Elsevier

Translational Research

Volume 179, January 2017, Pages 168-182
Translational Research

Review Article
Does the vaginal microbiota play a role in the development of cervical cancer?

https://doi.org/10.1016/j.trsl.2016.07.004Get rights and content

Persistent infection with oncogenic human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the VM and the presence of an HPV infection using next-generation sequencing techniques identified higher microbial diversity in HPV-positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with preinvasive disease (squamous intraepithelial neoplasia [SIL]) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host’s innate immune response, susceptibility to infection, and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks.

Introduction

Although cervical cancer is largely preventable through detection and treatment of the preinvasive precursor, high-grade squamous intraepithelial lesions (HSILs), it remains the commonest female malignancy in virtually all low-resource countries and the seventh more frequent malignancy in females worldwide.1 It is estimated that, globally, almost 530,000 women develop cervical invasive disease annually and more than 265,000 die from the disease.2 The comparatively low incidence of cervical cancer in affluent societies is largely related to the presence of population-based screening programs and education that led to a dramatic decrease in the incidence and mortality from the disease.3 Although the human papillomavirus (HPV) vaccine has the potential to dramatically decrease these rates, introduction into most developing countries has been slow, so these changes are not expected to impact cervical cancer rates for at least 1 to 2 decades.

Section snippets

HPV and Cervical Carcinogenesis

There is strong evidence that infection with HPV is necessary but not sufficient for the development of cervical preinvasive and invasive disease. With more than 200 HPV subtypes recognized today, it is only a fraction of these that has been found to have a carcinogenic potential.4 Of these, subtypes HPV-16 and HPV-18 are most commonly associated with invasive cancers and are thought to cause approximately 65–75% of the cases. It is now recognized that it is the persistence of infection by

The Vaginal Microbiome

Much of the work to date on mucosal microbiota has been focused on the gut including its influence on immune function, behavior as well as local and systemic inflammatory diseases.22, 23, 24 The Human Microbiome Project has extensively examined the vaginal microbiota although in contrast to the gut, less is understood about the role of the VM in human disease. A detailed description of the VM is outside the scope of this article and can be found in several review articles.25, 26 In the

Vaginal Microbiome, HPV, and Immune Response

There are no good direct data that show how altered VM influences local immune function. However, it is plausible that the stability and composition of the VM may play an important role in determining host innate immune response and susceptibility to infection as well as playing a role further downstream regarding the development of cervical disease.

Several studies have shown that BV and BV-associated bacteria effect immune parameters within the vagina including cytokines/chemokines,

HPV Infection and the Vaginal Microbiome

Several pieces of evidence suggest that HPV is affected by the VM. In meta-analyses of mostly cross-sectional studies, the presence of BV was associated with higher rates of HPV infection (12 studies; odds ratio [OR]: 1.43, 95% confidence interval (CI): 1.11–1.84)74 suggesting that a diverse, Lactobacillus-depleted microbiome may contribute to HPV persistence. There is also evidence to suggest that persistence is more likely in those with altered microbiome. In one study, women with persistent

Preinvasive and Invasive Cervical Cancer and the Vagina Microbiome

More recently, we published the first study describing the VM in 169 women with biopsy-proven cervical preinvasive and invasive disease and compared them to healthy HPV-negative controls.81 We found that the rate of Lactobacillus-depleted high-diversity microbiome (CST IV) was increased 2 fold in women with low-grade squamous intraepithelial neoplasia (LSIL), 3 fold in women with high-grade squamous intraepithelial neoplasia (HSIL), and 4 fold in women with invasive disease (normal = 2/20, 10%;

Barriers and Limitations of the Existing Literature

Rapidly evolving evidence suggests the importance of the interactions between the human host, the innate immunity, the microbiome and virome in the genital tract with health and disease. Despite variations among the studies, the results consistently demonstrate differences in the microbiota noted in women with cervical disease that appear to correlate with the severity of the disease. Lactobacilli produce hydrogen peroxide and preserve an acid protective environment in the vagina with low pH.

Future Directions

There appears to be a complex relationship between the host and the VM, and composition of the VM may play a role in host susceptibility to HPV infection, its persistence, and subsequent development of dysplastic and ultimately neoplastic lesions. The evaluation of all these interactions can be challenging, as the VM shows significant intraindividual variability, whereas different HPV subtypes that may be present at a given time may follow a different independent course, and these shifts in

Conclusion

There is a wealth of emerging evidence to suggest that the cervico-vaginal bacterial population plays a substantial role in the persistence of the virus and the presence of subsequent cervical preinvasive disease. The role of the microbiome in other HPV-related cancers such as vulvar, anal, and oropharyngeal cancers has not yet been explored but likely play important roles. Future studies assessing the impact of the VM in cervical carcinogenesis should explore the causal link in longitudinal

Acknowledgments

Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare.

The article conforms to the relevant ethical guidelines for human and animal research.

British Society of Colposcopy Cervical Pathology Jordan/Singer Award (P47773, M. Kyrgiou); Imperial College Healthcare Charity (M. Kyrgiou, A. Mitra; P47907); Genesis Research Trust (M. Kyrgiou; P55549); Imperial Healthcare NHS Trust NIHR Biomedical Research Centre (M.

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