The role of Chlamydia trachomatis in the pathogenesis of female reproductive organs cancers

  • Louis C Ajonuma Department of Physiology, Lagos State University College of Medicine (LASUCOM), # 1 – 5 Oba Akinjobi Way, Ikeja, Lagos, Nigeria.
  • Kehinde Segun Nathaniel
  • Adebisi Saka Bamiro
  • Samira Lobo Makanjuola


Chlamydia trachomatis (C. trachomatis) is an intracellular obligate bacterium. It is the most common cause of pelvic inflammatory disease (PID) amongst a spectrum of diseases. Chlamydia infection is of a major public health concern especially in developing countries. It is estimated that about 600 million people are infected worldwide annually yet its roles in the pathogenesis of gynecological cancers are poorly understood and has not been fully elucidated. An understanding of the mechanisms underlying cancer development following PID due to C. trachomatis will be essential in prevention and providing more rational treatments. This review discusses the mechanisms and sequence of events linking Chlamydial infections to carcinogenesis in the female reproductive organs. Possible links between C. trachomatis infection and cancer development in the female reproductive organs are proposed. C. trachomatis infection as a co factor is also re-examined in light of these possible mechanisms.


1. Ajonuma LC, Ng EHY, Chan HC New insights into the mechanisms underlying hydrosalpinx fluid formation and its adverse effect on IVF outcome. Hum. Reprod. Update, 2002 8,255–64.
2. Geneva: World Health Organization; Global prevalence and incidence of selected curable sexually transmitted diseases: Overview and estimates. 2011
3. Abdelsamed Hossam, Peters Jan, and Byrne Gerald I Genetic variation in Chlamydia trachomatis and their hosts: impact on disease severity and tissue tropism. Future Microbiol. 2013 Sep; 8(9): 1129–1146.
4. Paavonen, J. and Eggert-Kruse, W. Chlamydia trachomatis: impact on human reproduction. Human Reprod Update, 1999 5, 433-47.
5. Walters, M.D., Eddy, C.A., Gibbs, R.S., Schachter, J., Holden, A.E.C. and Pauerstein, C.J. Antibodies to Chlamydia trachomatis and risk for tubal pregnancy. Am. J. Obstet. Gynecol., 1988 159, 942-946.
6. Cates, W. and Wasserheit, J.N. Genital chlamydial infections: epidemiology and reproductive sequelae. Am. J. Obstet. Gynecol., 1991 164, 1771±1781.
7. Paavonen, J. and Eggert-Kruse, W. Chlamydia trachomatis: impact on human reproduction. Hum. Reprod. Update, 1999 5, 433 - 447.
8. Jones, R.B., Mammel, J.B., Shepard, M.K. and Fisher, R.R. Recovery of Chlamydia trachomatis from the endometrium of women at risk for chlamydial infection. Am. J. Obstet Gynecol., 1986 155, 35-39.
9. Gump, D.W., Dickstein, S. and Gibson, M. Endometritis related to Chlamydia trachomatis infection. Ann. Intern. Med., 1981 95, 61.
10. Mardh, P.A., Moller, B.R. and Paavonen, J. Chlamydial infection of the female genital tract with emphasis on pelvic in¯ammatory disease. A review of Scandinavian studies. Sex. Transm. Dis., 1981, 8, 140.
11. Wolner-Hanssen, P., Mardh, P.A., Moller, B. and Westrom, L. Endometrial infection in women with chlamydial salpingitis. Sex. Transm. Dis., 1982 9, 84.
12. Winkler, B., Gallo, L., Reumann, W., Richart, R.M., Mitao, M. and Crum, C.P. Chlamydial endometritis: a histological and immunohistochemical analysis. Am. J. Surg. Pathol., 1984 8, 771.
