Understanding the role of microbiomes in the development of HPV-cervical cancer

Cervical cancer (CC) is the fourth most common female cancer worldwide. Despite the popularized international vaccination efforts against human papillomavirus (HPV)—the primary causative agent of CC—it remains a significant global problem. Indeed, it is the 4^th and the 2^nd most common cancer in women globally and developing countries (1,2). In the United States, disparities in CC incidence also exist, with higher rates and presentation at more advanced disease (3) observed among Hispanics/Latinos compared to non-Hispanics whites. Additionally, in the US, underserved white populations, such as those of Appalachia, known for its geographic isolation and high rates of poverty (4,5), also show high rates of CC (6).

The factors associated with viral persistence and progression to CC are not yet apparent, however, recent work has shown a possible role of the epithelial microbiome in viral infections and cancer progression. With the advent of the human microbiome discoveries—we now know that microbes supply essential ecosystem services that contribute to homeostasis (7) and that microbiomes play a role in the susceptibility to HPV and neoplasia (8).

The female reproductive tract is characterized by low microbial diversity and dominance of one or a few species of Lactobacillus, who are believed to be the significant element needed to maintain healthy genital homeostasis (9). Lactobacillus is the dominant bacterial genus, with a protective role of the lactic acid product of fermentation, which maintains a low pH <4.5 (10), restricting colonization of other anaerobic species (11). Any perturbations to the vaginal flora results in an increase in bacterial diversity (12-14). The high diversity profile can also be associated with inflammatory diseases (15), transmitted sexual infections such as Chlamydia (16), HIV (17), or HPV (14). Vaginal infections such as those by HPV also apparently increase bacterial diversity by yet unknown mechanisms.

HPV infections are a major etiologic agent for CC (18,19). For the virus to enter the basal cells of the stratified squamous epithelium (20), direct skin to skin contact is required. Among the oncogenic high-risk HPV subtypes associated with CC progression 16, 18, 31, 33, 45, 52, and 58 are included in the HPV 9-valent vaccine (21). Low-risk subtypes such as 6, 11, 40, 42, 43, 44, and 54, are associated with genital warts (22). The most important high-risk subtypes are 16 and 18 which cause 70% of cervical lesions and tumors.

Among the pap test results (cytology classification) there are mainly four categories: (I) negative for squamous intraepithelial lesion (NSIL); (II) atypical squamous cells of undetermined significance (ASC-US); (III) low-grade squamous intraepithelial lesion (LSIL); and (IV) high-grade squamous intraepithelial lesion (HGSIL). Results of cervical biopsy are reported as cervical intraepithelial neoplasia (CIN) of grades 1, 2 and 3 for severity (23).

Microbial infections in the context of HPV infections and cervical lesions remain largely unexplored. Ethnicity has been associated with changes in bacterial community composition, with Caucasians and Asians having a significantly higher prevalence of Lactobacillus spp and compared to Hispanics or African Americans (14,24).

The study of the bacterial communities associated with dysbiosis in different human populations will be essential for the appropriate translational development of probiotic and early detection methods for HPV-related cancer prevention.

Women in Appalachia—a US region with the highest annual rate of CC mortality in the United States (25), were recruited and their cervical microbiomes studied.

