly prominent, on average about nine times more abundant in cancerous tissue, compared to nearby non-cancerous tissue.
In further tests, the team found that even among cancerous samples, the same metabolite was four times more abundant in the presence of biofilms. In other words, the cancerous cells and the biofilms both seemed to be contributing to its overproduction. Using "nanostructure imaging mass spectrometry" (NIMS), the team was able to map the precise locations of N1, N12-diacetylspermine in tissue samples, confirming its higher levels in both tumors and biofilms.
The researchers also carried out a technique called "global isotope metabolomics," using an isotope of N1, N12-diacetylspermine to trace its metabolic fate in cells in an unbiased manner, finding that it appears to be a metabolic end-product.
That colon tumors would produce abnormally high amounts of N1, N12-diacetylspermine is not surprising. The molecule belongs to a family of metabolites called polyamines, which are known to have roles in driving cell growth and which are commonly upregulated in cancers as well as in healthy fast-growing tissues. N1, N12-diacetylspermine itself has been observed at higher levels in colon cancer and is considered a potential biomarker for early cancer diagnosis.
But why would bacterial biofilms also be linked to higher levels of N1, N12-diacetylspermine? It turns out that bacteria, too, use polyamines to drive their own cells' proliferation and to build biofilms. Polyamines are such ancient, ubiquitous molecules that bacteria apparently can even use those produced by their animal hosts.
Thus, biofilms may promote cancer in the colon by inducing chronic inflammation and associated cell proliferation. That increased cell proliferation would be accompanied by a rise in the production of polyamines. Resident bacteria, in turn, could use this abundance of polyamines to make more biofilms--completing the vicious circle. Along the way, levels of the by-product N1, N12-diacetylspermine would be driven higher and higher.
Treatment with antibiotics may be an option for removing colonic biofilms and reducing the cancer risks they bring. The scientists found that colon cancer samples from patients who had taken oral antibiotics 24 hours prior to surgery harbored no biofilms and no cultivable bacteria and exhibited significantly less N1, N12-diacetylspermine, on average, than samples from patients who had not taken antibiotics.