Bacterial Infections Role in Gynecological Cancers Development: Narrative Review.

Women's reproductive organs have a dynamic and relative microbial balance. Gynecologic cancers originate in the reproductive organs of women, commonly affecting the cervix, endometrium, and ovaries, while cancers of the vagina and vulva are less frequent. Alterations in the gut and vaginal microbiome composition influence the immune and metabolic signaling of host cells, leading to chronic inflammation, angiogenesis, cellular proliferation, genome instability, breaches in the epithelial barrier, and metabolic dysregulation that may trigger the progression of gynecologic cancers. An imbalance in the microbiome, as well as, gynecological cancers. The association of different types of gynecological cancers including cervical, ovarian, uterine (endometrial cancer and uterine sarcoma), vaginal, and vulvar cancers with different bacterial infections has been investigated in several researches which are discussed in the following sections. The most important bacteria associated with different types of gynecological cancers and the related mechanisms are summarized in Table  2 and Figure  1 , respectively. The different bacterial infections associated with gynecological cancers development. The different bacteria and their induced mechanisms associated with various gynecological organs.

Robab Azargun: methodology, writing – original draft. Maryam Azargoon: methodology, writing – review and editing. Zahra Asefy: investigation, writing – review and editing. Mina Yekani: software, writing – review and editing. Vahideh Tarhriz: investigation, writing – review and editing. Fatemeh Yeganeh: methodology, writing – original draft. Mohammad Yousef Memar: supervision, writing – review and editing. Shirin Eyvazi: validation, writing – review and editing.

The authors have nothing to report.

The authors have nothing to report.

In this review, data on the role of bacterial infections in the development of gynecological cancers were collected from databases including PubMed, Scopus, and Google Scholar. Published manuscripts were searched using keywords such as bacterial infections, gynecological cancers, and microbiome in reproductive organs. All English‐language articles were screened and independently read by two authors. An overview of the literature search strategy, including inclusion/exclusion criteria and results, is provided in Figure  S1 .

Vaginal cancer is one of the rarest of gynecological cancers and is only 2% of all gynecological cancers with about 1 of every 1100 women. It was estimated that 5170 new cases and 1430 deaths in the United States in 2019 ( www.cancer.org ). The risk of vaginal cancer is associated with women 70 years old or older in more than half of the cases, prenatal exposure to diethylstilbestrol, smoking, a previous history of cervical cancer, and viral infections such as human papillomavirus (HPV 16 and HPV 18) and human immunodeficiency virus (HIV) [ 99 ]. In addition, bacterial infections may be involved in the pathogenesis of vaginal cancer. The most common causes of bacteria in vaginal cancer are Lactobacillus spp. including L. iners , L. crispatus , L. jensenii , and L. gasseri , with L. iners , and L. crispatus being the dominant species among them [ 100 ]. Lactobacillus spp. through the induction of cytokine production including TNF‐α, IFN‐γ, IL‐12, IL‐18, Nod2, and TLR2 activate innate immune responses to protect the genital tract host [ 101 ]. On the other hand, Lactobacillus spp. through lactic acid production provide a pH > 4.5, which prevents the invasion of pathogenic bacteria in the vaginal environment [ 102 ]. Mycoplasma spp . is a commensal bacterium of humans that switch into a pathogenic state by altered host immunity or microbial environment, causing vaginal cancer [ 103 ]. Alteration of the vaginal flora, a decrease in the proportion of Lactobacillus spp., can lead to increase incidence of bacterial vaginosis such as Gardnerella vaginalis , Atopobium vaginae , Mycoplasma spp., Clostridiales , Prevotella spp., and Megasphaera spp. [ 104 ]. The vaginal Lactobacillus spp. seem to be protective, and a disruption of them can cause reduced immune protection and damage the epithelial lining of reproductive tissues, as well as, replacement of bacterial vaginosis, thereby promoting carcinogenesis [ 105 ]. The important known bacteria, which promote inflammation in vagina are A. vaginae , G. vaginalis , and Mycoplasma hominis . A. vaginae induces pro‐inflammatory cytokines IL‐6, IL‐8, and the antimicrobial peptide b‐defensin 4 via the binding TLR1, −2 and −6 to NF‐kB signaling from vaginal epithelial cells [ 106 ]. G. vaginalis induces IL‐6 and IL‐8 and Mycoplasma hominis induces TNFα, which are involved in inflammation and may be in cancer development [ 107 ].

