Tumor Targeting by Fusobacterium nucleatum: A Pilot Study and Future Perspectives
Jawad Abed, Naseem Maalouf, Lishay Parhi, Stella Chaushu, Ofer Mandelboim, Gilad Bachrach, Jawad Abed, Naseem Maalouf, Lishay Parhi, Stella Chaushu, Ofer Mandelboim, Gilad Bachrach
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.
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References
- Abed J., Emgard J. E., Zamir G., Faroja M., Almogy G., Grenov A., et al. . (2016). Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe 20, 215–225. 10.1016/j.chom.2016.07.006
- Babjuk M., Oosterlinck W., Sylvester R., Kaasinen E., Bohle A., Palou-Redorta J., et al. . (2011). EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur. Urol. 59, 997–1008. 10.1016/j.eururo.2011.03.017
- Bashiardes S., Tuganbaev T., Federici S., Elinav E. (2017). The microbiome in anti-cancer therapy. Semin. Immunol. [Epub ahead of print]. 10.1016/j.smim.2017.04.001
- Castellarin M., Warren R. L., Freeman J. D., Dreolini L., Krzywinski M., Strauss J., et al. . (2012). Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22, 299–306. 10.1101/gr.126516.111
- Chen Y., Peng Y., Yu J., Chen T., Wu Y., Shi L., et al. . (2017). Invasive Fusobacterium nucleatum activates beta-catenin signaling in colorectal cancer via a TLR4/P-PAK1 cascade. Oncotarget 8, 31802–31814. 10.18632/oncotarget.15992
- Dicksved J., Lindberg M., Rosenquist M., Enroth H., Jansson J. K., Engstrand L. (2009). Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls. J. Med. Microbiol. 58(Pt 4), 509–516. 10.1099/jmm.0.007302-0
- Flanagan L., Schmid J., Ebert M., Soucek P., Kunicka T., Liska V., et al. . (2014). Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome. Eur. J. Clin. Microbiol. Infect. Dis. 33, 1381–1390. 10.1007/s10096-014-2081-3
- Gur C., Ibrahim Y., Isaacson B., Yamin R., Abed J., Gamliel M., et al. . (2015a). Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42, 344–355. 10.1016/j.immuni.2015.01.010
- Gur C., Mandelboim O., Bachrach G. (2015b). “Messieurs, c'est les microbes qui auront le dernier mot”: gentlemen, it is the microbes who have the last word (Louis Pasteur)-Fusobacterium nucleatum protect tumors from killing by immune cells. Oncoimmunology 4:e1038690. 10.1080/2162402X.2015.1038690
- Hajishengallis G., Liang S., Payne M. A., Hashim A., Jotwani R., Eskan M. A., et al. . (2011). Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe 10, 497–506. 10.1016/j.chom.2011.10.006
- Han Y. W. (2011). Oral health and adverse pregnancy outcomes - what's next? J. Dent. Res. 90, 289–293. 10.1177/0022034510381905
- Hieken T. J., Chen J., Hoskin T. L., Walther-Antonio M., Johnson S., Ramaker S., et al. . (2016). The microbiome of aseptically collected human breast tissue in benign and malignant disease. Sci. Rep. 6:30751. 10.1038/srep30751
- Hill G. B. (1998). Preterm birth: associations with genital and possibly oral microflora. Ann. Periodontol. 3, 222–232.
- Hiraki A., Matsuo K., Suzuki T., Kawase T., Tajima K. (2008). Teeth loss and risk of cancer at 14 common sites in Japanese. Cancer Epidemiol. Biomarkers Prev. 17, 1222–1227. 10.1158/1055-9965.EPI-07-2761.
- Kolenbrander P. E., London J. (1993). Adhere today, here tomorrow: oral bacterial adherence. J. Bacteriol. 175, 3247–3252.
