- Email: [email protected]
Tumor Potentiating Mechanisms of Fusobacterium nucleatum, A Multifaceted Microbe
Accepted Manuscript Tumor potentiating mechanisms of Fusobacterium nucleatum, a multifaceted microbe Robert A. Holt, Kyla Cochrane
PII: DOI: Reference:
S0016-5085(17)30084-7 10.1053/j.gastro.2017.01.024 YGAST 60940
To appear in:
Gastroenterology
Please cite this article as: Holt RA, Cochrane K, Tumor potentiating mechanisms of Fusobacterium nucleatum, a multifaceted microbe, Gastroenterology (2017), doi: 10.1053/j.gastro.2017.01.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Tumor potentiating mechanisms of Fusobacterium nucleatum, a multifaceted microbe
M AN U
British Columbia Cancer Research Centre 675 W. 10th Avenue Vancouver, British Columbia Canada V5Z 1L3 [email protected]
SC
Kyla Cochrane British Columbia Cancer Agency Genome Sciences Centre
RI PT
Robert A. Holt British Columbia Cancer Agency Genome Sciences Centre, University of British Columbia Department of Medical Genetics, Simon Fraser University Department of Biochemistry & Molecular Biology
The authors declare no conflicts of interest
EP
TE D
Fusobacterium nucleatum is an unlikely candidate for a cancer-instigating microbe. For years, F. nucleatum has been regarded as a common constituent of the commensal oral microbiome and recognized as one of many different microbes associated with gingivitis and periodontitis. What has set F. nucleatum apart is extreme strain-to-strain variation in its genotype, fusiform morphology, and adhesive and invasive properties 1, 2. The increasingly frequent reports of associations of F. nucleatum non-oral pathologies, ranging from GI abcesses and acute appendicitis to intra-amniotic infection, and most recently colorectal 3-6, pancreatic 7 and oral cancers 8, have raised the alert level of F. nucleatum to that of an emerging pathogen.
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A link between F. nucleatum and cancer was first established upon detection of highly abundant F. nucleatum gene signatures in bio-banked colorectal carcinoma (CRC) specimens using unbiased metagenomics methods 3-6. Obvious questions followed regarding the relevance of this observation to the initiation and progression of tumorigenesis, and the mechanisms involved. Chronic exposure of APCmin/- mice by gavage to an invasive human F. nucleatum isolate was shown to increase colonic tumor burden 9. This observation, together with consistent reports of Fn tumor burden being increased even in early stage clinical lesions 6,9, is consistent with the involvement of F. nucleatum in the transformation process in the host. New studies have shown that tumor accumulation of Fn relies in part on interactions between fusobacterial lectin Fap2 and host Gal-GalNAc10 and that binding of fusobacterial FadA adhesins to host cadherins 11 can stimulate potentially
ACCEPTED MANUSCRIPT
oncogenic beta-catenin signaling. However, given the enormous heterogeneity of F. nucleatum isolates, it is likely that multiple oncogenic mechanisms are at play.
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The very comprehensive study in the current issue by Yang et al. confirms many earlier observations and adds extensive data, uncovering a novel miRNA mediated pathway by which Fn can modulate host cell properties and oncogenic states. The authors demonstrate that co-culture of F. nucleatum (subspecies nucleatum ATCC 25586) with CRC cell lines increases CRC cell proliferation in vitro and in vivo and that APC min/- mice gavaged with F. nucleatum show increased tumor burden and decreased survival. Further, prompted by their earlier work and work by others implicating miRNA deregulation in colorectal tumorigenesis 12-16 these investigators profiled miRNA expression in F. nucleatum exposed tumor cell lines. They noted strong induction of miR21 upon engagement of host cell TLR4 by fusobacterial LPS, leading to activation of RAS-MAPK signaling through modulation of the miR-21 target Ras GTPase, RASA1. In human CRC tissues, F. nucleatum and miR-21 levels were co-elevated and correlated with advanced stage disease and poor prognosis. Taken as a whole, these extensive data solidify the association between F. nucleatum and CRC, further implicate F. nucleatum as a pathogen rather than bystander in CRC, and highlight a novel miRNA mediated mechanism of host-pathogen interaction.
