Case Report

First Report of Propionibacterium acnes in Prostate from Chilean Patients

Catherine Sánchez1*, Hector R. Contreras2, Iván Gallegos2, Takashi Ito3, Yoshinobu Eishi3, Juan Fulla1 and Christian Ramos1
1Department of Urology, Las Condes Clinic, Chile
2Department of Urology University of Chile, Chile
3Department of Urology, Tokyo Medical and Dental University, Japan


*Corresponding author: Catherine Sánchez Núñez, Department of Urology, Las Condes Clinic. Estoril 450, Las Condes, Santiago, Chile


Published: 25 Nov, 2016
Cite this article as: Sánchez C, Contreras HR, Gallegos I, Ito T, Eishi Y, Fulla J, et al. First Report of Propionibacterium acnes in Prostate from Chilean Patients. Clin Oncol. 2016; 1: 1143.

Abstract

Introduction: In prostate, inflammatory foci are usual and could be associated with chronic infections, and later with cancer development. Propionibacterium acnes were described as the most abundant bacteria in prostatic tissue and our goal was to detect it for the first time in prostate tissue samples of Chilean patients.
Material and Methods: Sixteen samples of prostate tissue from patients with cancer and benign prostatic hyperplasia were obtained from tissue bank from two clinical centers with authorization of the institutional ethics committee. Immunohistochemistry was performed to detect Propionibacterium acnes positive glands.
Results: Propionibacterium acnes was detected in 7 cancer samples (100%, n=7) and 4 non cancer samples (44%, n=9). In all cancer samples, the bacteria were mainly located in non-cancerous glands (100% of patients), with low presence in cancerous glands (only 4 patients, 57.1%). Inflammatory infiltrate associated with the presence of bacteria was not significant.
Conclusion: This is the first report of the presence of Propionibacterium acnes in prostate from Chilean patients. Consistent with other populations, its prevalence is high in prostate, moreover in patients with cancer, where the bacteria are located in non-tumor glands. Its presence, causing chronic infection, could have a role in prostate carcinogenesis.
Keywords: Propionibacterium acnes; Prostate cancer; Prostate


Introduction

Prostate cancer (PCa) is the second leading cause of cancer death among males in developed countries. At least one in six men will be diagnosed with CaP at some point in their lives [1]. In 2012, 2,045 men died from PCa in Chile, and its mortality, unlike other tumors, keeps rising [2].
Early diagnosis of the disease allows performing surgery or radiotherapy with curative intention, but in advanced stages there are no therapies that achieve significant survival improvement. The study of prostate carcinogenesis would help to develop new strategies to prevent progression, improve treatment and reduce the mortality associated with PCa in our country [3].
Prostate carcinogenesis is mainly related with somatic mutations and environmental factors. Among these last is chronic inflammation, which has been linked to the development of various types of cancer. Persistent Helicobacter pylori, Hepatitis B Virus, Schistosoma species and Bacteroides infection are risk factor for the development of gastric cancer, hepatocellular carcinoma, bladder cancer and colon respectively [4].
In prostate, proliferative inflammatory atrophy is a common finding abundant in inflammatory cells that was first described by De Marzo et al. [5] in 1999, who identified it as a precursor lesion of prostatic intraepithelial neoplasia. The inflammatory foci could be associated with bacteria that inhabit chronically prostate and could be responsible for the development of prostatic diseases. Within these, Propionibacterium acnes (P. acnes) are the most abundant bacteria in hyperplastic prostate tissue and its presence is more common in patients who were diagnosed with cancer later [6]. P. acnes are usually located on the skin and are the primarily responsible for acne. However, a number of reports have described its presence in other organs. Cohen et al. [7] reported that P. acnes are detected by culture in 35% of PCa samples. Fassi Fehri et al. [8] detected P. acnes by in situ immunofluorescence in 81.7% of samples from patients with PCa, while non-cancer patients tested negative for the bacteria.
The presence of P. acnes in prostate would activate an inflammatory response, which could trigger tumor development [5]. Cohen et al. [7] described in P. acnes positive prostatectomies samples a greater number of foci of acute or chronic inflammation compared to foci negative to the bacteria. Besides, Fassi Fehri et al. [8] described that P. acnes infection in prostate cells promotes a strong inflammatory response, while the chronic infection changes cell proliferation and growth. All these findings suggest a possible role of P. acnes in prostate carcinogenesis.
Despite the high prevalence of acne caused by P. acnes worldwide, and high presence of this bacteria in the prostate, acne have not relation with increased risk of developing PCa [9]. So far, little is known about the role of chronic infection by P. acnes in organs other than the skin and the prevalence of this infection in prostate patients of Latin-American population. That is why we decided, first, to detect P. acnes in prostates Chilean patients and the future to establish a relationship with tumor development.


Materials and Methods

Samples
Prostates samples formalin-fixed paraffin-embedded (FFPE), surgically obtained from patients with benign prostatic hyperplasia (BPH) and PCa were included. Samples were obtained from the Pathology Departments of two Chilean clinical centers. PCa samples included tumors with different Gleason Score.
The use of these samples was done under the consent of the institutional ethics committee.
Immunohistochemistry (IHC)
P. acnes were detected by IHC performed with previously characterized antibodies developed by the Department of Pathology from the Tokyo Medical and Dental University (Japan). The technique was performed according to protocols previously described, using FFPE liver samples from rats inoculated with the bacteria as positive control [10]. Prostate glands were considered as positive if at least one epithelial cell was positive to P. acnes. An institutional pathologist analyzed the presence of bacteria in normal and cancer glands.