- Kostic A. D., Gevers D., Pedamallu C. S., Michaud M., Duke F., Earl A. M., et al. . (2012). Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298. 10.1101/gr.126573.111
- Kostic Â. D., Chun E., Robertson L., Glickman J. N., Gallini C. A., Michaud M., et al. . (2013). Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207–215. 10.1016/j.chom.2013.07.007
- Lin W. M., Karsten U., Goletz S., Cheng R. C., Cao Y. (2011). Expression of CD176 (Thomsen-Friedenreich antigen) on lung, breast and liver cancer-initiating cells. Int. J. Exp. Pathol. 92, 97–105. 10.1111/j.1365-2613.2010.00747.x
- Mitsuhashi K., Nosho K., Sukawa Y., Matsunaga Y., Ito M., Kurihara H., et al. . (2015). Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget 6, 7209–7220. 10.18632/oncotarget.3109
- Moore W. E., Moore L. V. (1994). The bacteria of periodontal diseases. Periodontol 2000 5, 66–77.
- Nardone G., Compare D. (2015). The human gastric microbiota: is it time to rethink the pathogenesis of stomach diseases? United Eur. Gastroenterol. J. 3, 255–260. 10.1177/2050640614566846
- Pihlstrom B. L., Michalowicz B. S., Johnson N. W. (2005). Periodontal diseases. Lancet 366, 1809–1820. 10.1016/S0140-6736(05)67728-8
- Plummer M., de Martel C., Vignat J., Ferlay J., Bray F., Franceschi S. (2016). Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob. Health 4, e609–e616. 10.1016/S2214-109X(16)30143-7
- Quispe-Tintaya W., Chandra D., Jahangir A., Harris M., Casadevall A., Dadachova E., et al. . (2013). Nontoxic radioactive Listeriaat is a highly effective therapy against metastatic pancreatic cancer. Proc. Natl. Acad. Sci. U.S.A. 110, 8668–8673. 10.1073/pnas.1211287110
- Rautemaa R., Lauhio A., Cullinan M. P., Seymour G. J. (2007). Oral infections and systemic disease–an emerging problem in medicine. Clin. Microbiol. Infect. 13, 1041–1047. 10.1111/j.1469-0691.2007.01802.x
- Rubinstein M. R., Wang X., Liu W., Hao Y., Cai G., Han Y. W. (2013). Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-Cadherin/Î2-Catenin signaling via its FadA adhesin. Cell Host Microbe 14, 195–206. 10.1016/j.chom.2013.07.012
- Siegel R., Naishadham D., Jemal A. (2012). Cancer statistics, 2012. CA Cancer J. Clin. 62, 10–29. 10.3322/caac.20138
- Socransky S. S., Haffajee A. D., Cugini M. A., Smith C., Kent R. L., Jr. (1998). Microbial complexes in subgingival plaque. J. Clin. Periodontol. 25, 134–144.
- Springer G. F. (1984). T and Tn, general carcinoma autoantigens. Science 224, 1198–1206.
- Yamamura K., Baba Y., Nakagawa S., Mima K., Miyake K., Nakamura K., et al. . (2016). Human microbiome Fusobacterium Nucleatum in esophageal cancer tissue is associated with prognosis. Clin. Cancer Res. 22, 5574–5581. 10.1158/1078-0432.CCR-16-1786
- Yang G. Y., Shamsuddin A. M. (1996). Gal-GalNAc: a biomarker of colon carcinogenesis. Histol. Histopathol. 11, 801–806.
- Yang Y. Z., Weng W. H., Peng J. J., Hong L. M., Yang L., Toiyama Y., et al. . (2017). Fusobacterium nucleatum Increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-kappa B, and up-regulating expression of MicroRNA-21. Gastroenterology 152, 851.e24–866.e24. 10.1053/j.gastro.2016.11.018
- Zeng X. T., Xia L. Y., Zhang Y. G., Li S., Leng W. D., Kwong J. S. (2016). Periodontal disease and incident lung cancer risk: a meta-analysis of cohort studies. J. Periodontol. 87, 1158–1164. 10.1902/jop.2016.150597
- Zheng J. H., Nguyen V. H., Jiang S. N., Park S. H., Tan W., Hong S. H., et al. . (2017). Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin. Sci. Transl. Med. 9:eaak9537. 10.1126/scitranslmed.aak9537
- zur Hausen H. (2009). The search for infectious causes of human cancers: where and why (Nobel lecture). Angew. Chem. Int. Ed Engl. 48, 5798–5808. 10.1002/anie.200901917
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