Candida albicans Enhances the Progression of Oral Squamous Cell Carcinoma In Vitro and In Vivo
Máté Vadovics,
Jemima Ho,
Nóra Igaz,
Róbert Alföldi,
Dávid Rakk,
Éva Veres,
Balázs Szücs,
Márton Horváth,
Renáta Tóth,
Attila Szücs,
Andrea Csibi,
Péter Horváth,
László Tiszlavicz,
Csaba Vágvölgyi,
Joshua D. Nosanchuk,
András Szekeres,
Mónika Kiricsi,
Rhonda Henley-Smith,
David L. Moyes,
Selvam Thavaraj,
Rhys Brown,
László G. Puskás,
Julian R. Naglik,
Attila Gácser
Affiliations
Máté Vadovics
Department of Microbiology, University of Szeged, Szeged, Hungary
Jemima Ho
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, United Kingdom
Nóra Igaz
Doctoral School of Biology, University of Szeged, Szeged, Hungary
Róbert Alföldi
AstridBio Technologies Ltd., Szeged, Hungary
Dávid Rakk
Department of Microbiology, University of Szeged, Szeged, Hungary
Éva Veres
Department of Microbiology, University of Szeged, Szeged, Hungary
Balázs Szücs
Department of Microbiology, University of Szeged, Szeged, Hungary
Márton Horváth
Department of Microbiology, University of Szeged, Szeged, Hungary
Renáta Tóth
Department of Microbiology, University of Szeged, Szeged, Hungary
Attila Szücs
Department of Microbiology, University of Szeged, Szeged, Hungary
Andrea Csibi
Department of Microbiology, University of Szeged, Szeged, Hungary
Péter Horváth
Synthetic and System Biology Unit, Biological Research Centre (BRC), Szeged, Hungary
László Tiszlavicz
Department of Pathology, University of Szeged, Szeged, Hungary
Csaba Vágvölgyi
Department of Microbiology, University of Szeged, Szeged, Hungary
Joshua D. Nosanchuk
Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
András Szekeres
Department of Microbiology, University of Szeged, Szeged, Hungary
Mónika Kiricsi
Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
Rhonda Henley-Smith
King’s Health Partners, Head and Neck Cancer Biobank, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
David L. Moyes
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, United Kingdom
Selvam Thavaraj
Centre for Oral, Clinical and Translational Science, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, United Kingdom
Rhys Brown
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, United Kingdom
László G. Puskás
AstridBio Technologies Ltd., Szeged, Hungary
Julian R. Naglik
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, United Kingdom
Attila Gácser
HCEMM-USZ Fungal Pathogens Research Group, Department of Microbiology, University of Szeged, Szeged, Hungary
ABSTRACT Oral squamous cell carcinoma (OSCC) is associated with oral Candida albicans infection, although it is unclear whether the fungus promotes the genesis and progression of OSCC or whether cancer facilitates fungal growth. In this study, we investigated whether C. albicans can potentiate OSCC tumor development and progression. In vitro, the presence of live C. albicans, but not Candida parapsilosis, enhanced the progression of OSCC by stimulating the production of matrix metalloproteinases, oncometabolites, protumor signaling pathways, and overexpression of prognostic marker genes associated with metastatic events. C. albicans also upregulated oncogenes in nonmalignant cells. Using a newly established xenograft in vivo mouse model to investigate OSCC-C. albicans interactions, oral candidiasis enhanced the progression of OSCC through inflammation and induced the overexpression of metastatic genes and significant changes in markers of the epithelial-mesenchymal transition. Finally, using the 4-nitroquinoline 1-oxide (4NQO) murine model, we directly correlate these in vitro and short-term in vivo findings with the progression of oncogenesis over the long term. Taken together, these data indicate that C. albicans upregulates oncogenes, potentiates a premalignant phenotype, and is involved in early and late stages of malignant promotion and progression of oral cancer. IMPORTANCE Oral squamous cell carcinoma (OSCC) is a serious health issue worldwide that accounts for 2% to 4% of all cancer cases. Previous studies have revealed a higher yeast carriage and diversity in oral cancer patients than in healthy individuals. Furthermore, fungal colonization in the oral cavity bearing OSCC is higher on the neoplastic epithelial surface than on adjacent healthy surfaces, indicating a positive association between oral yeast carriage and epithelial carcinoma. In addition to this, there is strong evidence supporting the idea that Candida contributes to carcinogenesis events in the oral cavity. Here, we show that an increase in Candida albicans burden promotes an oncogenic phenotype in the oral cavity.