Results

Samples of 9 patients without cancer (BPH) and 7 samples from patients with PCa with different Gleason Score (Table 1) were analyzed. Tissue sections were stained with hematoxylin and eosin for delimiting areas with cancerous tissue. Subsequently, in a serial cut, P. acnes presence was evaluated by IHC, using as positive control rat livers inoculated with the bacteria where it is detected primarily inside Kupffer cells (Figure 1a).
The presence of the bacteria was higher in cancer patients (Figure 1b), since the bacteria were detected in all PCa patients (100% positive) (Table 2). In these samples the bacteria were mainly located in non-cancerous glands (100% of the samples, Table 2, Figure 1c), while in cancerous glands its presence was very low, and was only found in 4 patients (57.1%, Figure 1d). The amount of positive cancer glands in the patients was significantly lower than in non-cancerous glands.
The inflammatory response associated with the presence of the bacteria was low. Foci of inflammatory infiltrate around cancerous and noncancerous glands were observed in cancer samples, with no relation with the presence of the bacteria.


Discussion

The results of this study allow us to demonstrate for the first time in Latin America, and particularly in Chilean patients, the presence of P. acnes in the prostate tissue.
There is small evidence about the prevalence of P. acnes in prostate worldwide, and our results confirm the few existing reports that were made in Asian population. Consistent with them, we found a high prevalence of the bacteria in samples of prostate tissue from patients Chileans, being greater in samples from PCa patients [6,7]. In these samples, the bacteria is present in cancerous glands, however, the amount of bacteria is higher in normal glands adjacent to tumor glands, according to what was reported in Asian populations [11,12]. In the samples analyzed, the bacteria were also found in patients without cancer. The presence of bacteria in normal glands, mainly those adjacent to the tumor, could be related to the development of cancer in the future, a phenomenon that has been reported previously [6].
To characterize the geographical distribution of the prostatic P. acnes infection is important because the strains isolated from prostate do not correspond to the same strains that cause acne (that have high prevalence and are distributed worldwide), but are similar strains of opportunistic infections and those located in urethral microflora [13]. These strains are able to induce chronic persistent inflammatory response with increased cell proliferation and decreased expression of the androgen receptor [14]. It is likely that the bacterial infection may not produce cancer, but as bacteria is located mainly in noncancer cells, the state of chronic inflammation could influence cancer development.
Inflammatory foci associated with infection were observed in some samples, especially in patients with PCa, although no difference between cancerous or infected hyperplastic glands was found. The foci of acute and chronic inflammation produce molecules with carcinogenic action. In particular, in infected glands the expression of NF-kB nuclear increases promoting prostate carcinogenesis [12].
Our results will allow us to continue large-scale studies that establish the relationship between the presence of P. acnes and PCa in order to establish possible molecular mechanisms to associate P. acnes, chronic inflammation and development PCa.


References

  1. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD. 2015.
  2. DEIS Ministerio de Salud Chile. Series de defunciones por tumor maligno, según sexo, Chile 2000 - 2012. Chile. 2012.
  3. Mottet N, Bastian PJ, Bellmunt J, Bergh R, Bolla M, Casteren N, et al. Guidelines on Prostate Cancer. 2015.
  4. Grivennikov SI, Greten FR, Karin M. Immunity, Inflammation, and Cancer. Cell. 2011; 140: 883-899.
  5. De Marzo AM, Marchi VL, Epstein JI, Nelson WG. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol. 1999; 155: 1985-1992.
  6. Alexeyev O, Marklund I, Shannon B, Golovleva I, Olsson J, Andersson C, et al. Direct visualization of Propionibacterium acnes in prostate tissue by multicolor fluorescent in situ hybridization assay. J Clin Microbiol. 2007; 45: 3721-3728.
  7. Cohen RJ, Shannon B, McNeal JE, Shannon T, Garrett KL. Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: a possible link to cancer evolution? J Urol. 2005; 173: 1969-1974.
  8. Fassi Fehri L, Mak TN, Laube B, Brinkmann V, Ogilvie L, Mollenkopf H, et al. Prevalence of Propionibacterium acnes in diseased prostates and its inflammatory and transforming activity on prostate epithelial cells. Int J Med Microbiol. 2011; 301: 69-78.
  9. Cremers RG, Aben KK, Vermeulen SH, den Heijer M, van Oort I, van de Kerkhof P, et al. Self-reported acne is not associated with prostate cancer. Urol Oncol Semin Orig Investig. 2014; 32: 941-945.
  10. Negi M, Takemura T, Guzman J, Uchida K, Furukawa A, Suzuki Y, et al. Localization of Propionibacterium acnes in granulomas supports a possible etiologic link between sarcoidosis and the bacterium. Mod Pathol. 2012; 25: 1284-1297.
  11. Chen Y, Wei J. Identification of pathogen signatures in prostate cancer using RNA-seq. PLoS One. 2015; 10: e0128955.
  12. Bae Y, Ito T, Iida T, Uchida K, Sekine M, Nakajima Y, et al. Intracellular Propionibacterium acnes infection in glandular epithelium and stromal macrophages of the prostate with or without cancer. PLoS One. 2014; 9: e90324.
  13. Mak TN, Yu S-H, De Marzo AM, Brüggemann H, Sfanos KS. Multilocus sequence typing (MLST) analysis of Propionibacterium acnes isolates from radical prostatectomy specimens. Prostate. 2013; 73: 770-777.
  14. Shinohara DB, Vaghasia AM, Yu S-H, Mak T, Brüggemann H, Nelson W, et al. A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. Prostate. 2013; 73: 1007-1015.