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Inflammation and prostate carcinogenesis: influence of immune characteristics and early-adulthood exposure to inflammatory conditions on prostate cancer risk
Örebro University, School of Medical Sciences.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic inflammation has been implicated in the development of several types of cancer, and evidence from observational and animal studies suggests that it may play a role also in prostate carcinogenesis. Recent observations have brought Cutibacterium acnes (C. acnes) forward as a possible causative agent in pro-oncogenic prostatic inflammation. However, evidence also suggest that underlying immune characteristics contribute to prostate cancer risk. The overall aim of this thesis was to explore potential mechanisms underlying the proposed link between inflammation and prostate cancer, by evaluating associations between inflammatory conditions during early adulthood, circulating inflammation markers, and prostate cancer. Due to the suggested role of C. acnes in both diseases, we aimed to investigate whether acne vulgaris is a determinant of prostate cancer. Using prospectively collected data from Swedish national registers, we observed that presence of acne during early adulthood conferred an increased risk of prostate cancer later in life. Similarly, we found that appendicitis before late adolescence – a proposed marker of individual immune characteristics – to be positively associated with subsequent prostate cancer. We further evaluated whether prostatic C. acnes infection is linked with elevated systemic levels of IL6 and CXCL8, two inflammation markers previously associated with prostate cancer. No association was observed, however, potentially explained by the subclinical low-grade infection typically caused by C. acnes. Finally, we evaluated 52 circulating inflammation markers as determinants for prostate cancer in a population-based case-control study. In this hypothesis-generating study, we identified CX3CL1, CCL21, PDGF-BB, CCL11 and IL10 as candidate markers for evaluation in prospective studies. If confirmed, these markers may hint at targetable molecular pathways involved in prostate carcinogenesis.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2019. , p. 100
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 191
Keywords [en]
Prostate cancer, inflammation, Cutibacterium acnes, acne, appendicitis, cytokines, circulating, inflammation marker, IL6, CXCL8
National Category
Surgery
Identifiers
URN: urn:nbn:se:oru:diva-72812ISBN: 978-91-7529-280-9 (print)OAI: oai:DiVA.org:oru-72812DiVA, id: diva2:1292267
Public defence
2019-05-10, Örebro universitet, Campus USÖ, hörsal C1, Södra Grev Rosengatan 32, Örebro, 12:30 (Swedish)
Opponent
Supervisors
Available from: 2019-02-27 Created: 2019-02-27 Last updated: 2019-04-10Bibliographically approved
List of papers
1. Acne in late adolescence and risk of prostate cancer
Open this publication in new window or tab >>Acne in late adolescence and risk of prostate cancer
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2018 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, p. 1580-1585Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence suggest that Propionibacterium acnes may play a role in prostate carcinogenesis, but data are so far limited and inconclusive. The aim of this population-based cohort study was therefore to test whether presence of acne vulgaris during late adolescence is associated with an increased risk of prostate cancer later in life. We identified a large cohort of young men born in Sweden between 1952 and 1956, who underwent mandatory assessment for military conscription around the age of 18 (n= 243,187). Test information along with health data including medical diagnoses at time of conscription was available through the Swedish Military Conscription Register and the National Patient Register. The cohort was followed through linkages to the Swedish Cancer Register to identify the occurrence of prostate cancer until December 31st 2009. We used Cox regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between acne in adolescence and prostate cancer risk. A total of 1,633 men were diagnosed with prostate cancer during a median follow-up of 36.7 years. A diagnosis of acne was associated with a statistically significant increased risk for prostate cancer (adjusted HR: 1.43 95%; CI: 1.06-1.92), particularly for advanced stage disease (HR: 2.37 95%; CI 1.19-4.73). A diagnosis of acne classified as severe conferred a 6-fold increased risk of prostate cancer (HR: 5.70 95% CI 1.42-22.85). Data from this large prospective population-based cohort add new evidence supporting a role of P acnes infection in prostate cancer.

