title: Microbiota organization is a distinct feature of proximal colorectal cancers.
abstract: Environmental factors clearly affect colorectal cancer (CRC) incidence, but the mechanisms through which these factors function are unknown. One prime candidate is an altered colonic microbiota. Here we show that the mucosal microbiota organization is a critical factor associated with a subset of CRC. We identified invasive polymicrobial bacterial biofilms (bacterial aggregates), structures previously associated with nonmalignant intestinal pathology, nearly universally (89%) on right-sided tumors (13 of 15 CRCs, 4 of 4 adenomas) but on only 12% of left-sided tumors (2 of 15 CRCs, 0 of 2 adenomas). Surprisingly, patients with biofilm-positive tumors, whether cancers or adenomas, all had biofilms on their tumor-free mucosa far distant from their tumors. Bacterial biofilms were associated with diminished colonic epithelial cell E-cadherin and enhanced epithelial cell IL-6 and Stat3 activation, as well as increased crypt epithelial cell proliferation in normal colon mucosa. High-throughput sequencing revealed no consistent bacterial genus associated with tumors, regardless of biofilm status. However, principal coordinates analysis revealed that biofilm communities on paired normal mucosa, distant from the tumor itself, cluster with tumor microbiomes as opposed to biofilm-negative normal mucosa bacterial communities also from the tumor host. Colon mucosal biofilm detection may predict increased risk for development of sporadic CRC.
authors.affiliation: Departments of Microbiology and Immunology and.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Dejea
authors.affiliation: Departments of Surgery.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Wick
authors.affiliation: Departments of Surgery.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hechenbleikner
authors.affiliation: Independent Consultant, Baltimore, MD 21231;
authors.forename: James R
authors.initials: JR
authors.lastname: White
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543;
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mark Welch
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543;
authors.forename: Blair J
authors.initials: BJ
authors.lastname: Rossetti
authors.affiliation: J. Craig Venter Institute, Rockville, MD 20850;
authors.forename: Scott N
authors.initials: SN
authors.lastname: Peterson
authors.affiliation: J. Craig Venter Institute, Rockville, MD 20850;
authors.forename: Erik C
authors.initials: EC
authors.lastname: Snesrud
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543;
authors.forename: Gary G
authors.initials: GG
authors.lastname: Borisy
authors.affiliation: Medicine, and.
authors.forename: Mark
authors.initials: M
authors.lastname: Lazarev
authors.affiliation: Medicine, and.
authors.forename: Ellen
authors.initials: E
authors.lastname: Stein
authors.affiliation: Department of Microbiology, University of Malaya, Kuala Lumpur 50603, Malaysia;
authors.forename: Jamuna
authors.initials: J
authors.lastname: Vadivelu
authors.affiliation: Departments of Surgery and.
authors.forename: April C
authors.initials: AC
authors.lastname: Roslani
authors.affiliation: Departments of Surgery and.
authors.forename: Ausuma A
authors.identifier: http://orcid.org/0000-0001-9738-8651
authors.initials: AA
authors.lastname: Malik
authors.affiliation: Medicine, and.
authors.forename: Jane W
authors.initials: JW
authors.lastname: Wanyiri
authors.affiliation: Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
authors.forename: Khean L
authors.initials: KL
authors.lastname: Goh
authors.affiliation: Department of Microbiology, University of Malaya, Kuala Lumpur 50603, Malaysia;
authors.forename: Iyadorai
authors.initials: I
authors.lastname: Thevambiga
authors.affiliation: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, MD 21287;
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, MD 21287; Department of Oncology and Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287; and.
authors.forename: Fengyi
authors.initials: F
authors.lastname: Wan
authors.affiliation: Pediatrics, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Llosa
authors.affiliation: Department of Oncology and Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287; and.
authors.forename: Franck
authors.initials: F
authors.lastname: Housseau
authors.affiliation: Ludwig Center and Howard Hughes Medical Institute, Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
authors.forename: Katharine
authors.initials: K
authors.lastname: Romans
authors.affiliation: Medicine, and.
authors.forename: XinQun
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology and Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287; and.
authors.forename: Florencia M
authors.initials: FM
authors.lastname: McAllister
authors.affiliation: Medicine, and.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Ludwig Center and Howard Hughes Medical Institute, Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Ludwig Center and Howard Hughes Medical Institute, Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Medicine, and Department of Oncology and Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287; and.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Departments of Microbiology and Immunology and Medicine, and Department of Oncology and Hopkins-Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287; and csears@jhmi.edu.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
mesh_terms: D001419:Bacteria / Q000145:classification / Q000302:isolation & purification; D018441:Biofilms; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000382:microbiology*; D006801:Humans; D064307:Microbiota
keywords: adenoma; bacterial communities; biofilm; colorectal cancer; microbiome