IADR Abstract Archives

Enhancement of 4-NQO-Induced OSCC by the Oral Microbiome in Gnotobiotic Mice

Objectives: Mounting evidence indicates that the human microbiome may promote the development and progression of various malignancies, particularly in the lower GI tract. In contrast, the role of, and mechanisms by which, the oral microbiome may contribute to oral squamous cell carcinoma (OSCC) development are uncertain. The goal of this study was to directly test this proposition in vivo in a well-defined system in gnotobiotic mice.
Methods: Groups (n=7) of germfree Swiss-Webster mice were colonized with two distinct murine oral microbiomes, in the presence/absence of the carcinogen 4-nitroquinilone 1-oxide (4-NQO) in the drinking water for 16 weeks. Animals were maintained under gnotobiotic conditions for 26 weeks, following which OSCC and related lesions were assessed by histopathology. The colonizing microbiomes were characterized by 16SrRNA sequencing and metatranscriptomics. Tumor-infiltrating leukocytes (TIL) were identified in paraffin sections of mouse tongues by immunohistochemistry.
Results: Mice exposed to 4-NQO and that were colonized with either microbiome developed significantly more, and more extensive, OSCC tumors (5/7 mice, 12 tumors; 4/7 mice, 7 tumors) than mice that received 4-NQO in the absence of a microbiome (2/7 mice, 3 tumors). Hyperplasia and dysplasia also developed in all 4-NQO groups. Mice with a microbiome but not exposed to 4-NQO did not develop lesions. Both tumorigenic microbiomes exhibited a broad diversity of colonizing species, some of which exhibited high transcriptional activity and expression of virulence-associated pathways. Tumor-infiltrating leukocytes had a profile consistent with immunosuppression, with prominent myeloid-derived cells and CD4+ > CD8+ consistent with elevated Treg.
Conclusions: Taken together these data demonstrate that the oral microbiome promotes tumor development, and further that certain key taxa may be implicated in this process. Enhanced tumorigenesis correlated with the presence of TIL with an immunosuppressive profile. Gnotobiotic systems have the potential to provide new insights into the mechanisms of OSCC development and for evaluating new therapeutics.
AADR/CADR Annual Meeting
2018 AADR/CADR Annual Meeting (Fort Lauderdale, Florida)
Fort Lauderdale, Florida
2018
0062
Oral Medicine & Pathology Research
  • Stashenko, Philip  ( The Forsyth Institute , Cambridge , Massachusetts , United States ;  Harvard School of Dental Medicine , Boston , Massachusetts , United States )
  • Nguyen, Daniel  ( The Forsyth Institute , Cambridge , Massachusetts , United States )
  • Pal, Bidisha  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • Frias-lopez, Jorge  ( University of Florida , Gainesville , Florida , United States )
  • Choi, Yoon Hee  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • Danciu, Theodora  ( University of Michigan , Ann Arbor , Michigan , United States )
  • Chen, Tsute  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • Kressirer, Christine  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • Ruiz-torruella, Montserrat  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • Kim, Jeremiah  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • Das, Bikul  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • Yoganathan, Subbiah  ( Forsyth Institute , Cambridge , Massachusetts , United States )
  • NIDCR/NIH DE021553, Forsyth Institute pilot grant funding
    None
    Oral Session
    Epithelial Tumors
    Wednesday, 03/21/2018 , 01:30PM - 03:00PM