Oral squamous cell carcinoma (OSCC) is the most prevalent cancer in the oral cavity. Oral cancers with OSCC are found in more than 90% of cases. OSCC is the fifth most common form of malignancy worldwide, along with oropharyngeal cancer. More than 70% of deaths from this cancer occur in Asia, and two-thirds of cases occur in Asian countries such as Sri Lanka, Indonesia, India, Pakistan, and Bangladesh.
Alcohol consumption, smoking, and betel nut chewing (menginang) are predisposing factors. Besides, other predisposing factors such as the microbiome environment can induce pro-oncogenic genetics which leads to the development of OSCC. In contrast to exogenous factors such as tobacco and alcohol, oral microbes in OSCC may result from the microbe being a commensal or secondary infection in the cancerous tissue. It has been previously reported how the oral microbiota is involved in carcinogenesis through chronic inflammation, microbial synthesis of carcinogens, and alteration of the integrity of the epithelial barrier. The presence of Candida albicans (as the normal flora) is able to contribute to the development of oral cancer. Among the other species of Candida, Candida albicans has the highest prevalence found in OSCC and always gained concerns in relation to the ability of pathogenic state shifting from the commensal condition. Its commensal condition can develop into an opportunistic pathogen linked explicitly with the initiation of oral neoplasia and the development of OSCC. It has also been reported that Candida invasion is a significant risk factor for the malignant transformation of oral potentially malignant disorder (OPMD) to oral cancer.
In general, the role of Candida albicans in the process of carcinogenesis tends to be complex, such as the role of virulence factors, the host genome, influence on the immune response, and oral dysbiosis. Several studies have been conducted, and no direct study of Candida albicans with OSCC or OPMD. In this systematic review, there are eight articles dominated by the Candida albicans virulence factor. In general, there are seven virulence factors of Candida albicans discussed in this article, mainly phenotype (Candida frequencies, hyphae, sphere, colonies, biofilm formation), genotype (Candida albicans alcohol dehydrogenase 1 (CaADH1) mRNA gene, genotypic diversity of Candida albicans strains, CSH), and metabolic production (acetaldehyde product, lipase, proteinase product, phospholipase, and esterase activity, NMBA production).
Increased colonization of Candida albicans is one of the strong associations with oral epithelial dysplasia and neoplastic transformation leading to the OSCC process. The number of colonies and excessive density of Candida albicans can damage host cells and promote the development of carcinogenesis.
Candida albicans can also affect the progression from OPMD to OSCC. Isolates from the oral leukoplakia group produced significantly higher levels of acetaldehyde than isolates from oral lichen planus when exposed to glucose–ethanol or glucose alone. Another study also confirmed that the leukoplakia with Candida albicans (or Candidal leukoplakia) has a high rate of cancer transformation because it highly expressed a fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA).
Factors affecting the ability of Candida albicans to accelerate the development of oral carcinogenesis also include virulence factors, protein-degrading ability, and lipolytic activity. The persistence of Candida also depends on the capacity to secrete hydrolytic exoenzymes that facilitate further tissue invasion. It has been shown statistically that Candida albicans proteinase, phospholipase, and lipase activity were higher in oral cancer patients.
Candida albicans also have the potential to induce OSCC by producing carcinogenic compounds. Certain strains of Candida albicans and other yeasts play an essential role in developing oral cancer by creating endogenous nitrosamines. Candida albicans can convert both nitrite and/or nitrate into nitrosamines and other substances to produce acetaldehyde, which has a carcinogenic role in the oral cavity. This conversion is facilitated by Candida albicans Alcohol dehydrogenase 1 (CaADH1). The study results showed that the CaADH 1 gene could be significantly associated with OSCC with and without metastases compared to healthy patients.
Besides, Candida albicans use the enzyme alcohol hydrogenase (ADH1) to convert alcohol and other substances, such as carbohydrates into carcinogenic acetaldehyde. Acetaldehyde can induce tumor development in various ways. This carcinogen binds to proteins and DNA, changes its structure and function, and the reduction in the antioxidant activity of glutathione increases the content of reactive oxygen species (ROS) in the cells. These changes can lead to genomic instability, inhibiting the apoptotic system and tumor development. Nitrosamines produced by Candida albicans individually or in combination with other carcinogenic compounds can activate specific proto-oncogenes that can cause the development of cancer lesions that lead to changes in dysplastic conditions in oral epithelium and cancer. Carcinogenic products and hydrolytic enzymes produced by Candida albicans also lead to further tissue destruction and trigger a continuous chronic inflammatory reaction.
In general, the relationship between fungal infections, especially Candida albicans, and oral cancer has been discussed in the literature for a long time. Many in vitro and in vivo studies show evidence of the parameters and markers involved in Candida albicans carcinogenesis. However, clinical evidence is still lacking, as it is difficult to find studies that deal specifically with this topic. Risk factors affecting the virulence factors of Candida albicans are also necessary to be researched in more articles involved. The exact mechanism by which Candida albicans is interested in developing OSCC also requires much research, particularly clinical research.
Author: Nurina Febriyanti Ayuningtyas, drg., MKes., PhD., Sp.PM(K)
Title: Role of Candida albicans in Oral Carcinogenesis
