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Chlamydia trachomatis and cancer
  1. Jorma Paavonen
  1. Department of Obstetrics and Gynecology, University of Helsinki, Haartmaninkatu 2, 00290 Helsinki, Finland jorma.paavonen{at}helsinki.fi

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    Genital Chlamydia trachomatis infections have been recognised as a major public health problem. The World Health Organization (WHO) estimates that 50 million cases of C trachomatis infection occur each year worldwide.1 C trachomatis is the major cause of mucopurulent cervicitis, pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy.25 Thus, the healthcare costs due to complications caused by C trachomatis infections are enormous.

    Cervical cancer is the most common cancer in women worldwide. Epidemiological studies have shown that early sexual activity is a risk factor for cervical cancer.6 High risk human papillomavirus (HPV) types are found in practically all cervical carcinomas.7 The evidence linking oncogenic HPV types in the aetiology of cervical carcinoma is beyond doubt. HPV DNA based longitudinal studies have confirmed the seroepidemiological findings that past HPV infection predisposes to the development of cervical carcinoma.8, 9 Since C trachomatis infection is also a marker of sexual activity, an association between C trachomatis and cervical cancer has been suggested. Previous case-control studies have found cytological or serological evidence of the role of C trachomatis in cervical neoplasia.1012 Recent longitudinal seroepidemiological studies also shown that C trachomatis infection is associated with cervical carcinoma.13, 14 This association remains after adjustment for smoking and serum antibodies to the high risk HPV types.15 The association was specific for squamous cell carcinoma, and not for adenocarcinoma.15 Of specific C trachomatis serotypes, serotype G was most strongly associated with cervical squamous cell carcinoma.16 Furthermore, the presence of serum IgG antibodies to more than one serotype increased the risk.17 The link between C trachomatis and squamous cell carcinoma is unexpected since it is well known that the targets for C trachomatis are endocervical glandular cells, and that women with cervical ectopy are more susceptible to C trachomatis than women without cervical ectopy. However, the endocervical epithelium of the transformation zone undergoes a process known as squamous metaplasia, and metaplastic cells are also targets for C trachomatis. In fact, persistent chlamydial infection may be one of the factors inducing squamous metaplasia and metaplastic cell atypia.12, 18

    No association has been shown between the presence of C trachomatis antibodies and the development of non-cervical anogenital cancers.19

    The incidence of ovarian cancer is increasing. Ovarian cancer is the number one killer among gynaecological malignancies. The aetiology of ovarian cancer is unknown. Incessant ovulation and exposure to high gonadotrophin concentrations increase the risk of ovarian cancer while pregnancy, breast feeding, oral contraceptive use, and tubal ligation all protect against ovarian cancer. Concern about the risk for ovarian cancer associated with infertility or infertility treatment has been heightened by several reports.17, 2022 However, although the association has become less convincing based on many subsequent larger studies,2327 it is tempting to speculate that a common cause of salpingitis, oophoritis, and infertility such as C trachomatis infection might explain the link between infertility and ovarian cancer found in some studies (fig 1). Interestingly, one study of cancer incidence correlations suggests that cervical cancer and ovarian cancer might have common aetiological factors.28 However, the presence or absence of HPV DNA or C trachomatis DNA in benign or malignant ovarian tumours has not been extensively studied. It is well known that chlamydial pelvic inflammatory disease (PID) is associated with elevated serum levels of ovarian cancer associated tumour markers CA-125 and TATI (tumour associated trypsin inhibitor).29, 30 These tumour markers may reflect the tissue damage and disruption of the basement membrane seen in severe oophoritis. An association between self reported PID and subsequent ovarian cancer has been reported in one case-control study of histologically verified epithelial ovarian cancer cases.31 Using the overall odds ratio and the estimated lifetime prevalence of history of PID, the authors calculated that approximately 9% of ovarian cancer in the population could be due to past PID. However, another recent study did not confirm these results.32 Epidemiological studies linking past history of PID and epithelial ovarian cancer in later life are problematic, because the self reported history of PID is unreliable and because chlamydial antibody levels decrease over time. Thus, the available epidemiological evidence to date is far from convincing.

    The link between chlamydia and cancer is biologically plausible because many other chronic bacterial infections have been linked to the development of malignant diseases.33 Already in 1936 lymphogranuloma venereum (LGV) caused by L2 strain of C trachomatis was linked to cancer.34 Furthermore, another common microbe, Helicobacter pylori has been associated with the development of gastric cancer.35, 36 The outcome and sequelae of chronic or subclinical chlamydial infection can be influenced by the host immune response. Chlamydial heat shock proteins (HSPs) induce deleterious humoral and cell mediated immune responses in individuals developing long term sequelae.37 Thus, cervical chlamydial infection may result in local immune perturbation favouring persistence or progression of infection caused by the high risk HPV types. Poor immune response may lead to the persistence of the organism and the development of immunologically mediated tissue injury which increases the risk for malignant transformation. Serotype G has been associated with symptomatic infections and upper genital tract infections.38, 39 Serotype G was also associated with cervical carcinoma.16 Thus, specific C trachomatis serotypes might be more virulent than others, and perhaps less sensitive to appropriate antimicrobials, and could thus play a part in carcinogenesis.

    The development of carcinoma takes several years, probably decades. The link between bacterial infections and carcinogenesis is not clear, but genetic damage and neoplastic changes can be induced in vitro by co-culturing cells with activated inflammatory cells.33 Release of nitric oxide occurs in C trachomatis infections.40 Recent studies have shown that C trachomatis inhibits host cell apoptosis by specific mechanisms.41 In chronic chlamydial infections these mechanisms could initiate or promote carcinogenesis. Both the serotype specific differences and the fact that the risk was higher in women exposed to more than one serotype suggest that C trachomatis may in some way have a role in cervical carcinogenesis. It is tempting to speculate on the potential molecular mechanisms explaining this association—for instance, if specific determinants related to specific chlamydial serotypes could be directly or indirectly carcinogenic. However, until confirmatory evidence of an association has been demonstrated it is premature to conclude that C trachomatis is causally related to these cancers.

    Figure 1

    Hypothetical link between C trachomatis and epithelial ovarian cancer. *PID = pelvic inflammatory disease; †PCO = polycystic ovaries.

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