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Expression of Toll-like receptor-9 is associated with poor progression-free survival in prostate cancer, "Beyond the Abstract," by Katri Selander, MD, PhD and Markku Vaarala, MD, PhD

BERKELEY, CA (UroToday.com) - Toll-like receptor-9 (TLR9) is an innate immune system DNA-receptor that was originally thought to recognize only microbial DNA.[1] It is now well established that beyond the immune system, TLR9 is also widely expressed in various cancer cell lines and in clinical cancer specimens such as prostate cancer.[2, 3, 4] It is also now known that self-DNA, derived from the cancer cells, can be recognized by TLR9.[5] Stimulation of TLR9 with synthetic TLR9-ligands or with bacterial DNA induces rapid inflammation, characterized by increased expression of cytokines and interleukins.[6] In the case of an invading microbe, this innate immune response also eventually activates the adaptive immune response, resulting in the neutralization of the invading organism.[6] In cancer cells, bacterial DNA as well as DNA that is derived from dead cancer cells also induce invasion.[2, 5] Whether or not TLR9 contributes to pathophysiology of any cancer has, however, remained unclear.

Our results in prostate cancer suggest that high tumor TLR9 expression predicts poor outcome.[3, 4] Is TLR9 only a biomarker, or does it actually contribute to the pathogenesis of prostate cancer? Based on our in vitro studies, we believe that tumor TLR9 does, indeed, affect the course of the disease. First, we have shown that TLR9 mediates hypoxia-induced invasion in various brain cancer cells in vitro.[7] Similar with prostate cancers, high TLR9 expression has been shown to predict poor prognosis in brain cancers.[8] Since prostate cancers typically are hypoxic,[9] we propose that a similar TLR9-mediated invasion in hypoxia is one reason for the poor prognosis. This needs to be experimentally demonstrated.

Second, we have also shown that bacterial DNA induces TLR9-mediated invasion in prostate cancer cells in vitro.[2] Thus, the occurrence of prostatic infection could also partially explain why high TLR9 expression is associated with poor prognosis in patients with prostate cancer. These hypotheses require further studies using pre-clinical animal models with prostate cancer cells whose TLR9 expression has been experimentally modified.

In conclusion, further experimentation may reveal TLR9 as novel target for controlling prostate cancer.

References:

  1. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K. et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature, 408, 740-745.
  2. Ilvesaro, J.M., Merrell, M.A., Swain, T.M., Davidson, J., Zayzafoon, M., Harris, K.W. and Selander, K.S. (2007) Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate, 67, 774-781.
  3. Vaisanen, M.R., Jukkola-Vuorinen, A., Vuopala, K.S., Selander, K.S. and Vaarala, M.H. (2013) Expression of Toll-like receptor-9 is associated with poor progression-free survival in prostate cancer. Oncology Letters, 5, 1659-1663.
  4. Vaisanen, M.R., Vaisanen, T., Jukkola-Vuorinen, A., Vuopala, K.S., Desmond, R., Selander, K.S. and Vaarala, M.H. Expression of toll-like receptor-9 is increased in poorly differentiated prostate tumors. Prostate, 70, 817-824.
  5. Tuomela, J., Sandholm, J., Kaakinen, M., Patel, A., Kauppila, J.H., Ilvesaro, J., Chen, D., Harris, K.W., Graves, D. and Selander, K.S. (2013) DNA from dead cancer cells induces TLR9-mediated invasion and inflammation in living cancer cells. Breast Cancer Res Treat.
  6. Akira, S. and Hemmi, H. (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett, 85, 85-95.
  7. Umemura, S., Yasuda, M., Osamura, R.Y., Kawarada, Y., Sugiyama, T. and Tsutsumi, Y. (1996) Enhancement of TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method using mung bean nuclease, a single-stranded DNA digestion enzyme. J Histochem Cytochem, 44, 125-132.
  8. Wang, C., Cao, S., Yan, Y., Ying, Q., Jiang, T., Xu, K. and Wu, A. TLR9 expression in glioma tissues correlated to glioma progression and the prognosis of GBM patients. BMC Cancer, 10, 415.
  9. Sooriakumaran, P. and Kaba, R. (2005) Angiogenesis and the tumour hypoxia response in prostate cancer: a review. Int J Surg, 3, 61-67.

Written by:
Katri Selander, MD, PhDa and Markku Vaarala, MD, PhDb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aAssistant professor, Dept. of Medicine, Division of Hematology and Oncology
University of Alabama at Birmingham
Birmingham, AL, U.S.A

bChief Urologist, Division of Operative Care
Oulu University Hospital
Oulu, Finland

Expression of Toll-like receptor-9 is associated with poor progression-free survival in prostate cancer - Abstract

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