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The role of microorganisms in prostate cancer development
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer is the most common cancer among Swedish men, but the aetiology of this disease is largely unknown. There is evidence for a linkage between chronic inflammation and prostate cancer. The mechanisms causing prostate inflammation and how this could promote tumour development and progression are however largely unknown. Chronic inflammatory infiltrates are common findings in prostate tissue samples and infection is proposed to be one possible cause for this inflammation. Inflammatory cells release free radicals, cytokines, and growth factors that facilitate increased cell proliferation, DNA damage, mutations, and angiogenesis. However, the present literature on the presence of microbes in prostate tissue and their possible linkage to inflammation and cancer development is limited. Therefore, the aim of this thesis was to investigate if microorganisms are present in prostate tissue and to evaluate their role in inducing prostatitis and prostate epithelial neoplasia.

The presence of microorganisms (virus, bacteria and fungi) was studied in clinical prostate tissue samples to evaluate whether or not the occurrences of microorganisms were different in patients that later developed cancer compared with matched controls that did not. Viruses, bacteria and fungi were found in prostate tissues. Out of eight different viruses investigated, EBV and JC virus were detected, but there were no differences in occurrence in the case group compared to the control group. The fungus Candida albicans was present in a very small proportion of the prostate tissue samples. The predominant bacterium was Propionibacterium acnes and the second most prevalent was Escherichia coli. The presence of Propionibacterium acnes was associated with inflammation and subsequent prostate cancer development. Propionibacterium acnes was further evaluated for its capacity to induce an inflammatory response both in vitro and in vivo. Live Propionibacterium acnes induced a strong immune reaction in prostate epithelial cells in vitro with up-regulation of inflammatory genes and secretion of pro-inflammatory cytokines. Infection with Propionibacterium acnes in rat prostate resulted in a lobe specific inflammation with the most intense inflammation in the dorso-lateral prostate, lasting up to 3 months post-inoculation. Propionibacterium acnes inflammation was also associated with altered epithelial cell morphology, signs of DNA damage and increased cell proliferation.

Taken together, this thesis shows that different viruses and bacteria can be found in prostate tissue. Propionibacterium acnes, the most abundant among the bacteria detected and more prevalent in the cancer than in the control group, exhibits strong prostatitis promoting properties both in vitro and in vivo. In addition, Propionibacterium acnes can induce some of the epithelial changes known to occur during prostate neoplasia formation. This thesis therefore suggests that Propionibacterium acnes induced chronic prostatitis could promote prostate cancer development. Further studies are needed to elucidate the molecular interplay linking Propionibacterium acnes induced inflammation and the formation of a pre-neoplastic state that could evolve into prostate cancer.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2012. , 46 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1521
Keyword [en]
prostate cancer, aetiology, inflammation, Propionibacterium acnes
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-59987ISBN: 978-91-7459-475-1 (print)OAI: oai:DiVA.org:umu-59987DiVA: diva2:557353
Public defence
2012-10-26, E04, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-10-05 Created: 2012-09-27 Last updated: 2013-01-22Bibliographically approved
List of papers
1. No link between viral findings in the prostate and subsequent cancer development
Open this publication in new window or tab >>No link between viral findings in the prostate and subsequent cancer development
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2007 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 1, 137-139 p.Article in journal (Refereed) Published
Abstract [en]

In an investigation of 201 prostate tissue samples from patients with benign prostate hyperplasia that later progressed to prostate cancer and 201 matched controls that did not, there were no differences in the prevalence of adenovirus, herpesvirus, papilloma virus, polyoma virus and Candida albicans DNA.

Place, publisher, year, edition, pages
London: Nature Publishing Group, 2007
Keyword
DNA virus, C. albicans, prostate, benign prostate hyperplasia
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-20655 (URN)10.1038/sj.bjc.6603480 (DOI)17117176 (PubMedID)
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2017-12-13Bibliographically approved
2. Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden)
Open this publication in new window or tab >>Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden)
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2006 (English)In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 17, no 9, 1127-1133 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To study bacterial 16S RNA in archival prostate samples from 352 patients with benign prostate hyperplasia (BPH) and evaluate whether the presence of bacterial DNA was different in those who later developed prostate cancer (n = 171) and in the matched controls that did not progress to cancer (n = 181).

