Inflammation and Infection in the Etiology of Prostate Cancer

Introduction

The idea of a link between inflammation and cancer is not unique to prostate cancer (PCa). The idea of an association between inflammation and cancer dates back at least 150 years. In 1863, Virchow proposed that cancer originates at sites of chronic inflammation. Chronic inflammation has been estimated to contribute to 15–20% of cancers and has been linked specifically to stomach cancer from Helicobacter pylori infection, liver cancer after infection with hepatitis B and C, colon cancer in association with inflammatory bowel disease and pertaining to urology, and bladder cancer after infection with schistosomiasis.

Inflammation is commonly found in association with PCa, on the order of 60%. There is evidence for an association for inflammation with PCa, but some reports do not confirm this. We will review the evidence for histologic inflammation with PCa, the data for certain types of inflammatory lesions, for clinical prostatitis, biomarkers, infection, genetics of inflammatory markers, diet, and finally the data on chemoprevention by inhibiting inflammation.

Histologic prostatic inflammation and prostate cancer

Studies have explored the inflammation/PCa hypothesis by examining possible associations between histologic prostatic inflammation and PCa. While these studies provide some direct evidence toward this hypothesis, they are complicated by difficulties in obtaining “normal” prostate control tissue to which to compare tissue from PCa cases. Therefore, most studies to date have used more readily available prostate tissue, such as from men undergoing prostate biopsy for indication because of either abnormal DRE findings or, more commonly because of elevated prostate-specific antigen (PSA) levels. In general, these studies have tended to observe null or even protective findings, which are opposite to what would be expected based on an inflammation/PCa hypothesis. However, as PSA levels may rise for many different reasons, including both prostate inflammation and PCa, these null to protective findings may reflect the dual influence of inflammation and PCa on PSA – that is, in men diagnosed with PCa, the predominant contribution to PSA may be cancer or initially undiagnosed cancer, whereas in men who remain undiagnosed, one of the predominant contributions to PSA may be inflammation, thereby creating a protective association. In contrast to these findings, in the only studies, to our knowledge, to compare tissue from PCa cases to controls without regard to indication for biopsy, the opposite findings were generally observed. In a study conducted in the Prostate Cancer Prevention Trial (PCPT), in which a large proportion of men not diagnosed with PCa during the trial underwent a prostate biopsy at the end of the trial irrespective of indication, a positive association was observed between histologic prostatic inflammation and high-grade PCa. Although a null association was observed in another small autopsy study that compared histologic inflammation among men with and without histologic PCa, very few men had high-grade disease in this study. Finally, positive associations have also been observed between tumor-associated histologic inflammation at PCa diagnosis, accompanied sometimes by postatrophic hyperplasia, and subsequent PCa recurrence or death.

Proliferative inflammatory atrophy

The lesion that links inflammation with PCa is called proliferative inflammatory atrophy or PIA. Whereas most areas of prostatic atrophy are quiescent, areas of atrophy next to inflammation have been found to proliferate. These areas, called PIA, have been suggested as precursors to PCa either directly or indirectly by progression to PIN. Morphologic studies have reported transition from PIA to PIN and from PIA to cancer. Proliferation in PAH lesions is significantly greater than in BPH or SA, but less than in PIN and PCa.

There are biochemical changes in PIA lesions that are also found in PIN and PCa :

• Glutathione- S -transferases (GST) is a cellular enzyme that neutralizes reactive oxygen species (ROS). Methylation inactivates this enzyme, increasing the chance of oxidative damage. This is found in areas of PIA, PIN, and PCa, but not found in normal prostate cells.

• Amplification of chromosome 8, reported as a marker for poor prognosis in prostate adenocarcinoma.

• Protein products of three prostate tumor suppressor genes, NKX3.1, CDKN1B, which encodes p27 and PTEN (phosphatase and tensin homolog), are all downregulated in focal atrophy lesions – present in normal prostate, and frequently decreased or absent in PIN and cancer.

• There is decreased apoptosis attributed to increased Bcl-2 expression.

PIA also appears to go along with prognosis. Davidsson et al. looked at TURP specimens in which stage T1a-b PCa was diagnosed. They compared men who died of PCa with those who lived 10 years without metastasis. Chronic inflammation itself had no correlation with survival but when chronic inflammation was associated with areas of atrophy, there was a fivefold increase in risk of dying of PCa.

Mechanisms of inflammatory carcinogenesis

One of the hypotheses linking inflammation to PCa is that chronic inflammation leads to release of inflammatory mediators and free radicals that damage the cells. The cells then attempt to regenerate in this environment to repair themselves. The mediators are also genotoxic and the end result is an increased risk of mutation and malignant transformation. Cytokines from macrophages, T lymphocytes or even tumor cells themselves may contribute to malignant progression.

Several cytokines and inflammatory mediators have been implicated in the development of PCa.