Oncotarget

Commentaries:

Mycoplasma and cancer: in search of the link

PDF |  HTML  |  Order a Reprint

Oncotarget. 2011; 2:271-273. https://doi.org/10.18632/oncotarget.264

Metrics: PDF 1396 views  |   HTML 2822 views  |   ?  

Melissa B. Rogers _

Abstract

Melissa B. Rogers

*Biochemistry & Molecular Biology, UMDNJ - NJ Medical School, Newark, New Jersey

Commentary on: Barykova, YA, DY Logunov, MM Shmarov, AZ Vinarov, DN Fiev, NA Vinarova, IV Rakovskaya, PS Baker, I Shyshynova, AJ Stephenson, EA Klein, BS Naroditsky, AL Gintsburg, and AV Gudkov, Association of Mycoplasma hominis infection with prostate cancer. Oncotarget, 2011; in press.

Received: April 18, 2011; Accepted: April 19, 2011; Published: April 19, 2011;

Correspondence:

Melissa B. Rogers, e-mail:


264

Identifying links between specific infectious agents and cancer greatly impacts the prevention of these cancers. Furthermore, understanding the role of cellular factors that mediate the effect of infectious agents may reveal additional cancer control strategies. A potential association between cancers and infection with mycoplasma, the smallest self-replicating prokaryote, has been suspected since the 1960’s (reviewed in [1]). However, early evidence was weakened by the difficult culture conditions demanded by these fastidious microbes. More recent studies have used techniques such as PCR, immunohistochemistry, and serum antibody status. These improved detection methods have shown that healthy individuals are often colonized without obvious clinical effects [2, 3]. Later studies continue to support an association between various species of mycoplasma and human cancers (e.g., [4-8]).

This study by Barykova et al. [7] is the latest of several that indicate a strong link between mycoplasma species and prostate cancer [8, 9]. Barykova et al. used real time PCR to demonstrate that Mycoplasma hominis levels in biopsies from patients with high-grade prostatic intraepithelial neoplasia (HGPIN) or prostate cancer (PCa) were triple that of patients with benign prostatic hyperplasia (BPH, p = 0.002). Other species commonly found in the urogenital tract, M. genitalium and Ureaplasma urealitycum, were detected at a lower frequency. Most significantly, no mycoplasma species were detected in control samples from lesion free men. Culturing confirmed the presence of M. hominis and U. urealitycum in prostate tissue (M. genitalium was not cultured). Finally, antibodies against M. hominis protein p120 were detected in the serum of HGPIN or PCa patients twice as frequently as in patients with BPH. The Barykova et al. study is corroborated by another study that determined that PCa patients were more likely to bear antibodies against U. urealitycum [8]. Finally, M. genitalium and M. hyorhinis infection caused the malignant transformation of benign human prostate (BPH-1) cells in vitro [9].

Laboratory studies strongly support the ability of mycoplasma to cause or promote oncogenic transformation. Several different species have been proven to transform rodent and human lines of diverse lineages in vitro [9-12]. Many plausible mechanisms would explain this pro-cancer effect: the induction of genetic instability [11, 13, 14], alterations in metabolism [2, 3, 15], and dramatic changes in the expression of many genes. Specific genes include known tumor suppressors and oncogenes [16, 17] and many potent cell signals, such as pro-inflammatory cytokines and other growth factors [15, 18-21]. Infected tumor cells or adjacent infected cells may synthesize cytokines and growth factors that promote the growth of nascent tumor cells. Increased growth rate, along with increased mutation rate, would facilitate the transformation of infected cells.

We were the first to demonstrate that mycoplasma oncogenically transformed human lung cells [12]. We also discovered that mycoplasma species rank among the best known inducers of bone morphogenetic protein (BMP) 2 [12]. This is particularly relevant to lung cancer, because BMP2 RNA and protein levels are abnormally elevated in lung tumors [22-24]. BMP2 activates pro-oncogenic pathways (e.g., PI3K/mTOR; Smad1,5/Id-1) and promotes lung tumor growth in mice [25-27]. The BMP2 antagonist, noggin, reduces mixed metastatic lung cancer lesions in bone [28] and the growth of transformed lung cells in monolayer and in soft agar [12]. Finally, high BMP2 levels are associated with poor patient survival [29].

At the least, mycoplasma infection is a potential biomarker for prostate malignancy. At best, the prostate cancer/mycoplasma link suggests that more aggressive antibiotic treatment of mycoplasma-infected men may be beneficial. Although smoking is the most important cause of lung cancer, other factors contribute to the development of lung cancer [30]. Proof that mycoplasma also influences lung cancer would facilitate the prevention and/or treatment of lung cancer. In addition, understanding the signals such as BMP2 that mediate the effect of mycoplasma may reveal other therapeutic options for a disease that is the leading cause of cancer deaths in the United States.

References

1. Cimolai, N, Do mycoplasmas cause human cancer? Can J Microbiol, 2001; 47: p. 691-7.

2. Waites, KB, B Katz, and RL Schelonka, Mycoplasmas and ureaplasmas as neonatal pathogens. Clin Microbiol Rev, 2005; 18: p. 757-89.

3. Waites, KB and DF Talkington, Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev, 2004; 17: p. 697-728.

4. Huang, S, JY Li, J Wu, L Meng, and CC Shou, Mycoplasma infections and different human carcinomas. World J Gastroenterol, 2001; 7: p. 266-9.

5. Pehlivan, M, G Itirli, H Onay, H Bulut, M Koyuncuoglu, and S Pehlivan, Does Mycoplasma sp. play role in small cell lung cancer? Lung Cancer, 2004; 45: p. 129-30.

