Prostate news article, May 2007
WHAT ROLE DOES INFLAMMATION PLAY IN THE PATHOGENISIS OF PROSTATE CANCER?
Miles Goldstraw and Professor Roger Kirby (Chairman, Prostate UK) |
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The role of inflammation in the pathogenesis of prostatic disease is unclear. Armitage et al. [1] suggested that it may be responsible for the development and progression of LUTS but recently it has been suggested to be an aetiological factor in prostate cancer [2]. Certainly inflammation has an established role in the aetiology of a number of other malignancies including hepatocellular carcinoma and oesophageal cancer but the role in prostate cancer is less clear. Much of the evidence has arisen from epidemiological studies involving the use of non-steroidal anti-inflammatory drugs (NSAIDs) in this particular disease but this has given conflicting results.
There are a number of confounding factors making the exact role of inflammation difficult to study:
- The incidence of prostatitis is uncertain. While the incidence of symptomatic prostatitis in men over the age of 40 is approximately 5-10%, many men have the condition but are asymptomatic [3].
- Men with symptomatic prostatitis are diagnosed with prostate cancer more frequently due to the increased biopsy prevalence.
- The offending pathogen is not known in a large number of cases of symptomatic prostatitis
Despite these apparent difficulties, an increase in prostate cancer has been correlated with symptoms of prostatitis and with sexually transmitted infections independent of the specific pathogen. This suggests that it is the associated inflammation that is significant rather than a particular causal agent involved in prostate cancer. One population based case-control study noted an OR of 1.6 in men with a history of gonorrhea or syphilis which increased to 3.3 with ≥3 episodes of gonorrhea [4]. A recent meta-analysis of 29 case-control studies published between 1971 and 2003 agreed with these findings and reported significantly increased odds of prostate cancer for gonorrhoea and HPV [5].
The precise mechanism behind the carcinogenic effect of inflammation is unclear. One possibility is that recurrent microbial infections can lead to the production of inflammatory cytokine mediators and genotoxic reactive oxygen radicals that increase cell proliferation and promote tumourigenesis [6]. The precise host response to this inflammatory cascade may determine the likelihood of tumour development. Two important genes identified are the prostate cancer susceptibility genes, RNASEL and macrophage scavenger receptor (MSR1). RNASEL is a ribonuclease that degrades viral and cellular RNA and can produce apoptosis on viral infection. MSR1 encodes a macrophage scavenger receptor responsible for cellular uptake of molecules, including bacterial cell wall products. MSR1 and RNASEL may both be crucial modulators of the host response to infection.
If inflammation does have a significant pathogenic role then the purported use of NSAIDs may be expected to reduce the incidence of this disease. Several epidemiological studies have examined this interaction with somewhat mixed results. One significant study involved 90,100 Kaiser Permanente members and examined the effect of aspirin use over a 9-year using a health questionnaire. Over this period it was discovered that aspirin appeared to have a chemoprotective effect with an OR 0.76 (95% CI, 0.60-098) [7]. Another large study of 70,144 men taken from the American Cancer Society’s cancer prevention study II nutrition cohort broadly agreed with this finding noting that the beneficial effect was only in those taking regular medication for ≥5 years [8]. However, the Health Professions Follow-up Study, involving 47,882 men noted a beneficial trend for aspirin intake only for those with metastatic prostate cancer [9]. A meta-analysis of twelve studies undertaken prior to January 2003 revealed that while almost all studies found an inverse relationship between aspirin and prostate cancer only two of these cases were statistically significant. The summary OR was 0.9 (95% CI: 0.82-0.99; test of homogeneity p=0.32) decreasing to 0.85 for prospective studies [10].
The potential mechanism of action of NSAIDs is also unclear. In vitro data shows that NSAIDs induce apoptosis, inhibit angiogenesis and cell proliferation, and suppress prostate cancer metastasis. One major target for NSAIDs is cyclooxygenase (COX)-2 which regulates the production of various inflammatory prostaglandins. COX-2 is overexpressed in prostate cancer and appears to positively correlate with tumour grade [11]. Furthermore COX-2 receptors are expressed in inflammatory cells in the prostate including proliferative inflammatory atrophy (PIA) lesions, a suspected prostate cancer precursor, but not in prostate intraepithelial neoplasia (PIN) lesions or in prostate carcinomas [12]. Genetic polymorphisms may have a significant impact on the response to NSAID therapy; a subgroup may have a variant gene which provides a protective effect for NSAIDs. One recently identified gene polymorphism is the lymphotoxin alpha (LTA) +80CC genotype which was noted to result in a particularly strong inverse association between aspirin use and prostate cancer [13]. This may suggest that any chemoprevention with NSAIDs may be most advantageous for those with this genotype and could explain the conflicting results from clinical studies.
Diagnostic histopathologists have also suggested inflammation in the aetiology of prostate cancer. PIA consists of areas of focal atrophic lesions associated with chronic inflammation and it is commonly found in the peripheral zone of the prostate adjacent to foci of PIN or prostate cancer. Significantly these lesions are thought to arise as a consequence of the regenerative proliferation of prostate epithelial cells in response to injury caused by inflammatory oxidants [14]. Transition from PIA to PIN may be related to loss of the tumour suppressor gene, GSTP1. GSTP1 can detoxify environmental electrophilic carcinogens and oxidants and may play a genome caretaker role by preventing oxidant and electrophilic DNA damage [15]. Expression of GSTP1 is induced to high levels at sites of inflammation.
In conclusion, while there is no conclusive data supporting a role for inflammation in the pathogenesis of prostate cancer there does appear to be accumulating data in favour of this hypothesis. Epidemiological, molecular and histopathological evidence all point towards this diagnosis. With the widespread prescribing of aspirin to reduce cardiovascular risk is it time to start informing patients of a possible chemotherapeutic effect in prostate cancer?
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