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How do these new findings fit within our currently limited understanding of F. nucleatum -associated cancer? F. nucleatum strain diversity is considerable and, therefore, the different host-pathogen links identified to date may show strainspecificity. Each of these links is a piece of the puzzle, but none on their own provide a complete account of F. nucleatum -associated CRC potentiation. For example, Fap2 mediated interactions between F. nucleatum and colorectal cancer cells are reduced, but not abrogated, in Fap2 null strains. FadA can mediate host cell invasion but invasive properties vary widely across F. nucleatum strains, despite FadA being ubiquitously expressed. In the current study, inhibitors of miR-21 limit F. nucleatum's proliferative effect on CRC cell lines and, while miR-21 knockout mice were less sensitive to F. nucleatum potentiated tumorigenesis, they were not protected entirely. It remains uncertain how directly virulence is linked to host cell invasion. Host cell invasion and cytokine production are independent of surface TLRs 17, yet TLR4 and miR-21 induction are highly relevant, as illustrated by Yang et al., herein. Inhibition of the host adaptive immune response through suppression of T cells 9, 18-19 and NK cells 20 are additional capabilities of F. nucleatum that are highly relevant to its tumor potentiating effect, through the promotion of an immunosuppressive microenvironment conducive to colorectal neoplasia progression. Finally, it is important to keep in mind that F. nucleatum functions in a complex environment and its effects are likely influenced directly and indirectly by other members of the microbial community, host factors in the tumor microenvironment, and the tumor mutational profile 21-22. Thus, a picture is emerging whereby the relationship between F. nucleatum and cancer is multifactorial. Important questions remain as to whether properties associated with F. nucleatum monoculture will be relevant to F. nucleatum in its
ACCEPTED MANUSCRIPT
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natural context, which is with a diversity of other microbes in a community setting. What is the most dangerous microbial cocktail? When is F. nucleatum dominant? It is unlikely that F. nucleatum acts alone, and it has even been shown to provide a conduit for pathogens to the otherwise unreachable confines of the host cytoplasm 23. This is an area than needs further exploration. Detailed mapping of virulence traits across diverse tumor and non-tumor isolates, and characterizing manifestation of these traits in different environments will be essential for identifying the most relevant markers and molecular targets, the goal being to develop the means to selectively neutralize or eradicate pathogenic F. nucleatum variants.
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References
Allen-Vercoe, E., J. Strauss, and K. Chadee. 2011. Fusobacterium nucleatum: An emerging gut pathogen? Gut Microbes 2:294–298. 2. McGuire, A. M., K. Cochrane, A. D. Griggs, B. J. Haas, T. Abeel, Q. Zeng, J. B. Nice, H. Macdonald, B. W. Birren, B. W. Berger, E. Allen-Vercoe, and A. M. Earl. 2014. Evolution of invasion in a diverse set of Fusobacterium species. mBio 5. 3. Castellarin, M., R. L. Warren, J. D. Freeman, L. Dreolini, M. Krzywinski, J. Strauss, R. Barnes, P. Watson, E. Allen-Vercoe, R. A. Moore, and R. A. Holt. 2012. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Research 22:299–306. 