6. Pehlivan, M, S Pehlivan, H Onay, M Koyuncuoglu, and Z Kirkali, Can mycoplasma-mediated oncogenesis be responsible for formation of conventional renal cell carcinoma? Urology, 2005; 65: p. 411-4.

7. Barykova, YA, DY Logunov, MM Shmarov, AZ Vinarov, DN Fiev, NA Vinarova, IV Rakovskaya, PS Baker, I Shyshynova, AJ Stephenson, EA Klein, BS Naroditsky, AL Gintsburg, and AV Gudkov, Association of Mycoplasma hominis infection with prostate cancer. Oncotarget, 2011; in press.

8. Hrbacek, J, M Urban, E Hamsikova, R Tachezy, V Eis, M Brabec, and J Heracek, Serum antibodies against genitourinary infectious agents in prostate cancer and benign prostate hyperplasia patients: a case-control study. BMC Cancer, 2011; 11: p. 53.

9. Namiki, K, S Goodison, S Porvasnik, RW Allan, KA Iczkowski, C Urbanek, L Reyes, N Sakamoto, and CJ Rosser, Persistent exposure to Mycoplasma induces malignant transformation of human prostate cells. PLoS One, 2009; 4: p. e6872.

10. Feng, SH, S Tsai, J Rodriguez, and SC Lo, Mycoplasmal infections prevent apoptosis and induce malignant transformation of interleukin-3-dependent 32D hematopoietic cells. Mol Cell Biol, 1999; 19: p. 7995-8002.

11. Tsai, S, DJ Wear, JW Shih, and SC Lo, Mycoplasmas and oncogenesis: persistent infection and multistage malignant transformation. Proc Natl Acad Sci U S A, 1995; 92: p. 10197-201.

12. Jiang, S, S Zhang, J Langenfeld, SC Lo, and MB Rogers, Mycoplasma infection transforms normal lung cells and induces bone morphogenetic protein 2 expression by post-transcriptional mechanisms. J Cell Biochem, 2007; 104: p. 580-594.

13. Fogh, J and H Fogh, Chromosome Changes in Pplo-Infected Fl Human Amnion Cells. Proc Soc Exp Biol Med, 1965; 119: p. 233-8.

14. Paton, GR, JP Jacobs, and FT Perkins, Chromosome changes in human diploid-cell cultures infected with Mycoplasma. Nature, 1965; 207: p. 43-5.

15. Miller, CJ, HS Kassem, SD Pepper, Y Hey, TH Ward, and GP Margison, Mycoplasma infection significantly alters microarray gene expression profiles. Biotechniques, 2003; 35: p. 812-4.

16. Zhang, B, JW Shih, DJ Wear, S Tsai, and SC Lo, High-level expression of H-ras and c-myc oncogenes in mycoplasma-mediated malignant cell transformation. Proc Soc Exp Biol Med, 1997; 214: p. 359-66.

17. Logunov, DY, DV Scheblyakov, OV Zubkova, MM Shmarov, IV Rakovskaya, KV Gurova, ND Tararova, LG Burdelya, BS Naroditsky, AL Ginzburg, and AV Gudkov, Mycoplasma infection suppresses p53, activates NF-kappaB and cooperates with oncogenic Ras in rodent fibroblast transformation. Oncogene, 2008; 27: p. 4521-31.

18. Yang, J, WC Hooper, DJ Phillips, and DF Talkington, Regulation of proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumoniae. Infect Immun, 2002; 70: p. 3649-55.

19. Zhang, S, S Tsai, and SC Lo, Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation. BMC Cancer, 2006; 6: p. 116.

20. Zhang, S, DJ Wear, and S Lo, Mycoplasmal infections alter gene expression in cultured human prostatic and cervical epithelial cells. FEMS Immunol Med Microbiol, 2000; 27: p. 43-50.

21. Yang, J, WC Hooper, DJ Phillips, and DF Talkington, Cytokines in Mycoplasma pneumoniae infections. Cytokine Growth Factor Rev, 2004; 15: p. 157-68.

22. Bieniasz, M, K Oszajca, M Eusebio, J Kordiak, J Bartkowiak, and J Szemraj, The positive correlation between gene expression of the two angiogenic factors: VEGF and BMP-2 in lung cancer patients. Lung Cancer, 2009; 66: p. 319-26.

23. Langenfeld, EM, J Bojnowski, J Perone, and J Langenfeld, Expression of bone morphogenetic proteins in human lung carcinomas. Ann Thorac Surg, 2005; 80: p. 1028-32.

24. Langenfeld, EM, SE Calvano, F Abou-Nukta, SF Lowry, P Amenta, and J Langenfeld, The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis, 2003; 24: p. 1445-54.

25. Langenfeld, EM, Y Kong, and J Langenfeld, Bone morphogenetic protein-2-induced transformation involves the activation of mammalian target of rapamycin. Mol Cancer Res, 2005; 3: p. 679-84.

26. Langenfeld, EM, Y Kong, and J Langenfeld, Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5. Oncogene, 2006; 25: p. 685-92.

27. Langenfeld, EM and J Langenfeld, Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res, 2004; 2: p. 141-9.

28. Feeley, BT, NQ Liu, AH Conduah, L Krenek, K Roth, WC Dougall, J Huard, S Dubinett, and JR Lieberman, Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and rank:Fc administration. J Bone Miner Res, 2006; 21: p. 1571-80.

29. Beer, DG, SL Kardia, CC Huang, TJ Giordano, AM Levin, DE Misek, L Lin, G Chen, TG Gharib, DG Thomas, ML Lizyness, R Kuick, S Hayasaka, JM Taylor, MD Iannettoni, MB Orringer, and S Hanash, Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med, 2002; 8: p. 816-24.

30. Sato, M, DS Shames, AF Gazdar, and JD Minna, A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol, 2007; 2: p. 327-43.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 264