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Kostic et al., 2012 Kostic A.D.

Gevers D.

Pedamallu C.S.

Michaud M.

Duke F.

Earl A.M.

Ojesina A.I.

Jung J.

Bass A.J.

Tabernero J.

et al. Castellarin et al., 2012 Castellarin M.

Warren R.L.

Freeman J.D.

Dreolini L.

Krzywinski M.

Strauss J.

Barnes R.

Watson P.

Allen-Vercoe E.

Moore R.A.

Holt R.A. McCoy et al. (2013) McCoy A.N.

Araújo-Pérez F.

Azcárate-Peril A.

Yeh J.J.

Sandler R.S.

Keku T.O. Bashir et al., 2015 Bashir A.

Miskeen A.Y.

Bhat A.

Fazili K.M.

Ganai B.A. Kostic et al. (2013) Kostic A.D.

Chun E.

Robertson L.

Glickman J.N.

Gallini C.A.

Michaud M.

Clancy T.E.

Chung D.C.

Lochhead P.

Hold G.L.

et al. Min/+). These mice, fed an invasive strain of F. nucleatum that was originally isolated from the gut of an inflammatory bowel disease (IBD) patient, exhibited increased tumorigenesis, which was associated with increased infiltrating cells of the myeloid lineage into tumors. In particular, CD11b+ cells, including macrophages, dendritic cells, and granulocytes, were observed to be significantly increased. These findings suggested that F. nucleatum promotes inflammation and tumorigenesis by modulating the tumor immune microenvironment via expansion and selective attraction of myeloid-derived immune cells. The findings from the mouse experiments were further confirmed in human colonic samples in which the authors observed a strong correlation between F. nucleatum abundance and expression of pro-inflammatory markers. F. nucleatum has also been shown to suppress anti-tumor immunity and inhibit tumor killing by natural killer (NK) cells and tumor-infiltrating lymphocytes ( Gur et al., 2015 Gur C.

Ibrahim Y.

Isaacson B.

Yamin R.

Abed J.

Gamliel M.

Enk J.

Bar-On Y.

Stanietsky-Kaynan N.

Coppenhagen-Glazer S.

et al. The human intestinal microbiota consists of diverse microbial species, wherein certain bacteria are considered drivers of carcinogenesis. In 2012, two independent studies demonstrated that Fusobacterium species as a whole, and Fusobacterium nucleatum in particular, is overabundant in colorectal cancer tissues compared to adjacent normal mucosa (). This observation was not anticipated, given that Fusobacterium is otherwise a normal resident of the oral microflora and a relatively poor colonizer of the healthy gut. However, in the following year these findings were not only successfully validated by, but in addition, the same group also showed overabundance of Fusobacterium in colorectal adenomas (CRAs), the colorectal cancer (CRC) precursors, compared to adjacent normal sites. Since then, several studies have confirmed the association of Fusobacterium with CRA as well (). To understand how F. nucleatum induces inflammation and promotes CRC,used mice with a genetic susceptibility for developing intestinal tumors (Apc). These mice, fed an invasive strain of F. nucleatum that was originally isolated from the gut of an inflammatory bowel disease (IBD) patient, exhibited increased tumorigenesis, which was associated with increased infiltrating cells of the myeloid lineage into tumors. In particular, CD11bcells, including macrophages, dendritic cells, and granulocytes, were observed to be significantly increased. These findings suggested that F. nucleatum promotes inflammation and tumorigenesis by modulating the tumor immune microenvironment via expansion and selective attraction of myeloid-derived immune cells. The findings from the mouse experiments were further confirmed in human colonic samples in which the authors observed a strong correlation between F. nucleatum abundance and expression of pro-inflammatory markers. F. nucleatum has also been shown to suppress anti-tumor immunity and inhibit tumor killing by natural killer (NK) cells and tumor-infiltrating lymphocytes (). All of these findings support the notion that F. nucleatum not only localizes to and is enriched in CRAs and adenocarcinomas, but that these bacteria may also promote tumor growth and survival by orchestrating changes to the microenvironment that are conducive for carcinogenesis.