4. Kostic, A. D., D. Gevers, C. S. Pedamallu, M. Michaud, F. Duke, A. M. Earl, A. I. Ojesina, J. Jung, A. J. Bass, J. Tabernero, J. Baselga, C. Liu, R. A. Shivdasani, S. Ogino, B. W. Birren, C. Huttenhower, W. S. Garrett, and M. Meyerson. 2012. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Research 22:292–298. 5. Warren, R. L., D. J. Freeman, S. Pleasance, P. Watson, R. A. Moore, K. Cochrane, E. AllenVercoe, and R. A. Holt. 2013. Co-occurrence of anaerobic bacteria in colorectal carcinomas. Microbiome 1:16. 6. Flanagan, L., J. Schmid, M. Ebert, P. Soucek, T. Kunicka, V. Liska, J. Bruha, P. Neary, N. Dezeeuw, M. Tommasino, M. Jenab, J. H. M. Prehn, and D. J. Hughes. 2014. Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome. European Journal of Clinical Microbiology and Infectious Diseases 33:1381– 1390. 7. Mitsuhashi, K., K. Nosho, Y. Sukawa, Y. Matsunaga, M. Ito, H. Kurihara, S. Kanno, H. Igarashi, T. Naito, Y. Adachi, M. Tachibana, T. Tanuma, H. Maguchi, T. Shinohara, T. Hasegawa, M. Imamura, Y. Kimura, K. Hirata, R. Maruyama, H. Suzuki, K. Imai, H. Yamamoto, and Y. Shinomura. 2015. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget 6:7209–7220. 8. Gallimidi, A. B., S. Fischman, B. Revach, R. Bulvik, A. Maliutina, A. M. Rubinstein, G. Nussbaum, M. Elkin, A. Binder Gallimidi, S. Fischman, B. Revach, R. Bulvik, A. Maliutina, A. M. Rubinstein, G. Nussbaum, and M. Elkin. 2015. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget 6:22613–23. 9. Kostic, A. D., E. Chun, L. Robertson, J. N. Glickman, C. A. Gallini, M. Michaud, T. E. Clancy, D. C. Chung, P. Lochhead, G. L. Hold, E. M. El-Omar, D. Brenner, C. S. Fuchs, M. Meyerson, and W. S. Garrett. 2013. Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis and Modulates the Tumor-Immune Microenvironment. Cell Host and Microbe 14:207–215. 10. Abed, J., J. E. M. Emgård, G. Zamir, M. Faroja, G. Almogy, A. Grenov, A. Sol, R. Naor, E. Pikarsky, K. A. Atlan, A. Mellul, S. Chaushu, A. L. Manson, A. M. Earl, N. Ou, C. A. Brennan, W. S. Garrett, and G. Bachrach. 2016. Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc. Cell Host & Microbe 20:215–225.
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11. Rubinstein, M. R., X. Wang, W. Liu, Y. Hao, G. Cai, and Y. W. Han. 2013. Fusobacterium nucleatum Promotes Colorectal Carcinogenesis by Modulating E-Cadherin/β-Catenin Signaling via its FadA Adhesin. Cell Host and Microbe 14:195–206. 12. Shi, C., Y. Yang, Y. Xia, Y. Okugawa, J. Yang, Y. Liang, H. Chen, P. Zhang, F. Wang, H. Han, W. Wu, R. Gao, C. Gasche, H. Qin, Y. Ma, and A. Goel. 2015. Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer. Gut:1–12. 13. Chi, Y., and D. Zhou. 2016. MicroRNAs in colorectal carcinoma--from pathogenesis to therapy. Journal of experimental & clinical cancer research : CR 35:43. 14. Asangani, I. A, S. A. K. Rasheed, D. A. Nikolova, J. H. Leupold, N. H. Colburn, S. Post, and H. Allgayer. 2008. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27:2128–36. 15. Zhu, S., H. Wu, F. Wu, D. Nie, S. Sheng, and Y.-Y. Mo. 2008. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Research 18:350–359. 16. Nosho, K., Y. Sukawa, Y. Adachi, M. Ito, K. Mitsuhashi, H. Kurihara, S. Kanno, I. Yamamoto, K. Ishigami, H. Igarashi, R. Maruyama, K. Imai, H. Yamamoto, and Y. Shinomura. 2016. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. World Journal of Gastroenterology 22:557-566. 17. Quah, S. Y., G. Bergenholtz, and K. S. Tan. 2014. Fusobacterium nucleatum induces cytokine production through Toll-like-receptor-independent mechanism. International Endodontic Journal 47:550–559. 