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Infection induced chronic inflammation and it's association with prostate cancer initiation and progression
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An association between cancer development and inflammation has long been suggested. Approximately 20% of all human cancers in adults are assumed to result from chronic inflammation. The aim of this thesis was to investigate if infection-induced chronic inflammation plays a role in prostate carcinogenesis.

Our results revealed a greater infiltration of the bacterium Propionibacterium acnes in the prostate tissue obtained from men with prostate cancer compared to men without any histological evidence of the disease. These findings indicate that prostate cancer could potentially be included in the list of cancers with an infectious etiology.

Further, we investigated whether chronic inflammation has a role in disease progression. Our results demonstrated that men with lethal prostate cancer had pronounced infiltration of immune cells with suppressive function of the anti-tumor immune response compared to men with a more indolent prostate cancer.

Confirmation of our results may open up avenues for targeted prostate cancer treatment by offering men with chronic inflammation alternative therapies such as anti-inflammatory drugs. If the involvement of P. acnes in prostate cancer development is replicated in other studies, vaccination therapies may be feasible. To further individualize prostate cancer therapy, bolstering the anti-tumor immune response in order to reduce tumor progression may be determined to be advantageous for some patients.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2013. , p. 65
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 86
Keywords [en]
Prostate cancer, chronic inflammation, CD4 helper T cells, CD8 cytotoxic T cells, regulatory T cells, Propionibacterium acnes
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-28466ISBN: 978-91-7668-920-2 (print)OAI: oai:DiVA.org:oru-28466DiVA, id: diva2:612760
Public defence
2013-05-31, Wilandersalen, Universitetssjukhuset i Örebro, Södra Grev Rosengatan 18, 703 62 Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-03-25 Created: 2013-03-25 Last updated: 2017-10-17Bibliographically approved
List of papers
1. Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer
Open this publication in new window or tab >>Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer
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2011 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 10, p. 2280-2287Article in journal (Refereed) Published
Abstract [en]

Background: A challenge in prostate cancer (PCa) management is identifying potentially lethal disease at diagnosis. Inflammation, focal prostatic atrophy, and prostatic intraepithelial neoplasia (PIN) are common in prostate tumor specimens, but it is not clear whether these lesions have prognostic significance. Methods: We conducted a case-control study nested in a cohort of men diagnosed with stage T1a-b PCa through transurethral resection of the prostate in Sweden. Cases are men who died of PCa (n = 228). Controls are men who survived more than 10 years after PCa diagnosis without metastases (n = 387). Slides were assessed for Gleason grade, inflammation, PIN, and four subtypes of focal prostatic atrophy: simple atrophy (SA), postatrophic hyperplasia (PAH), simple atrophy with cyst formation, and partial atrophy. We estimated OR and 95% CI for odds of lethal PCa with multivariable logistic regression. Results: Chronic inflammation and PIN were more frequently observed in tumors with PAH, but not SA. No specific type of atrophy or inflammation was significantly associated with lethal PCa overall, but there was a suggestion of a positive association for chronic inflammation. Independent of age, Gleason score, year of diagnosis, inflammation, and atrophy type, men with PIN were 89% more likely to die of PCa (95% CI: 1.04-3.42). Conclusion: Our data show that PIN, and perhaps presence of moderate or severe chronic inflammation, may have prognostic significance for PCa. Impact: Lesions in tumor adjacent tissue, and not just the tumor itself, may aid in identification of clinically relevant disease. Cancer Epidemiol Biomarkers Prev; 20(10); 2280-7. (C) 2011 AACR.

National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-30105 (URN)10.1158/1055-9965.EPI-11-0373 (DOI)000295717900034 ()
Available from: 2013-08-02 Created: 2013-08-02 Last updated: 2018-05-05Bibliographically approved
2. Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin
Open this publication in new window or tab >>Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin
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2012 (English)In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 18, no 4, p. 392-399Article in journal (Refereed) Published
Abstract [en]

Propionibacterium acnes is a gram-positive bacillus predominantly found on the skin. Although it is considered an opportunistic pathogen it is also been associated with severe infections. Some specific P. acnes subtypes are hypothesized to be more prone to cause infection than others. Thus, the aim of the present study was to investigate the ability to discriminate between P. acnes isolates of a refined multilocus sequence typing (MLST) method and a genotyping method, DiversiLab, based on repetitive-sequence-PCR technology.

