The same bacteria that cause gum disease might be paving the way for oral cancer to spread along your nerves.
Published: June 2024 | Reading time: 8 min
For decades, we've understood oral cancer primarily through traditional risk factors like smoking, alcohol consumption, and HPV infection. Yet, a mysterious question has persisted: why do some cancers become exceptionally aggressive, spreading along nerve pathways in a process known as perineural invasion (PNI)? The answer may lie in an unexpected place—the complex ecosystem of microbes living in our mouths. Recent groundbreaking research reveals that specific oral bacteria not only thrive in cancerous environments but may actively reshape them, creating a perfect storm for cancer aggression.
Perineural invasion (PNI) is not merely cancer growing near nerves; it's an active process where cancer cells invade the space surrounding nerves, using them as pathways for spread1 . Think of it as cancer discovering a highway system within the body that allows it to travel far beyond its original location.
This phenomenon is particularly common and dangerous in oral squamous cell carcinoma (OSCC), which constitutes over 90% of all oral cancers1 4 . When pathologists find PNI in oral cancer patients, the clinical implications are severe:
Key Insight: For years, the molecular mechanisms behind PNI remained elusive. Why are some cancers neurotropic (nerve-seeking)? The search for answers has led scientists to investigate the invisible inhabitants of our oral cavity—the microbiome.
The human mouth hosts a complex community of bacteria, fungi, and viruses. In healthy states, these microbes maintain a delicate balance. However, this equilibrium can be disrupted—a state known as dysbiosis—creating opportunities for disease-promoting species to flourish.
Metagenomic sequencing technologies have allowed scientists to map these microbial communities with unprecedented precision, comparing samples from healthy individuals, those with precancerous lesions, and oral cancer patients4 . The findings have been striking:
Oral cancer patients show distinct microbial signatures, with decreased beneficial species and increased pathogenic bacteria. Certain bacteria like Fusobacterium nucleatum, Prevotella intermedia, and Peptostreptococcus stomatis consistently appear in greater abundances in cancer samples4 6 .
These aren't merely passive residents; they actively interact with cancer cells and the immune system. Some pathogens can even translocate from their original sites in the oral cavity to infiltrate tumor microenvironments elsewhere, as demonstrated in nasopharyngeal carcinoma6 .
| Microbial Category | Healthy Oral Environment | Oral Cancer Environment |
|---|---|---|
| Phylum Level | Balanced Firmicutes/Bacteroidetes | Increased Bacteroidetes4 |
| Genus Level | Diverse commensals | Increased Prevotella, Peptostreptococcus4 |
| Species Level | Balanced community | Enriched P. intermedia, P. stomatis4 6 |
| Functional Potential | Homeostatic metabolism | Increased coenzyme A biosynthesis, inflammatory pathways4 |
Balanced microbial community with diverse commensal species.
Dysbiotic community with increased pathogenic bacteria.
To confirm whether oral bacteria were merely associated with cancer or actively participating in its progression, researchers designed a sophisticated experiment to track their movements and interactions.
A 2024 study published in Nature Communications took a comprehensive approach6 :
Researchers gathered matched nasopharyngeal and oral samples from 148 nasopharyngeal carcinoma (NPC) patients and 124 controls, creating 272 sample pairs.
They performed 16S rRNA gene sequencing using both PacBio long-read technology (for species-level identification) and Illumina platforms.
Advanced algorithms (FEAST and SourceTracker2) calculated "translocation scores" quantifying how much oral microbiota had migrated to nasopharyngeal sites.
Microbial culturomics isolated and grew the suspected translocated bacteria, confirming their viability.
Meta-transcriptomic analysis of nasopharyngeal biopsies verified these microbes were alive and active within tumors, not just passing through.
The findings revealed a dramatic story of microbial mislocalization:
Greater cancer risk with abnormal microbial translocation6
Oral species identified consistently translocating to cancerous tissues6
| Bacterial Species | Association with Cancer | Potential Mechanisms |
|---|---|---|
| Fusobacterium nucleatum | Colorectal & oral cancers | Produces FadA adhesin; stimulates cancer signaling pathways9 |
| Prevotella intermedia | Oral squamous cell carcinoma | Correlated with increased C-reactive protein (inflammation marker)4 |
| Peptostreptococcus stomatis | Oral & nasopharyngeal cancers | Forms co-occurrence networks with other pathobionts6 |
| Porphyromonas gingivalis | Periodontal pathogen linked to oral cancer | Chronic inflammation; tissue invasion capabilities |
Understanding how these bacteria influence cancer progression requires examining their molecular toolkit. The relationship appears to operate through several interconnected mechanisms:
Fusobacterium nucleatum exemplifies how bacteria can actively drive cancer aggression. This common oral pathogen creates a molecule called FadA adhesin that binds to a specific protein on colon cells: Annexin A19 .
Genetic mutations make cells cancerous
F. nucleatum binds to Annexin A1 on cancerous cells
Positive feedback loop accelerates tumor growth9
Chronic inflammation creates a fertile environment for cancer progression. Multiple studies show that oral pathogens like P. intermedia correlate with increased C-reactive protein levels4 . Inflammatory signaling molecules can:
Metabolomic analyses reveal that oral cancer patients exhibit distinct metabolic profiles in their saliva, with specific metabolites like 13(S)-HOTrE and 13-HODE significantly downregulated, while others like docosanamide are upregulated. These metabolic changes likely create favorable conditions for pathogen growth while hampering protective human cells.
| Research Tool | Function in Experiments | Application Example |
|---|---|---|
| Metagenomic Sequencing (16S rRNA) | Microbial community profiling | Identifying bacterial taxa differences between healthy and cancerous samples4 |
| Liquid Chromatography-Mass Spectrometry (LC-MS) | Metabolite detection and quantification | Revealing metabolic changes in saliva from oral cancer patients |
| Selective Culture Media | Enrichment of specific bacterial taxa | Isolating translocated pathogens from tissue samples6 |
| Source Tracking Algorithms (FEAST) | Quantifying microbial translocation | Calculating oral-to-nasopharyngeal microbiota translocation scores6 |
| Benzonase & Proteinase K | Selective host DNA degradation in MEM protocol | Enriching microbial DNA from tissue samples for better sequencing2 |
The implications of these findings extend far beyond academic interest—they open new avenues for managing oral cancer:
Specific bacterial signatures could serve as early detection markers for aggressive oral cancers4 .
Patients with high levels of cancer-associated bacteria might receive more intensive monitoring and treatment.
Targeting specific pathogens or their virulence factors could represent a new adjunctive approach9 .
Enhanced oral hygiene might take on new importance in cancer prevention for high-risk individuals.
Clinical Implication: The discovery that oral microbes play an active role in cancer progression represents a paradigm shift in oncology. No longer can we view cancer as solely a disease of human cells gone rogue; we must consider the microbial passengers that may be steering toward more aggressive behavior.
The discovery that oral microbes play an active role in cancer progression represents a paradigm shift in oncology. No longer can we view cancer as solely a disease of human cells gone rogue; we must consider the microbial passengers that may be steering toward more aggressive behavior.
The connection between differential microbial enrichment and perineural invasion illustrates a complex biological dialogue between our cells and our microbiota—one that sometimes goes terribly wrong. As research continues to unravel these relationships, we move closer to innovative approaches that might one day target these bacterial accomplices alongside the cancer cells they befriend.
Perhaps most importantly, these findings remind us that maintaining a healthy oral microbiome through proper hygiene and regular dental care isn't just about preserving teeth—it might be a crucial strategy in cancer prevention and management.