18. Mima, K., Y. Sukawa, R. Nishihara, Z. R. Qian, M. Yamauchi, K. Inamura, S. A. Kim, A. Masuda, J. A. Nowak, K. Nosho, A. D. Kostic, M. Giannakis, H. Watanabe, S. Bullman, D. A. Milner, C. C. Harris, E. Giovannucci, L. A. Garraway, G. J. Freeman, G. Dranoff, A. T. Chan, W. S. Garrett, C. Huttenhower, C. S. Fuchs, and S. Ogino. 2015. Fusobacterium nucleatum and T Cells in Colorectal Carcinoma. JAMA Oncology 1:653–661. 19. Shenker, B. J., and S. Datar. 1995. Fusobacterium nucleatum inhibits human T-cell activation by arresting cells in the mid-G1 phase of the cell cycle. Infect Immun 63:4830–4836. 20. Gur, C., Y. Ibrahim, B. Isaacson, R. Yamin, J. Abed, M. Gamliel, J. Enk, Y. Bar-On, N. Stanietsky-Kaynan, S. Coppenhagen-Glazer, N. Shussman, G. Almogy, A. Cuapio, E. Hofer, D. Mevorach, A. Tabib, R. Ortenberg, G. Markel, K. Miklić, S. Jonjic, C. A. Brennan, W. S. Garrett, G. Bachrach, and O. Mandelboim. 2015. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42:344– 355. 21. Tahara, T., E. Yamamoto, H. Suzuki, R. Maruyama, W. Chung, J. Garriga, J. Jelinek, H. O. Yamano, T. Sugai, B. An, I. Shureiqi, M. Toyota, Y. Kondo, M. R. H. Estecio, and J. P. J. Issa. 2014. Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Research 74:1311–1318. 22. Ito, M., S. Kanno, K. Nosho, Y. Sukawa, K. Mitsuhashi, H. Kurihara, H. Igarashi, T. Takahashi, M. Tachibana, H. Takahashi, S. Yoshii, T. Takenouchi, T. Hasegawa, K. Okita, K. Hirata, R. Maruyama, H. Suzuki, K. Imai, H. Yamamoto, and Y. Shinomura. 2015. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. International Journal of Cancer 137:1258–1268. 23. Saito, A., S. Inagaki, R. Kimizuka, K. Okuda, Y. Hosaka, T. Nakagawa, and K. Ishihara. 2008. Fusobacterium nucleatum enhances invasion of human gingival epithelial and aortic endothelial cells by Porphyromonas gingivalis. FEMS Immunology and Medical Microbiology 54:349–355.
PII: DOI: Reference:
S0016-5085(17)30084-7 10.1053/j.gastro.2017.01.024 YGAST 60940
To appear in:
Gastroenterology
Please cite this article as: Holt RA, Cochrane K, Tumor potentiating mechanisms of Fusobacterium nucleatum, a multifaceted microbe, Gastroenterology (2017), doi: 10.1053/j.gastro.2017.01.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Tumor potentiating mechanisms of Fusobacterium nucleatum, a multifaceted microbe
M AN U
British Columbia Cancer Research Centre 675 W. 10th Avenue Vancouver, British Columbia Canada V5Z 1L3 [email protected]
SC
Kyla Cochrane British Columbia Cancer Agency Genome Sciences Centre
RI PT
Robert A. Holt British Columbia Cancer Agency Genome Sciences Centre, University of British Columbia Department of Medical Genetics, Simon Fraser University Department of Biochemistry & Molecular Biology
The authors declare no conflicts of interest
EP
TE D
Fusobacterium nucleatum is an unlikely candidate for a cancer-instigating microbe. For years, F. nucleatum has been regarded as a common constituent of the commensal oral microbiome and recognized as one of many different microbes associated with gingivitis and periodontitis. What has set F. nucleatum apart is extreme strain-to-strain variation in its genotype, fusiform morphology, and adhesive and invasive properties 1, 2. The increasingly frequent reports of associations of F. nucleatum non-oral pathologies, ranging from GI abcesses and acute appendicitis to intra-amniotic infection, and most recently colorectal 3-6, pancreatic 7 and oral cancers 8, have raised the alert level of F. nucleatum to that of an emerging pathogen.
