Implications of oral dysbiosis and HPV infection in head and neck cancer: from molecular and cellular mechanisms to early diagnosis and therapy

Abstract

Head and neck cancer (HNC) is the sixth most common type of cancer, with more than half a million new cases annually. This review focuses on the role of oral dysbiosis and HPV infection in HNCs, presenting the involved taxons, molecular effectors and pathways, as well as the HPV-associated particularities of genetic and epigenetic changes and of the tumor microenvironment occurred in different stages of tumor development. Oral dysbiosis is associated with the evolution of HNCs, through multiple mechanisms such as inflammation, genotoxins release, modulation of the innate and acquired immune response, carcinogens and anticarcinogens production, generation of oxidative stress, induction of mutations. Thus, novel microbiome-derived biomarkers and interventions could significantly contribute to achieving the desideratum of personalized management of oncologic patients, regarding both early diagnosis and treatment. The results reported by different studies are not always congruent regarding the variations in the abundance of different taxons in HNCs. However, there is a consistent reporting of a higher abundance of Gram-negative species such as Fusobacterium, Leptotrichia, Treponema, Porphyromonas gingivalis, Prevotella, Bacteroidetes, Haemophilus, Veillonella, Pseudomonas, Enterobacterales, which are probably responsible of chronic inflammation and modulation of tumor microenvironment. Candida albicans is the dominant fungi found in oral carcinoma being also associated with shorter survival rate. Specific microbial signatures (e.g., F. nucleatum, Bacteroidetes and Peptostreptococcus) have been associated with later stages and larger tumor, suggesting their potential to be used as biomarkers for tumor stratification and prognosis. On the other hand, increased abundance of Corynebacterium, Kingella, Abiotrophia is associated with a reduced risk of HNC. Microbiome could also provide biomarkers for differentiating between oropharyngeal and hypopharyngeal cancers as well as between HPV-positive and HPV-negative tumors. Ongoing clinical trials aim to validate non-invasive tests for microbiome-derived biomarkers detection in oral and throat cancers, especially within high-risk populations. Oro-pharyngeal dysbiosis could also impact the HNCs therapy and associated side-effects of radiotherapy, chemotherapy, and immunotherapy. HPV-positive tumors harbor fewer mutations, as well as different DNA methylation pattern and tumor microenvironment. Therefore, elucidation of the molecular mechanisms by which oral microbiota and HPV infection influence the HNC initiation and progression, screening for HPV infection and vaccination against HPV, adopting a good oral hygiene, and preventing oral dysbiosis are important tools for advancing in the battle with this public health global challenge.

Keywords: HNC; HPV infection; oral microbiota; risk factors; signaling pathways; tumor microenvironment.

Figure 1

Schematic overview of the predisposing factors for HNCs and the general pattern of carcinogenesis. The activated carcinogens can produce DNA damage or are excreted. When the cellular repairing mechanisms are functioning properly, the DNA damage is repaired, but when these mechanisms are ineffective, genetic defects are perpetuated and can ultimately lead to HNCs.

Figure 2

Mechanisms of carcinogenesis induced by persistent HPV infections. Viral particles infect epithelial cells in the oral or oropharyngeal mucosa (A), with HPV DNA randomly integrating into the host cell genome (B). It is replicated as the epithelial cells multiply, and the virus is activated when it reaches the surface. After integration into the host cell genome, viral DNA is copied into mRNA, and proteins are released into the nucleus and cytoplasm. The E6 protein recruits the cellular ubiquitin-protein ligase E6AP and targets the cellular protein TP53 (C), which is involved in maintaining the genetic health of cells. Complexed with E6 and E6AP, TP53 protein is degraded in proteasomes (D), an event that promotes resistance to apoptosis and malignant progression. Lacking the DNA integrity checkpoint mechanism, the cell can accumulate defects, leading to genomic instability and malignant progression. On the other hand, the E6 protein, and less E7, forms a complex with E6AP and NEX1 (neurogenic differentiation factor 6) (E), which activates TERT/hTERT (F). This telomerase reverse transcriptase promotes telomere elongation and cell immortalization. Further, cells with inactive TP53 due to proteasomal degradation may acquire genetic instability and be transformed toward malignant progression. The E6 protein inactivates IFR3 (G), normally promoting the IFNA-IFNAR complex (H) formation. By inhibiting the formation of this complex, E6 decreases immune recognition of HPV and helps the spreading of HPV infection. The E5 protein activates the EGFR-mediated signaling pathway (I), promoting cell division and proliferation toward malignant progression. The E7 protein forms a complex with RB, leading to proteasome degradation (J). In the absence of RB, P16 synthesis is activated (K), which binds and disrupts CCND1 complexes with CDK4 and CDK6 (L), CCND1 contributing to uncontrolled DNA replication and cell division, which can further lead to malignant progression. The E7 protein stimulates CDK2 activity (M), leading to cell proliferation and malignant progression.

Figure 3

Effects of HPV infection and microbiota on head and neck tumors. HPV infection favors the development of head and neck cancers (mainly from the oral and oropharyngeal sphere), but their general prognosis is better than that of HPV-negative tumors (A); Corynebacterium and Kingella have a preventive effect on head and neck cancers (B); Bacillus, Lactobacillus and Sphingomonas sustain favorable prognosis (C); Leuconostoc, Streptococcus and Abiotrophia increase the risk of head and neck cancers (D); Streptococcus salivarius, Corynebacterium and Stomatococcus favor oncogenesis and the development of oral tumors (E); Stenophotromonas, Staphylococcus, Centipeda, Selenomonas, Alloscordovia and Acinetobacter predict poor prognosis and poorer survival rate for OSCCs (F); Fusobacterium nucleatum is generally associated with early oral squamous cell carcinomas stages, reduced recurrence and increased survival duration (G); the fungus Candida albicans stimulates pro-tumor signaling pathways (H); Veillonella is an indicator for better overall prognosis for OSCCs (I); Bacteroidetes and Peptostreptococcus are associated with large oral squamous cell carcinomas (J); the presence of the genera Corynebacterium, Kingella, Neisseria, Abiotrophia and Capnocytophaga reduce the risk of the appearance or progression of laryngeal tumors (K); the species Actinomyces oris and Veillonella denticariosi are associated with reduced risk of occurrence or progression of pharyngeal tumors (L); species from the genera Faecalibacterium, Prevotella and Phascolarctobacterium reduce the risk of pharyngeal cancer recurrence (M).