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. 2022 Apr 14;18(4):e1010413. doi: 10.1371/journal.ppat.1010413

Fig 1. Mechanisms by which Candida albicans may play a role in oral cancer development.

Fig 1

(A) (1) Production of carcinogenic substances. C. albicans, using the enzyme ADH1, is capable of metabolizing alcohol to acetaldehyde, which is carcinogenic. Acetaldehyde binds to proteins and DNA modifying their structure and functionality, resulting in mitochondrial damage, and also reducing antioxidant activity of glutathione leading to increased intracellular levels of ROS. These alterations may produce genome instability linked with inhibition of the apoptotic machinery ultimately leading to tumor development. (2) Activation of oncogenic pathways in epithelial cells by candidalysin. C. albicans secrete candidalysin toxin that damages the epithelial barrier and activates EGFR with downstream up-regulation of the MAPK pathway that has been implicated in various types of cancer. (3) Induction of tumor-promoting immunity. EGFR activation also causes downstream up-regulation of the NFκΒ pathway in epithelial cells resulting in the expression of IL-1a, IL-1b, IL-36, and G-CSF. Myeloid cells including antigen presenting cells and macrophages recognize Candida and secrete tumor promoting cytokines including IL-23, IL-6, and IL-1. Additionally, the NLRP3 inflammasome pathway is activated. Collectively, cytokines secreted by epithelial and myeloid cells result in activation of Th17 (IL-17 secreting) cells. Type 17 immune responses further support cancer progression by antagonizing Th1 (IFNγ secreting) cells. (B) At the oral mucosa, these tumor promoting mechanisms may have the potential of causing cytologic and architectural alterations in the oral epithelium (dysplasia), and their accumulation may lead to the development of OSCC, which is characterized by tumor islands (red arrows) invading the underlying connective tissue. ADH1, alcohol dehydrogenase 1; EGFR, epidermal growth factor receptor; G-CSF, granulocyte colony-stimulating factor; IFNγ, interferon gamma; IL, interleukin; NFκΒ, nuclear factor kappa B; OSCC, oral squamous cell carcinoma; ROS, reactive oxygen species; Th, T helper.