Gynecological cancers are one of the most common cancers in women that affect their reproductive organs. The role of bacterial infection as an external factor has been established in several cancers, as well as gynecological cancers. However, the mechanisms of carcinogenesis of bacteria are unclear. Women's reproductive organs have a dynamic and relative microbial balance. The disruption in the balance of the microbiome could result in numerous gynecological diseases and gynecological cancers. Among the different bacterial infections, infections caused by Chlamydia , Mycoplasma , and Bacteriodes species are important infections associated with the malignancies. Evaluation of the microbiome in the reproductive organs of gynecological cancer patients and studies on the prevention and control of the infections in the patients could be useful in verifying the pathogenesis of the diseases and also the identification of suitable therapeutic strategies.

Gynecological cancers are some of the most common cancers in women, originating from the reproductive organs [ 1 , 2 ]. These malignancies are the fourth most frequently diagnosed neoplasms in women of childbearing age, accounting for 16% of all neoplasms [ 3 ]. The main types of gynecological cancers are cervical, ovarian, uterine (endometrial cancer and uterine sarcoma), vaginal, and vulvar cancers [ 4 ]. The etiology of gynecological cancers is multifactorial; genetic and epigenetic factors, environmental factors, and infection are the most common risk factors for these malignancies [ 5 ]. Recently, the role of the microbiome in the development of various diseases has been well established [ 6 , 7 ]. Microbes are involved not only in the onset of gynecologic cancer but also emerge as a result of the physiological disruptions it causes [ 8 , 9 ]. During dysbiosis, characterized by an imbalance of commensal and pathogenic microorganisms [ 6 ], the reduction and absence of Lactobacillus is often observed and replaced by specialized or facultative anaerobic bacteria, compromising the vaginal immune defense [ 10 ]. Decreased estrogen levels are associated with vaginal dysbiosis, characterized by a reduction of regular hydrogen peroxide‐ and lactic acid‐producing Lactobacillus species in the vagina and an overgrowth of anaerobic bacteria such as Gardnerella, Mycoplasma, and Prevotella. This shift leads to an increase in vaginal pH above 4.5. Anaerobic bacteria like Gardnerella vaginalis possess virulence factors that allow them to adhere to the host epithelium and form a biofilm [ 11 ]. Dysbiotic bacterial communities release enzymes such as sialidase that compromise the integrity of the mucus barrier and damage the cervicovaginal epithelium, increasing the susceptibility of basal cells to HPV infection. Additionally, certain bacterial toxins can cause DNA damage in host cells, promoting the integration of viral oncogenes into the host genome [ 12 ]. The association between viral infections—particularly Human Papillomavirus (HPV) and Human Immunodeficiency Virus (HIV)—and the development of cervical cancer is well established in the literature [ 13 , 14 , 15 ]. Additionally, chronic infections resulting from PID can contribute to the release of tumor‐promoting factors such as cytokines, chemokines, and reactive oxygen species, fostering genetic and epigenetic changes associated with carcinogenesis [ 16 ]. For example, bacterial infections localized in the peritoneum and vaginal infections (such as Neisseria gonorrhoeae or Chlamydia trachomatis ) may contribute to the progression and metastasis of ovarian cancer. This may be due to inflammation‐induced oxidative stress, which leads to the accumulation of DNA damage and mutations [ 17 ]. However, the role of bacterial infections in these malignancies has received less attention. Bacteria colonize various human organs and, beyond causing infection‐related conditions, they are implicated in numerous disorders such as obesity, diabetes, fatty liver disease, allergic diseases, atherosclerosis, autoimmune diseases, Alzheimer's disease, and cancer [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The association between bacterial infections and cancer development is complex and not yet fully understood. However, genetic susceptibility and inflammation appear to be key mediators in this association. In this study, we aim to present new findings on the role of different bacterial infections in various types of gynecological cancers by reviewing recent literature.

The authors declare no conflicts of interest.

Figure S1: An overview of the literature search strategy.