Place, publisher, year, edition, pages
Hoboken, NJ, USA: John Wiley & Sons, 2018
Keywords
Propionibacterium acnes; prostate cancer; acne vulgaris; inflammation; acne vulgaris
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-63302 (URN)10.1002/ijc.31192 (DOI)000425184800009 ()29205339 (PubMedID)2-s2.0-85037982996 (Scopus ID)
Note

Funding Agency:

UK Economic and Social Research Council (ESRC)  RES-596-28-0001  ES/JO19119/1

Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2019-04-09Bibliographically approved
2. The influence of prostatic Cutibacterium acnes infection on serum levels of IL6 and CXCL8 in prostate cancer patients
Open this publication in new window or tab >>The influence of prostatic Cutibacterium acnes infection on serum levels of IL6 and CXCL8 in prostate cancer patients
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2018 (English)In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 13, article id 34Article in journal (Refereed) Published
Abstract [en]

Background: Chronic prostatic inflammation, caused by Cutibacterium acnes (C. acnes), has been proposed to influence the risk of prostate cancer development. In vitro studies have demonstrated the capacity of C. acnes to induce secretion of Interleukin 6 (IL6) and C-X-C motif chemokine ligand 8 (CXCL8) by prostate epithelial cells. Both these inflammatory mediators have been implicated in prostate cancer pathophysiology. In this cohort study, we aimed to investigate the influence of prostatic C. acnes on serum levels of IL6 and CXCL8.

Methods: We recruited 99 prostate cancer patients who underwent radical prostatectomy at orebro University Hospital. The cultivation of pre-operatively obtained prostate biopsies identified C. acnes in 60 of the 99 patients. Levels of IL6 and CXCL8 in pre-operative serum samples were analyzed using ELISA, and concentrations were compared between prostate cancer patients with and without prostatic C. acnes infection using standard statistical methods.

Results: No statistical differences were observed in serum levels of IL6 and CXCL8 between subjects with and without prostatic C. acnes infection.

Conclusions: Our results indicate that prostatic C. acnes infection may give rise to low-grade inflammation with little effect on systemic levels of IL6 and CXCL8.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Prostate cancer, Inflammation, Cutibacterium acnes, IL6, CXCL8, Cytokines
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:oru:diva-70366 (URN)10.1186/s13027-018-0204-7 (DOI)000450287500001 ()30473726 (PubMedID)2-s2.0-85056906445 (Scopus ID)
Note

Funding Agency:

Foundation Lions Cancerforskningsfond vid Akademiska sjukhuset i Uppsala 

Available from: 2018-11-29 Created: 2018-11-29 Last updated: 2019-04-08Bibliographically approved
3. Appendicitis before age 20 years is associated with an increased risk of later prostate cancer
Open this publication in new window or tab >>Appendicitis before age 20 years is associated with an increased risk of later prostate cancer
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2018 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 27, no 6, p. 660-664Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Appendicitis before age 20 years has been observed to influence the risk of several inflammatory conditions, possibly through underlying immunological mechanisms. Inflammation has further been suggested to be involved in prostate cancer development. We therefore hypothesized that immunological characteristics signaled by appendicitis before late adolescence might influence the risk of later prostate cancer, and aimed to evaluate this association in a population-based study.

METHODS: We identified a large cohort of Swedish men who underwent assessment for military conscription around the age of 18 years (n= 242,573). Medical diagnoses at time of conscription were available through the Swedish Military Conscription Register. The Swedish Cancer Register was used to identify diagnoses of prostate cancer. Multivariable adjusted Cox regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between appendicitis and prostate cancer.

RESULTS: During a median of 36.7 years of follow-up, 1,684 diagnoses of prostate cancer occurred. We found a statistically significant association between appendicitis and overall prostate cancer (adjusted HR: 1.70; 95% CI: 1.08-2.67). The risk was notably increased for advanced (HR: 4.42; 95% CI: 1.74-11.22) and lethal (HR: 8.95; 95% CI: 2.98-26.91) prostate cancer.

CONCLUSION: These results suggest that a diagnosis of appendicitis before adulthood potentially signals underlying immune characteristics and a pattern of inflammatory response relevant to prostate cancer risk.

IMPACT: The study lends support to the proposed role of inflammation in prostate carcinogenesis, and adds another area of investigation potentially relevant to prostate cancer development.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-66449 (URN)10.1158/1055-9965.EPI-17-1204 (DOI)000433945800006 ()29588305 (PubMedID)2-s2.0-85047896683 (Scopus ID)
Note

Funding Agency:

UK Economic and Social Research Council (ESRC)  RES-596-28-0001  ES/JO19119/1

Available from: 2018-04-13 Created: 2018-04-13 Last updated: 2019-04-09Bibliographically approved
4. Circulating inflammation markers and prostate cancer
Open this publication in new window or tab >>Circulating inflammation markers and prostate cancer
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(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:oru:diva-73573 (URN)
Available from: 2019-04-08 Created: 2019-04-08 Last updated: 2019-04-08Bibliographically approved

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