In the study by McKee et al. (26), women with abnormal cervical cytology or who were HPV+ were more likely to have a diverse vaginal microbiota characterized by higher Gardnerella vaginalis relative abundance and reduced relative abundance of L. iners and L. gasseri, compared to women without either condition. This study adds to the current knowledge of cervicovaginal microbiome dynamics, highlighting the importance of using microbiomes for early detection of cancers.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine for the series “The Role of Microbiomes in the Development of HPV-cervical Cancer”. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.org/article/view/10.21037/gpm-2020-hpv-02/coif). The series “The Role of Microbiomes in the Development of HPV-cervical Cancer” was commissioned by the editorial office without any funding or sponsorship. FGV served as the unpaid Guest Editor of the series, and serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from Sep 2019 to Aug 2021. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that the questions related to the accuracy and integrity of any part of the work are thoroughly investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bardach AE, Garay OU, Calderon M, et al. Health economic evaluation of Human Papillomavirus vaccines in women from Venezuela by a lifetime Markov cohort model. BMC Public Health 2017;17:152. [Crossref] [PubMed]
2. Lopez MS, Baker ES, Maza M, et al. Cervical cancer prevention and treatment in Latin America. J Surg Oncol 2017;115:615-8. [Crossref] [PubMed]
3. Eng TY, Chen T, Vincent J, et al. Persistent Disparities in Hispanics with Cervical Cancer in a Major City. J Racial Ethn Health Disparities 2017;4:165-8. [Crossref] [PubMed]
4. Paskett ED, Fisher JL, Lengerich EJ, et al. Disparities in underserved white populations: the case of cancer-related disparities in Appalachia. Oncologist 2011;16:1072-81. [Crossref] [PubMed]
5. Lengerich EJ, Tucker TC, Powell RK, et al. Cancer incidence in Kentucky, Pennsylvania, and West Virginia: disparities in Appalachia. J Rural Health 2005;21:39-47. [Crossref] [PubMed]
6. Cohen EL, Scott AM, White CR, et al. Evaluation of Patient Needs and Patient Navigator Communication about Cervical Cancer Prevention in Appalachian Kentucky. J Commun 2013;63:72-94. [Crossref] [PubMed]
7. Godoy-Vitorino F. Human microbial ecology and the rising new medicine. Ann Transl Med 2019;7:342. [Crossref] [PubMed]
8. Mitra A, MacIntyre DA, Lee YS, et al. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci Rep 2015;5:16865. [Crossref] [PubMed]
9. Ronnqvist PD, Forsgren-Brusk UB, Grahn-Hakansson EE. Lactobacilli in the female genital tract in relation to other genital microbes and vaginal pH. Acta Obstet Gynecol Scand 2006;85:726-35. [Crossref] [PubMed]
10. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis: diagnostic criteria and microbial and epidemiologic associations. The American journal of medicine 1983;74:14-22. [Crossref] [PubMed]
11. Boris S, Barbes C. Role played by lactobacilli in controlling the population of vaginal pathogens. Microbes Infect 2000;2:543-6. [Crossref] [PubMed]
12. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol 1991;29:297-301. [Crossref] [PubMed]
13. Sweet RL. Role of bacterial vaginosis in pelvic inflammatory disease. Clin Infect Dis 1995;20:S271-5. [Crossref] [PubMed]
14. Godoy-Vitorino F, Romaguera J, Zhao C, et al. Cervicovaginal Fungi and Bacteria Associated With Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Infections in a Hispanic Population. Front Microbiol 2018;9:2533. [Crossref] [PubMed]
15. Larsson PG, Platz-Christensen JJ, Thejls H, et al. Incidence of pelvic inflammatory disease after first-trimester legal abortion in women with bacterial vaginosis after treatment with metronidazole: a double-blind, randomized study. Am J Obstet Gynecol 1992;166:100-3. [Crossref] [PubMed]
16. van Houdt R, Ma B, Bruisten SM, et al. Lactobacillus iners-dominated vaginal microbiota is associated with increased susceptibility to Chlamydia trachomatis infection in Dutch women: a case-control study. Sex Transm Infect 2018;94:117-23. [Crossref] [PubMed]
17. Borgdorff H, Tsivtsivadze E, Verhelst R, et al. Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women. ISME J 2014;8:1781-93. [Crossref] [PubMed]
18. van der Noordaa J. Cancer and virus. Ned Tijdschr Geneeskd 1980;124:1726-9. [PubMed]
19. Walboomers JMM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-9. [Crossref] [PubMed]
20. Braaten KP, Laufer MR. Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine. Rev Obstet Gynecol 2008;1:2-10. [PubMed]
21. Petrosky E, Bocchini JA Jr, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 2015;64:300-4. [PubMed]
22. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27. [Crossref] [PubMed]
23. Waxman AG, Chelmow D, Darragh TM, et al. Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix. Obstet Gynecol 2012;120:1465-71. [Crossref] [PubMed]
24. Ravel J, Gajer P, Abdo Z, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A 2011;108:4680-7. [Crossref] [PubMed]
25. Horner MJ, Altekruse SF, Zou Z, et al. U.S. geographic distribution of prevaccine era cervical cancer screening, incidence, stage, and mortality. Cancer Epidemiol Biomarkers Prev 2011;20:591-9. [Crossref] [PubMed]
26. McKee KS, Carter KA, Bassis C, et al. The vaginal microbiota, high-risk human papillomavirus infection, and cervical cytology: results from a population-based study. Gynecol Pelvic Med 2020; [Crossref]