The MLST and DiversiLab analysis were performed on 29 P. acnes isolates of diverse origins; orthopedic implant infections, deep infections following cardiothoracic surgery, skin, and isolates from perioperative tissue samples from prostate cancer. Subtyping was based on recA, tly, and Tc12S sequences.

The MLST analysis identified 23 sequence types and displayed a superior ability to discriminate P. acnes isolates compared to DiversiLab and the subtyping. The highest discriminatory index was found when using seven genes. DiversiLab was better able to differentiate the isolates compared to the MLST clonal complexes of sequence types.

Our results suggest that DiversiLab can be useful as a rapid typing tool for initial discrimination of P. acnes isolates. When better discrimination is required, such as for investigations of the heterogeneity of P. acnes isolates and its involvement in different pathogenic processes, the present MLST protocol is valuable.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Propionibacterium acnes; Multilocus sequence typing (MLST); DiversiLab; Discrimination index; Molecular epidemiology
National Category
Microbiology in the medical area
Research subject
Microbiology
Identifiers
urn:nbn:se:oru:diva-25346 (URN)10.1016/j.anaerobe.2012.04.015 (DOI)000307688500003 ()22609518 (PubMedID)2-s2.0-84864371234 (Scopus ID)
Note

Funding Agencies:

Örebro County Council Research Committee

Foundation for Medical Research at Orebro University Hospital, Sweden 

Available from: 2012-08-27 Created: 2012-08-27 Last updated: 2018-04-16Bibliographically approved
3. Prevalence and typing of Propionibacterium acnes in prostate tissue obtained from men with prostate cancer and from health controls
Open this publication in new window or tab >>Prevalence and typing of Propionibacterium acnes in prostate tissue obtained from men with prostate cancer and from health controls
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(English)Manuscript (preprint) (Other academic)
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-30106 (URN)
Available from: 2013-08-02 Created: 2013-08-02 Last updated: 2017-10-17Bibliographically approved
4. CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer
Open this publication in new window or tab >>CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer
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2013 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, no 3, p. 448-455Article in journal (Refereed) Published
Abstract [en]

Prostate cancer represents a major contributor to cancer mortality, but the majority of men with prostate cancer will die of other causes. Thus, a challenge is identifying potentially lethal disease at diagnosis. Conflicting results have been reported when investigating the relationship between infiltration of lymphocytes and survival in prostate cancer. One of the mechanisms suggested is the recruitment of regulatory T cells (T(regs)), a subpopulation of T cells that have a role in promoting tumor growth. T(regs) counteract tumor rejection through suppressive functions on the anti-immune response but their prognostic significance is still unknown. We report here the results of a conducted case-control study nested in a cohort of men treated with transurethral resection of the prostate and diagnosed incidentally with prostate cancer. Cases are men who died of prostate cancer (n=261) and controls are men who survived >10 years after their diagnosis (n=474). Infiltration of both T(helper) and T(cytotoxic) cells was frequently observed and the majority of the T(regs) were CD4(+). T(helper) or T(cytotoxic) cells were not associated with lethal prostate cancer. However, we found a nearly twofold increased risk of lethal prostate cancer when comparing the highest with the lowest quartile of CD4(+) T(reg) cells (95% confidence interval: 1.3-2.9). Our conclusion is that men with greater numbers of CD4(+) T(regs) in their prostate tumor environment have an increased risk of dying of prostate cancer. Identification of CD4(+) T(regs) in tumor tissue may predict clinically relevant disease at time of diagnosis independently of other clinical factors.Modern Pathology advance online publication, 5 October 2012; doi:10.1038/modpathol.2012.164.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-27801 (URN)10.1038/modpathol.2012.164 (DOI)000315664100015 ()23041830 (PubMedID)2-s2.0-84875209263 (Scopus ID)
Available from: 2013-03-01 Created: 2013-03-01 Last updated: 2018-08-27Bibliographically approved

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