13. Patton DL, Askienazy-Elbhar M, Henry-Suchet J, Campbell LA, Cappuccio A, Tannous W, Wang SP, Kuo CC. Detection of Chlamydia trachomatis in fallopian tube tissue in women with postinfectious tubal infertility. Am. J. Obstet. Gynecol., 1994, 171, 95-101
14. Witkin, S.S. (1999) Immunity to heat shock proteins and pregnancy outcome. Infect. Dis. Obstet. Gynecol., 7, 35-38.
15. Toth, M., Jeremias, J., Ledger, W.J. and Witkins, S.S. In vivo tumour necrosis factor reproduction in women with salpingitis. Surg. Gynecol. Obstet., 1992, 174, 359-362.
16. Licciardi, F., Grifo, J.A., Rosenwaks, Z. and Witkin, S. Relation between antibodies to Chlamydia trachomatis and spontaneous abortion following in vitro fertilization. J. Assist. Reprod. Genet. 1992, 9, 207±209.
17. Witkin, S.S., Sultan, K.M., Neal, G.S., Jeremias, J. Grifo, J.A. and Rosenwaks, Z. Unsuspected Chlamydia trachomatis infection and in vitro fertilization outcome. Am. J. Obstet. Gynecol., 1994, 171, 208±214.
18. La Verda, D., Albanese, L.N., Ruther, P.E., Morrison, S.G., Morrison, R.P., Ault, K.A. and Bryne, G.I. Seroreactivity to Chlamydia trachomatis Hsp10 correlates with severity of human genital tract disease. Infect. Immun., 2000, 68, 303-309.
19. La Verda, D., Kalayoglu, M.V. and Bryne, G.IChlamydial heat shock proteins and disease pathology: new paradigms for old problems? Infect. Dis. Obstet. Gynecol., 1999, 7, 64-71.
20. Vogelmann R, M.R. Amieva. The role of bacterial pathogens in cancer Curr. Opin. Microbiol., 2007, 10, pp. 76-81.
21. Arnheim Dahlström, K. Andersson, T. Luostarinen, S. Thoresen, H. Ögmundsdottír, L. Tryggvadottír, F. Wiklund, G.B. Skare, C. Eklund, K. Sjölin, et al..B Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer Cancer Epidemiol. Biomarkers Prev., 20 2011, pp. 2541-2550.
22. Koskela, P., T. Anttila, T. Bjorge, A. Brunsvig, J. Dillner, M. Hakama, T. Hakulinen, E. Jellum, M. Lehtinen, P. Lenner, T. Luostarinen, E. Pukkala, P. Saikku, S. Thoresen, L. Youngman, and J. Paavonen.. Chlamydia trachomatis infection as a risk factor for invasive cervical cancer. Int. J. Cancer 2000, 85:35-39.
23. Shanmughapriya S, G. Senthilkumar, K. Vinodhini, B.C. Das, N. Vasanthi, K. Natarajaseenivasan . Viral and bacterial aetiologies of epithelial ovarian cancer Eur. J. Clin. Microbiol. Infect. Dis., 2012, 31, 2311-2317.
24. Mpiga P, Ravaoarinoro M. Chlamydia trachomatis persistence: an update. Microbiol Res. 2006, 161(1):9-19.
25. Gurumurthy R K, Mäurer A P., Machuy N, Hess S, Pleissner K P., Schuchhardt J, Rudel T and Meyer T F. A Loss-of-Function Screen Reveals Ras- and Raf-Independent MEK-ERK Signaling During Chlamydia trachomatis Infection. Science Signaling 2010, 3 (113), ra21.
26. Vignola M J., Kashatus D F., Taylor G A., Counter C M., and Valdivia R H. cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis. J Biol Chem. 2010 285(28): 21625–21635.
27. Abdul-Sater, N. Saïd-Sadier, V.M. Lam, B. Singh, M.A. Pettengill, F. Soares, I. Tattoli, S. Lipinski, S.E. Girardin, P. Rosenstiel, D.M. Ojcius. Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1 J. Biol. Chem., (2010) 285, 41637-41645.
28. Greene W., Zhong G. Inhibition of host cell cytokinesis by Chlamydia trachomatis infection. J. Infect. 2003, 47:45–51.