AC C
A link between F. nucleatum and cancer was first established upon detection of highly abundant F. nucleatum gene signatures in bio-banked colorectal carcinoma (CRC) specimens using unbiased metagenomics methods 3-6. Obvious questions followed regarding the relevance of this observation to the initiation and progression of tumorigenesis, and the mechanisms involved. Chronic exposure of APCmin/- mice by gavage to an invasive human F. nucleatum isolate was shown to increase colonic tumor burden 9. This observation, together with consistent reports of Fn tumor burden being increased even in early stage clinical lesions 6,9, is consistent with the involvement of F. nucleatum in the transformation process in the host. New studies have shown that tumor accumulation of Fn relies in part on interactions between fusobacterial lectin Fap2 and host Gal-GalNAc10 and that binding of fusobacterial FadA adhesins to host cadherins 11 can stimulate potentially
ACCEPTED MANUSCRIPT
oncogenic beta-catenin signaling. However, given the enormous heterogeneity of F. nucleatum isolates, it is likely that multiple oncogenic mechanisms are at play.
M AN U
SC
RI PT
The very comprehensive study in the current issue by Yang et al. confirms many earlier observations and adds extensive data, uncovering a novel miRNA mediated pathway by which Fn can modulate host cell properties and oncogenic states. The authors demonstrate that co-culture of F. nucleatum (subspecies nucleatum ATCC 25586) with CRC cell lines increases CRC cell proliferation in vitro and in vivo and that APC min/- mice gavaged with F. nucleatum show increased tumor burden and decreased survival. Further, prompted by their earlier work and work by others implicating miRNA deregulation in colorectal tumorigenesis 12-16 these investigators profiled miRNA expression in F. nucleatum exposed tumor cell lines. They noted strong induction of miR21 upon engagement of host cell TLR4 by fusobacterial LPS, leading to activation of RAS-MAPK signaling through modulation of the miR-21 target Ras GTPase, RASA1. In human CRC tissues, F. nucleatum and miR-21 levels were co-elevated and correlated with advanced stage disease and poor prognosis. Taken as a whole, these extensive data solidify the association between F. nucleatum and CRC, further implicate F. nucleatum as a pathogen rather than bystander in CRC, and highlight a novel miRNA mediated mechanism of host-pathogen interaction.
AC C
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How do these new findings fit within our currently limited understanding of F. nucleatum -associated cancer? F. nucleatum strain diversity is considerable and, therefore, the different host-pathogen links identified to date may show strainspecificity. Each of these links is a piece of the puzzle, but none on their own provide a complete account of F. nucleatum -associated CRC potentiation. For example, Fap2 mediated interactions between F. nucleatum and colorectal cancer cells are reduced, but not abrogated, in Fap2 null strains. FadA can mediate host cell invasion but invasive properties vary widely across F. nucleatum strains, despite FadA being ubiquitously expressed. In the current study, inhibitors of miR-21 limit F. nucleatum's proliferative effect on CRC cell lines and, while miR-21 knockout mice were less sensitive to F. nucleatum potentiated tumorigenesis, they were not protected entirely. It remains uncertain how directly virulence is linked to host cell invasion. Host cell invasion and cytokine production are independent of surface TLRs 17, yet TLR4 and miR-21 induction are highly relevant, as illustrated by Yang et al., herein. Inhibition of the host adaptive immune response through suppression of T cells 9, 18-19 and NK cells 20 are additional capabilities of F. nucleatum that are highly relevant to its tumor potentiating effect, through the promotion of an immunosuppressive microenvironment conducive to colorectal neoplasia progression. Finally, it is important to keep in mind that F. nucleatum functions in a complex environment and its effects are likely influenced directly and indirectly by other members of the microbial community, host factors in the tumor microenvironment, and the tumor mutational profile 21-22. Thus, a picture is emerging whereby the relationship between F. nucleatum and cancer is multifactorial. Important questions remain as to whether properties associated with F. nucleatum monoculture will be relevant to F. nucleatum in its
ACCEPTED MANUSCRIPT
RI PT
natural context, which is with a diversity of other microbes in a community setting. What is the most dangerous microbial cocktail? When is F. nucleatum dominant? It is unlikely that F. nucleatum acts alone, and it has even been shown to provide a conduit for pathogens to the otherwise unreachable confines of the host cytoplasm 23. This is an area than needs further exploration. Detailed mapping of virulence traits across diverse tumor and non-tumor isolates, and characterizing manifestation of these traits in different environments will be essential for identifying the most relevant markers and molecular targets, the goal being to develop the means to selectively neutralize or eradicate pathogenic F. nucleatum variants.