Ashare et al., 2009 Ashare A.

Stanford C.

Hancock P.

Stark D.

Lilli K.

Birrer E.

Nymon A.

Doerschug K.C.

Hunninghake G.W. Abed et al. (2016) Abed J.

Emgård J.E.M.

Zamir G.

Faroja M.

Almogy G.

Grenov A.

Sol A.

Naor R.

Pikarsky E.

Atlan K.A.

et al. Several key questions, however, have persisted. How does F. nucleatum, an oral bacterium, make its way to the gut? Once there, how does it attach, allowing it to become enriched in a CRC microenvironment? It has long been known that transient bacteremia is a common manifestation during tooth brushing and is believed to be heightened even more during periodontal disease, when F. nucleatum is prevalent in high numbers (). It is, therefore, not beyond the realm of possibility that transient bacteremia may enable oral fusobacteria to reach CRA and CRC sites via the circulatory system. In this issue of Cell Host & Microbe,, using an orthotopic rectal CT26 adenocarcinoma model, provide substantial evidence that an intravascularly injected oral F. nucleatum strain prefers to colonize CRC tissue over adjacent healthy tissue, thereby supporting the idea that oral fusobacteria may colonize CRC through a hematogeous route. This will only be confirmed once evidence emerges that oral and CRC F. nucleatum strains are genetically identical.

Abed et al. (2016) Abed J.

Emgård J.E.M.

Zamir G.

Faroja M.

Almogy G.

Grenov A.

Sol A.

Naor R.

Pikarsky E.

Atlan K.A.

et al. Coppenhagen-Glazer et al., 2015 Coppenhagen-Glazer S.

Sol A.

Abed J.

Naor R.

Zhang X.

Han Y.W.

Bachrach G. Gur et al., 2015 Gur C.

Ibrahim Y.

Isaacson B.

Yamin R.

Abed J.

Gamliel M.

Enk J.

Bar-On Y.

Stanietsky-Kaynan N.

Coppenhagen-Glazer S.

et al. Interestingly,have uncovered a mechanism for homing of F. nucleatum to CRC. By staining tissue microarrays with fluorescein (FITC)-labeled peanut agglutinin (PNA), a Gal-GalNAc [Gal - β (1→3) GalNAc]-specific lectin, the authors discovered that the polysaccharide D-galactose-β (1-3)-N-acetyl-D-galactosamine (Gal-GalNAc) is overexpressed in colorectal tumor tissue when compared to adjacent normal tissue, and that the fusobacterial lectin, Fap2, binds it. Fap2, a galactose-sensitive hemagglutinin and adhesin, is quite promiscuous, as it has been shown to play a role in fusobacterial virulence in a preterm-birth model by promoting placental colonization of F. nucleatum (). It also directly interacts with TIGIT (T cell immunoreceptor with Ig and ITIM domains), leading to the inhibition of both NK cell cytotoxicity and T cell activity in tumor-infiltrating lymphocytes expressing TIGIT ().

Abed et al. (2016) Abed J.

Emgård J.E.M.

Zamir G.

Faroja M.

Almogy G.

Grenov A.

Sol A.

Naor R.

Pikarsky E.

Atlan K.A.

et al. In the new study,report a hitherto unknown role of Fap2 in the attachment of F. nucleatum in CRC. By developing a method to visualize binding of F. nucleatum to formalin-fixed, paraffin-embedded human adenocarcinoma samples, they observed that the abundance of organisms binding to adenocarcinoma versus normal colonic tissue correlated with higher Gal-GalNAc expression levels in the CRC tissues. The role of Fap2 in binding of F. nucleatum to CRC tissue was further substantiated by using fap2-inactivated mutant strains. Fluorescence microscopy analysis of human CRC sections demonstrated co-localization of FITC-labeled Fap2-expressing F. nucleatum with tumor Gal-GalNAc detected in tumor sections, supporting the concept that F. nucleatum Fap2 and tumor-expressed Gal-GalNAc play an important role in F. nucleatum CRC localization and enrichment.