29. Fujiwara T., et al.. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005, 437:1043–1047.
30. Ganem N. J., Storchova Z., Pellman D. Tetraploidy, aneuploidy, and cancer. Curr. Opin. Genet. Dev. 2007, 17:157–162.
31. Hamon and Cossart, M.A. Hamon, P. Cossart .Histone modifications and chromatin remodeling during bacterial infections Cell Host Microbe, 2008, 4 , 100-109.
32. Schmeck B, W. Beermann, P.D. N’Guessan, A.C. Hocke, B. Opitz, J. Eitel, Q.T. Dinh, M. Witzenrath, M. Krüll, N. Suttorp, S. Hippenstiel. Simvastatin reduces Chlamydophila pneumoniae-mediated histone modifications and gene expression in cultured human endothelial cells .Circ. Res., 2008 102, 888-895.
33. Pennini M.E, S. Perrinet, A. Dautry-Varsat, A. Subtil .Histone methylation by NUE, a novel nuclear effector of the intracellular pathogen Chlamydia trachomatis PLoS Pathog., 6 (2010), p. e1000995.
34. Füllgrabe et al., 2011 J. Füllgrabe, E. Kavanagh, B. Joseph. Histone onco-modifications Oncogene, 30 2011, 3391-3403.
35. Knowlton Andrea E., Heather M. Brown, Theresa S. Richards, Lauren A. Andreolas, Rahul K. Patel, and Scott S. Grieshaber (2011) Chlamydia trachomatis infection causes mitotic spindle pole defects independently from its effects on centrosome amplification. Traffic. 2011 12(7): 854–866.
36. Fan, T., H. Lu, H. Hu, L. Shi, G. A. McClarty, D. M. Nance, A. H. Greenberg, and G. Zhong. Inhibition of apoptosis in chlamydia-infected cells: blockade of mitochondrial cytochrome c release and caspase activation. J. Exp. Med. 1998, 187:487-496.
37. Greene W., Xiao Y., Huang Y., McClarty G., Zhong G. Chlamydia-infected cells continue to undergo mitosis and resist induction of apoptosis. Infect. Immun. 2004. 72, 451–460
38. Grieshaber S.S., Grieshaber N.A., Miller N., Hackstadt T. Chlamydia trachomatis causes centrosomal defects resulting in chromosomal segregation abnormalities Traffic, (2006), 7. 940-949.
39. Di Micco R.., Sulli G., Dobreva M, Liontos M., Botrugno O.A., Gargiulo G., G.dal Zuffo G., Matti V., d’Ario G., Montani E., et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer Nat. Cell Biol., 13 (2011), pp. 292-302.
40. Roberts P.J. and Der, C.J.Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer Oncogene, 26 (2007), 3291-3310.
41. Xia, M.S., Bumgarner, R.E., Lampe, M.F. and Stamm, W.E. chlamydia trachomatis infection alters host Cell transcription in diverse Cellular pathways. J Infect Dis (2003) 187, 424-434.
42. Bliska, J.B., Galan, J.E. and Falkow, S. Signal transduction in the mammalian cell during bacteria attachment and entry. Cell, 1993, 73, 903-920.
43. Birkelund, S., Johnson, H. and Christiansen, G. Chlamydia trachomatis serovar L2 induces protein tyrosine phosphorylation during uptake by Hela cells. Infect. Immun., 1994, 62, 4900-4908.
44. Fawaz, F.S., Van Ooij, C. and Homola, E. Infection with Chlamydia trachomatis alters the tyrosine phosphorylation and/or localization of several host cell protein including contacting. Infect. Immun., 1997, 5, 301-5308.
45. Miller K.M, Jackson S.P. Histone marks: repairing DNA breaks within the context of chromatin Biochem. Soc. Trans., 40 (2012), pp. 370-376.
46. O’Driscoll M, P.A. Jeggo. The role of double-strand break repair - insights from human genetics Nat. Rev. Genet., 7 (2006), pp. 45-54.