Methods: 16S DNA PCR followed by cloning and sequencing the positive samples.

Results: In 96/352 (27%) of the prostate tissue specimens 16S RNA were detected. Sequence analysis revealed Propionibacterium acnes as the predominant microorganism (23% of 16S RNA positive patients). The second most frequent isolate—Escherichia coli was found in 12 (12%) patients. The other isolates included Pseudomonas sp. (3 patients), Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2),Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P. acnes positive samples 62% exhibited severe histological inflammation versus 50% in the bacteria-negative group (p = 0.602). The presence of P. acnes in the prostate was associated with prostate cancer development (OR 2.17, 95% CI 0.77–6.95).

Conclusions: This study has revealed P. acnes as the most common bacteria in the prostate in BPH. Further studies are needed to clarify its role in contributing to the development of prostatic inflammation and prostate cancer.

Place, publisher, year, edition, pages
Dordrecht: Kluwer Academic Publishers, 2006
Keyword
16S RNA, propionibacterium, prostate
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-13555 (URN)10.1007/s10552-006-0054-2 (DOI)
Available from: 2008-02-11 Created: 2008-02-11 Last updated: 2017-12-14Bibliographically approved
3. Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells
Open this publication in new window or tab >>Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells
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2010 (English)In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 10, 126- p.Article in journal (Refereed) Published
Abstract [en]

Background: The immune stimulating bacterium Propionibacterium acnes is a frequent colonizer of benign and malignant prostate tissue. To understand the pathogenesis of the earliest phase of this infection, we examined the P. acnes triggered immune response in cultivated prostate epithelial cells.

Results: Prostate epithelial cells are triggered to secrete IL-6, IL-8 and GM-CSF when infected with P. acnes. The secretion of cytokines is accompanied by NFκB related upregulation of the secreted cytokines as well as several components of the TLR2-NFκB signaling pathway.

Conclusions: P. acnes has potential to trigger a strong immune reaction in the prostate glandular epithelium. Upon infection of prostate via the retrograde urethral route, the induced inflammatory reaction might facilitate bacterial colonization deeper in the prostate tissue where persistent inflammation may impact the development of prostate diseases as hyperplasia and/or malignancy.

Place, publisher, year, edition, pages
BioMed Central, 2010
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-41876 (URN)10.1186/1471-2180-10-126 (DOI)000277522700001 ()20420679 (PubMedID)
Available from: 2011-04-01 Created: 2011-04-01 Last updated: 2017-12-11Bibliographically approved
4. Chronic prostatic infection and inflammation by propionibacterium acnes in a rat prostate infection model
Open this publication in new window or tab >>Chronic prostatic infection and inflammation by propionibacterium acnes in a rat prostate infection model
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, e51434- p.Article in journal (Refereed) Published
Abstract [en]

Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the Gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic inflammation may be induced by P. acnes infection.

Place, publisher, year, edition, pages
Public library of science, 2012
Keyword
bacterial inflammation; mouse prostate; cancer; hyperplasia; carcinogenesis; pathogenesis; castration; specimens; proteins; cells
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-63922 (URN)10.1371/journal.pone.0051434 (DOI)000312290800058 ()
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2017-12-06Bibliographically approved
5. Propionibacterium acnes induces chronic inflammation and precancerous epithelial lesions in the dorso-lateral prostate in rats
Open this publication in new window or tab >>Propionibacterium acnes induces chronic inflammation and precancerous epithelial lesions in the dorso-lateral prostate in rats
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-59980 (URN)
Available from: 2012-09-27 Created: 2012-09-27 Last updated: 2012-10-05Bibliographically approved

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