Chemotherapy-induced oral mucositis and associated infections in a novel organotypic model

Mol Oral Microbiol. 2018 Jun;33(3):212-223. doi: 10.1111/omi.12214. Epub 2018 Feb 20.


Oral mucositis is a common side effect of cancer chemotherapy, with significant adverse impact on the delivery of anti-neoplastic treatment. There is a lack of consensus regarding the role of oral commensal microorganisms in the initiation or progression of mucositis because relevant experimental models are non-existent. The goal of this study was to develop an in vitro mucosal injury model that mimics chemotherapy-induced mucositis, where the effect of oral commensals can be studied. A novel organotypic model of chemotherapy-induced mucositis was developed based on a human oral epithelial cell line and a fibroblast-embedded collagen matrix. Treatment of organotypic constructs with 5-fluorouracil (5-FU) reproduced major histopathologic characteristics of oral mucositis, such as DNA synthesis inhibition, apoptosis and cytoplasmic vacuolation, without compromising the three-dimensional structure of the multilayer organotypic mucosa. Although structural integrity of the model was preserved, 5-FU treatment resulted in a widening of epithelial intercellular spaces, characterized by E-cadherin dissolution from adherens junctions. In a neutrophil transmigration assay we discovered that this treatment facilitated transport of neutrophils through epithelial layers. Moreover, 5-FU treatment stimulated key proinflammatory cytokines that are associated with the pathogenesis of oral mucositis. 5-FU treatment of mucosal constructs did not significantly affect fungal or bacterial biofilm growth under the conditions tested in this study; however, it exacerbated the inflammatory response to certain bacterial and fungal commensals. These findings suggest that commensals may play a role in the pathogenesis of oral mucositis by amplifying the proinflammatory signals to mucosa that is injured by cytotoxic chemotherapy.

Keywords: Candida; Streptococcus; adherens junction; chemotherapy; cytokine; oral mucositis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adherens Junctions / drug effects
  • Apoptosis / drug effects
  • Bacteria / growth & development
  • Bacteria / pathogenicity
  • Biofilms / growth & development
  • Cadherins / metabolism
  • Cell Line / drug effects
  • Cell Proliferation / drug effects
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Drug Therapy*
  • Drug-Related Side Effects and Adverse Reactions*
  • Epithelial Cells / drug effects
  • Fibroblasts / drug effects
  • Fluorouracil / administration & dosage
  • Fluorouracil / pharmacology
  • Fungi / growth & development
  • Fungi / pathogenicity
  • HL-60 Cells
  • Humans
  • Mucous Membrane / drug effects
  • Mucous Membrane / injuries
  • Mucous Membrane / microbiology
  • Stomatitis / chemically induced*
  • Stomatitis / etiology*
  • Stomatitis / microbiology
  • Stomatitis / pathology


  • Cadherins
  • Cytokines
  • Fluorouracil