47. Clayton A.L., Mahadevan L.C., MAP kinase-mediated phosphoacetylation of histone H3 and inducible gene regulation FEBS Lett., (2003), 546 51-58.
48. Dehoux P, Flores R, Dauga C, Zhong G, Subtil A. Multi-genome identification and characterization of Chlamydiae-specific type III secretion substrates: the Inc proteins. BMC Genomics. 2011; 12:109.
49. Lutter EI, Martens C, Hackstadt T. Evolution and conservation of predicted inclusion membrane proteins in Chlamydiae. Comp. Funct. Genomics. 2012; 2012:362104.
50. Moore ER, Ouellette SP. Reconceptualizing the chlamydial inclusion as a pathogen-specified parasitic organelle: an expanded role for Inc proteins. Front. Cell. Infect. Microbiol. 2014; 4:157.
51. Hackstadt T. In: Intracellular Pathogens 1: Chlamydiales. Tan M, Bavoil PM, editors. Vol. 1. ASM press; 2012. pp. 126–148.
52. Gauliard E, Ouellette SP, Rueden KJ, Ladant D. Characterization of interactions between inclusion membrane proteins from Chlamydia trachomatis. Front. Cell. Infect. Microbiol. 2015; 5:13.
53. Mital J, Miller NJ, Fischer ER, Hackstadt T. Specific chlamydial inclusion membrane proteins associate with active Src family kinases in microdomains that interact with the host microtubule network. Cell. Microbiol. 2010; 12:1235–1249.
54. Mital J, Miller NJ, Dorward DW, Dooley CA, Hackstadt T. Role for chlamydial inclusion membrane proteins in inclusion membrane structure and biogenesis. PLoS ONE. 2013; 8:e63426.
55. Mirrashidi KM, et al. Global mapping of the Inc–human interactome reveals that retromer restricts Chlamydia infection. Cell Host Microbe. 2015; 18:109–121.
56. Ajonuma LC, Chan PSK, Ng EHY, Fok KL, Wong CHY, Tsang LL, Tang XX, Ho LS, Lau MC, Chung CM, He Q, Huang HY, Yang DZ, Rowlands DK, Chung YW, Chan HC Involvement of Cystic fibrosis transmembrane conductance regulator (CFTR) in the pathogenesis of hydrosalpinx induced by Chlamydia trachomatis infection. J Obstet. Gynaecol. Res. (2008) 34,923–30.
57. Ajonuma LC, Ng EHY, Tsang LL, Cheung ANY, Chow PH, Hung CY, Briton-Jones C, Lok IH, J Haines CJ, Chan HC Increased cystic fibrosis transmembrane conductance regulator (CFTR) expression in human hydrosalpinx. Hum. Reprod. 20, 1228–34.
58. Deluca GD, Basiletti J, Schelover E, Vásquez ND, Alonso JM, Marín HM, Lucero RH, Picconi MA.( 2011) Chlamydia trachomatis as a probable cofactor in human papillomavirus infection in aboriginal women from northeastern Argentina. Braz J Infect Dis. (2005) 15(6):567-72.
59. Knowlton A E., Fowler L J., Patel R K, Wallet S M., Grieshaber S S. Chlamydia induces Anchorage Indepence in 3T3 cells and Detrimental cytological Defects in an infection model. Plos one, (2013) 8(1): e54022.
60. Smith, J. S., C. Bosetti, N. Munoz, R. Herrero, F. X. Bosch, J. Eluf-Neto, C. J. Meijer, A. J. Van Den Brule, S. Franceschi, and R. W. Peeling. Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study. Int. J. Cancer 2004, 111:431-439.
61. Di Felice, V., S. David, F. Cappello, F. Farina, and G. Zummo. Is chlamydial heat shock protein 60 a risk factor for oncogenesis? Cell. Mol. Life Sci. (2005). 62:4-9.
