When looking at prostate cancer tissue under the microscope, a strange phenomenon is often seen: in addition to cancer cells and some abnormal precancerous cells, there is a wilted, sickly-looking cell that can divide rapidly and is surrounded by long-standing inflammation. This is no accident; the phenomenon is common in patients with prostatitis and prostate cancer. Dr. Marzo, a pathologist and oncologist at Hopkins University School of Medicine, suspects that inflammation may be both a cause and a symptom of prostate cancer, and this support is currently growing. If this is the case, it may one day be possible to treat or prevent prostate cancer simply by lowering the body’s immune response. Inflammation is a double-edged sword The immune system is a fickle one, protecting the body from pathogens and smothering the pre-cancerous cells that are on the move; however, inflammation is at the center of the body’s immune action and can be unnecessarily damaging when controlling pathogens, so it is a “double-edged sword. Over the past 20 years, scientists have begun to try to clarify how chronic inflammation actually causes tumors. The classic example is gastric cancer, where persistent H. pylori infection can lead to gastric cancer, and inflammation also seems to play a role in liver, colon and bladder cancers. Professor Lucia, a pathologist at the Anschutz Medical School in Colorado, believes that about 1 in 5 cancers is attributable to inflammation. Results from animal and human studies suggest that inflammation may also be the cause of prostate cancer, although clear evidence is lacking because most of the specimens studied were human ex vivo prostate specimens, most often due to biopsies performed for elevated PSA. PSA is produced by the prostate gland and elevated levels indicate the possibility of prostate cancer, but chronic inflammation alone can also lead to elevated PSA, so men with prostate inflammation are more likely to undergo biopsy and have a better chance of finding small, overlooked tumors. To avoid this confirmation bias, Dr. Marzo and colleagues used data from the Prostate Cancer Prevention Trial, which was conducted from 1993 to 2004 to determine whether finasteride could prevent prostate cancer. All participants who did not have a biopsy during the study were biopsied at the end of the study, regardless of PSA level. A total of 400 men in the trial were treated with placebo, half of whom had a previous diagnosis of prostate cancer. A study of non-cancerous prostate tissue specimens revealed that 78% of specimens from patients without prostate cancer had inflammation, while inflammation was more common in about 86% of specimens from patients with prostate cancer and 88% of patients with the more aggressive high-grade prostate cancer, suggesting an association between prostate cancer and inflammation, with an increased risk of cancer, especially high-grade cancer, with increased inflammation. Although Dr. Marzo’s study confirms the relationship between inflammation and prostate cancer, it does not answer the question of which is the cause and which is the effect, nor does it answer the question of whether the risk of prostate cancer is reduced if inflammation is removed. Infection and diet If inflammation does contribute to the development of prostate cancer, what is the cause? Infection may bear the brunt of the problem. Studies as early as the 1950s found that prostate cancer was more common in uncircumcised men, leading to the suggestion that prostate cancer may be promoted by a sexually transmitted pathogen that is more likely to be found in uncircumcised men. Population-based studies support this hypothesis, particularly that gonorrhea, chlamydia and trichomonas infections are associated with an increased risk of prostate cancer. Although such infections can now be rapidly controlled with antimicrobials, rodent models have shown that short-term infections can trigger long-term inflammatory responses. Professor Sfanos, a pathologist at Hopkins University School of Medicine, found that inflammation in the prostate gland persisted for the rest of the animal’s life after the bacterial infection was cleared in rats or mice, and that even a single infection could lead to a chronic inflammatory response. Sexually transmitted bacteria and protozoa are not the only pathogens that can invade the prostate, which is also highly likely to be continuously exposed to microorganisms due to the passage of the urethra through the prostate. sfanos demonstrated that E. coli associated with urinary tract infections can cause an inflammatory response in the rodent prostate. Propionibacterium acnes, which is associated with skin acne, can also cause an inflammatory response in the prostate: Propionibacterium acnes can be cultured in inflammatory prostate tissue, leading to the finding that men with a history of severe acne have a significantly higher risk of dying from prostate cancer. Professor Platz of the Hopkins School of Public Health believes that in addition to infections that may lead to chronic inflammation of the prostate, diet may also play a role. Studies have found that certain specific foods may increase or decrease the risk of prostate cancer, such as a diet rich in red meat (especially burnt meat) appears to increase the risk of prostate cancer. marzo and his colleagues found that rats fed PhIP (a carcinogenic complex, abundant in fully cooked meat) had increased inflammatory cells in the ventral lobe of the prostate and were prone to cancer. Epidemiological studies have shown that foods with anti-inflammatory effects such as soy and green tea are associated with a lower incidence of prostate cancer. Marzo believes that a combination of many factors may be responsible for chronic inflammation of the prostate, and that some factors have the ability to target the prostate, and that infectious and dietary factors alone may be responsible for targeting the prostate in combination with each other and leading to prostate cancer. Carcinogenic leakage Marzo calls the wilted, sickly-looking cells proliferative inflammatory atrophy (PIA). After noticing PIA, Marzo began studying prostate inflammation and found that the cells in PIA damage proliferated at a rate almost identical to cancer cells, and sometimes the PIA cells fused with abnormal cells from prostatic intraepithelial neoplasia (PIN, often considered a precancerous prostate lesion), along with chronic signs of inflammation around the PIA. In summary, it appears that inflammation is the initial manifestation, which then leads to the development of damage. Proliferative inflammatory atrophy may be a precursor to prostate cancer or prostatic intraepithelial neoplasia, and this damage is mostly associated with chronic inflammation. Inflammatory cells can produce oxidants that cause DNA damage and secrete a number of signaling cytokines that are important for the regulation of surrounding cells and promote their proliferation. In other words when oxidative stress is present, there is genetic instability and uncontrolled cell division in the mix of PIA, PIN and inflammatory cells, leading to the first step in cancer production. Not all inflammatory cells are anti-cancerous and only some of them can prevent the spread of precancerous damage, which still needs to be further clarified. One cytokine called growth differentiation factor (GDF-15), which has a role in regulating inflammation and slows colon tumor growth in animals, is common in healthy prostate tissue but rare in chronic inflammatory prostate specimens, so GDF-15 may act as a switch in inflammation and have a protective effect on the prostate, and if GDF-15 is suppressed, chronic inflammation can develop. In addition GDF-15 may also inhibit the production of pro-tumor factors by certain inflammatory cells, which may be useful in preventing prostate cancer. The possible risk of inflammatory cells increasing prostate cancer development can be explored by counting and localizing different types of inflammatory cells in the prostate, starting with inflammatory cells that have been shown to be associated with the development of other cancers. The researchers hope this work will suggest which inflammatory cells are harmful to the body and which are protective, and clarify which inflammatory cell associations are beneficial and which pools of cells are harmful and allow cancer to progress to more advanced stages. Physicians can use physical examination laboratory tests to identify which immune cells are present in the prostate tissue of cancer patients, in addition to clarifying which type of inflammatory cells or more types of immune cells have prognostic value, and if they can indicate prognosis it is possible to direct follow-up examinations. If it can be confirmed that infection is a cause of prostate cancer development, then research work on inflammation has important implications for the prevention of prostate cancer and may prevent many prostate-related diseases by treating inflammation.