SC
References
Allen-Vercoe, E., J. Strauss, and K. Chadee. 2011. Fusobacterium nucleatum: An emerging gut pathogen? Gut Microbes 2:294–298. 2. McGuire, A. M., K. Cochrane, A. D. Griggs, B. J. Haas, T. Abeel, Q. Zeng, J. B. Nice, H. Macdonald, B. W. Birren, B. W. Berger, E. Allen-Vercoe, and A. M. Earl. 2014. Evolution of invasion in a diverse set of Fusobacterium species. mBio 5. 3. Castellarin, M., R. L. Warren, J. D. Freeman, L. Dreolini, M. Krzywinski, J. Strauss, R. Barnes, P. Watson, E. Allen-Vercoe, R. A. Moore, and R. A. Holt. 2012. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Research 22:299–306. 4. Kostic, A. D., D. Gevers, C. S. Pedamallu, M. Michaud, F. Duke, A. M. Earl, A. I. Ojesina, J. Jung, A. J. Bass, J. Tabernero, J. Baselga, C. Liu, R. A. Shivdasani, S. Ogino, B. W. Birren, C. Huttenhower, W. S. Garrett, and M. Meyerson. 2012. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Research 22:292–298. 5. Warren, R. L., D. J. Freeman, S. Pleasance, P. Watson, R. A. Moore, K. Cochrane, E. AllenVercoe, and R. A. Holt. 2013. Co-occurrence of anaerobic bacteria in colorectal carcinomas. Microbiome 1:16. 6. Flanagan, L., J. Schmid, M. Ebert, P. Soucek, T. Kunicka, V. Liska, J. Bruha, P. Neary, N. Dezeeuw, M. Tommasino, M. Jenab, J. H. M. Prehn, and D. J. Hughes. 2014. Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome. European Journal of Clinical Microbiology and Infectious Diseases 33:1381– 1390. 7. Mitsuhashi, K., K. Nosho, Y. Sukawa, Y. Matsunaga, M. Ito, H. Kurihara, S. Kanno, H. Igarashi, T. Naito, Y. Adachi, M. Tachibana, T. Tanuma, H. Maguchi, T. Shinohara, T. Hasegawa, M. Imamura, Y. Kimura, K. Hirata, R. Maruyama, H. Suzuki, K. Imai, H. Yamamoto, and Y. Shinomura. 2015. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget 6:7209–7220. 8. Gallimidi, A. B., S. Fischman, B. Revach, R. Bulvik, A. Maliutina, A. M. Rubinstein, G. Nussbaum, M. Elkin, A. Binder Gallimidi, S. Fischman, B. Revach, R. Bulvik, A. Maliutina, A. M. Rubinstein, G. Nussbaum, and M. Elkin. 2015. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget 6:22613–23. 9. Kostic, A. D., E. Chun, L. Robertson, J. N. Glickman, C. A. Gallini, M. Michaud, T. E. Clancy, D. C. Chung, P. Lochhead, G. L. Hold, E. M. El-Omar, D. Brenner, C. S. Fuchs, M. Meyerson, and W. S. Garrett. 2013. Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis and Modulates the Tumor-Immune Microenvironment. Cell Host and Microbe 14:207–215. 10. Abed, J., J. E. M. Emgård, G. Zamir, M. Faroja, G. Almogy, A. Grenov, A. Sol, R. Naor, E. Pikarsky, K. A. Atlan, A. Mellul, S. Chaushu, A. L. Manson, A. M. Earl, N. Ou, C. A. Brennan, W. S. Garrett, and G. Bachrach. 2016. Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc. Cell Host & Microbe 20:215–225.
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