62. Hinkula, M., E. Pukkala, P. Kyyronen, P. Laukkanen, P. Koskela, J. Paavonen, M. Lehtinen, and A. Kauppila. A population-based study on the risk of cervical cancer and cervical intraepithelial neoplasia among grand multiparous women in Finland. Br. J. Cancer (2004). 90:1025-1029.
63. Naucler, P., H. C. Chen, K. Persson, S. L. You, C. Y. Hsieh, C. A. Sun, J. Dillner, and C. J. Chen. Seroprevalence of human papillomaviruses and Chlamydia trachomatis and cervical cancer risk: nested case-control study. J. Gen. Virol. 2007.88:814-822.
64. Paavonen, J., K. P. Karunakaran, Y. Noguchi, T. Anttila, A. Bloigu, J. Dillner, G. Hallmans, T. Hakulinen, E. Jellum, P. Koskela, M. Lehtinen, S. Thoresen, H. Lam, C. Shen, and R. C. Brunham. Serum antibody response to the heat shock protein 60 of Chlamydia trachomatis in women with developing cervical cancer. Am. J. Obstet. Gynecol. 2003.189:1287-1292.
65. Wallin, K. L., F. Wiklund, T. Luostarinen, T. Angstrom, T. Anttila, F. Bergman, G. Hallmans, I. Ikaheimo, P. Koskela, M. Lehtinen, U. Stendahl, J. Paavonen, and J. Dillner. A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma. Int. J. Cancer 2002. 101:371-374.
66. Anttila, T., P. Saikku, P. Koskela, A. Bloigu, J. Dillner, I. Ikaheimo, E. Jellum, M. Lehtinen, P. Lenner, T. Hakulinen, A. Narvanen, E. Pukkala, S. Thoresen, L. Youngman, and J. Paavonen. Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. JAMA 2001. 285:47-51.
67. Madeleine, M. M., T. Anttila, S. M. Schwartz, P. Saikku, M. Leinonen, J. J. Carter, M. Wurscher, L. G. Johnson, D. A. Galloway, and J. R. Daling. Risk of cervical cancer associated with Chlamydia trachomatis antibodies by histology, HPV type and HPV cofactors. Int. J. Cancer 2007, 120:650-655.
68. Kiviat, N. B., J. A. Paavonen, J. Brockway, C. W. Critchlow, R. C. Brunham, C. E. Stevens, W. E. Stamm, C. C. Kuo, T. DeRouen, and K. K. Holmes. Cytologic manifestations of cervical and vaginal infections. I. Epithelial and inflammatory cellular changes. JAMA 1985. 253:989-996.
69. Samoff, E., E. H. Koumans, L. E. Markowitz, M. Sternberg, M. K. Sawyer, D. Swan, J. R. Papp, C. M. Black, and E. R. Unger.. Association of Chlamydia trachomatis with persistence of high-risk types of human papillomavirus in a cohort of female adolescents. Am. J. Epidemiol. 2005 162:668-675.
70. Silins, I., W. Ryd, A. Strand, G. Wadell, S. Tornberg, B. G. Hansson, X. Wang, L. Arnheim, V. Dahl, D. Bremell, K. Persson, J. Dillner, and E. Rylander. Chlamydia trachomatis infection and persistence of human papillomavirus. Int. J. Cancer 2005.116:110-115.
71. Schlott, T., H. Eiffert, W. Bohne, J. Landgrebe, E. Brunner, B. Spielbauer, and B. Knight. Chlamydia trachomatis modulates expression of tumor suppressor gene caveolin-1 and oncogene c-myc in the transformation zone of non-neoplastic cervical tissue. Gynecol. Oncol. 2005. 98:409-419.
How to Cite
AJONUMA, Louis C et al. The role of Chlamydia trachomatis in the pathogenesis of female reproductive organs cancers. International Archives of Medicine, [S.l.], v. 11, aug. 2018. ISSN 1755-7682. Available at: <>. Date accessed: 21 sep. 2018. doi:
Obstetrics & Gynecology