Tumor Targeting by Fusobacterium nucleatum: A Pilot Study and Future Perspectives

Abstract

Colorectal adenocarcinoma (CRC) is a common tumor with high mortality rates. Interestingly, CRC was found to be colonized by the oral anaerobic bacteria Fusobacterium nucleatum, which accelerates tumor progression and enables immune evasion. The CRC-specific colonization by fusobacteria is mediated through the recognition of tumor displayed Gal-GalNAc moieties by the fusobacterial Fap2 Gal-GalNAc lectin. Here, we show high Gal-GalNAc levels in additional adenocarcinomas including those found in the stomach, prostate, ovary, colon, uterus, pancreas, breast, lung, and esophagus. This observation coincides with recent reports that found fusobacterial DNA in some of these tumors. Given the tumorigenic role of fusobacteria and its immune evasion properties, we suggest that fusobacterial elimination might improve treatment outcome of the above tumors. Furthermore, as fusobacteria appears to specifically home-in to Gal-GalNAc-displaying tumors, it might be engineered as a platform for treating CRC and the above common, lethal, adenocarcinomas.

Keywords: Fusobacterium nucleatum; Gal-GalNAc; adenocarcinoma; bacterioncology; cancer.

Figure 1

Images of representative tumors displaying high and low Gal-GalNAc levels. Tissue microarray (TMA) (Boimax inc.: MC5003b, MC2082a, BN1002b) were used to quantify Gal-GalNAc in tumor and matching normal control sections. Lung (top) and pancreas (bottom) adenocarcinomas displaying high Gal-GalNAc levels are presented in (A). Sarcoma (top) and hepatocellular liver cancer (bottom) non-adenocarcinoma tumors displaying low Gal-GalNAc levels are shown in (B). Left panels present H&E staining. Middle and right panels present FITC-labeled Gal-GalNAc-specific PNA (green) and Hoechst dye (blue) of tumor (middle panel) and normal (right panel). Bars shown are 250 μm scale.

Figure 2

High Gal-GalNAc levels are displayed in human adenocarcinomas. (A) Tumors were arranged according to increasing Gal-GalNAc levels. As can be seen, all examined adenocarcinomas (dark gray) displayed high levels of Gal-GalNAc. (B) Gal-GalNAc levels in the tumors (closed symbols) described in (A) were compared to those in the matching normal tissue controls (open symbols). As can be seen, Gal-GalNAc levels in 7 out of the 9 presented adenocarcinomas were statistically significantly higher than those measured in the matching normal control tissues The normal tissue controls for esophagus, lung and skin were used twice for the respective esophagus adenocarcinoma and squamous cell carcinoma (SCC): the respective lung adenocarcinoma and SCC, and for the melanoma and SCC. Each symbol represents the fluorescent intensity of a different sample. Error bars indicate mean ± SEM. ^*p < 0.05, ^**p < 0.01, ^***p = 0.0001 Two-tailed Mann-Whitney test. ^****p < 0.0001 using two-tailed t-test.