What causes prostate cancer? Why is prostate cancer so common in the United States and Western cultures? Why is prostate cancer infrequent in China and Japan (tenfold to fortyfold less)? Clues to these puzzling questions may come from studies of liver cancer.
We now know that the main cause of liver cancer, a leading cause of death in East Asia, Africa, and Asia, stems from the hepatitis B virus. This virus causes chronic hepatitis, a condition in which the immune system, perhaps over the course of 20 to 30 years, is actively trying to eradicate the infection. Certain immune cells are capable of releasing toxic oxygen- and nitrogen-based chemicals termed "radicals" that can kill bacteria and viruses. However, they can also damage our own cells. If DNA is replicated in the setting of excess oxygen/nitrogen radicals, chemical reactions involving DNA may take place, giving rise to mutations. Mutations thus formed are permanent and are transmitted to all daughter cells. When genes involved in cell growth are mutated, cancer may result. Thus, the same system that frequently saves us from infection can damage tissues and lead to cancer--a case of "friendly fire." Interestingly, dietary factors have been shown to dramatically increase the rate of liver cancer beyond that seen with viral infection. For example, the highest prevalence of liver cancer in China occurs in areas where the naturally occurring fungal toxin aflatoxin (similar to bread molds) is endemic. While any agent that repeatedly damages the liver and causes chronic inflammation (e.g., alcohol) can lead to liver cancer, the relatively low rate of Hepatitis B infection in this country is likely the reason why liver cancer is uncommon in the United States. Notably, cancers of the stomach, colon, bladder, esophagus, and bile ducts have all been associated with the process of chronic inflammation. Might chronic inflammation be involved in the formation of prostate cancer?
Research from a number of investigators at Johns Hopkins University, and elsewhere, has generated a provocative new hypothesis that may answer these questions. Based on microscopic and molecular biology data, we have proposed that areas of prostate atrophy, which are usually associated with inflammation and are extremely common and widespread in older men in the United States, increase the risk of prostate cancer development. While the cause of chronic inflammation in the prostate remains unknown, clues that inflammation may be involved in prostate carcinogenesis have emerged. Familial genetic studies have demonstrated an increased risk of prostate cancer in men with inherited variants of several genes (e.g., RNAseL, MSR1) associated with inflammation. Furthermore, alterations of genes known to be active during the inflammatory process, such as those involved in defenses against inflammatory damage (e.g., GSTP1), are extremely common in prostate cancer specimens. Additional evidence that oxidant damage is critical for prostate cancer development comes from reports suggesting a decreased risk of prostate cancer in men consuming adequate amounts of anti-oxidants such as vitamin E, selenium, lycopene, and soy.
The consumption of red meats and well-done or charred meats has been associated with both the occurrence and lethality of prostate cancer; Westerners consume more red meat than people in Asia. The most prevalent of the carcinogens found in charred meats, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), has been shown to cause prostate cancer in laboratory rats. Using an original animal model, our preliminary data indicate that viral-induced prostate inflammation incited in the context of dietary PhIP exposure markedly increases the rate of prostate DNA mutations and, importantly, produces chronic prostate inflammation. This novel discovery suggests a provocative hypothesis: The deleterious effects of dietary carcinogens may be augmented by the presence of prostate inflammation and that prostate inflammation, itself, may be potentiated by dietary carcinogens.
Employing our animal model, we propose to (1) assess the ability of candidate dietary prostate cancer preventive agents (e.g., broccoli tea, soy, vitamin E, lycopene) to alter DNA mutagenesis and chronic prostate inflammation, (2) determine the capacity of alternative methods of inciting acute prostate inflammation (e.g., heat-killed bacteria and portions thereof known to induce inflammation) to induce chronic inflammation, and (3) determine the ability of virally induced prostate inflammation to accelerate prostate carcinogenesis.
The proposed research may yield the mechanisms by which proposed dietary prostate cancer preventive agents affect prostate DNA mutagenesis, chronic inflammation, and carcinogenesis, thus providing rationale for human clinical trials with candidate compounds for the prevention and/or treatment of prostate cancer. Vitamin E and selenium are already in clinical trials to prevent prostate cancer. If the addition of inflammation to PhIP can accelerate prostate cancer beyond that obtained by PhIP alone (Aim 3), our model may offer an innovative system in which the interactions between dietary carcinogens and inflammation in the development of prostate cancer may be studied. This information may prove to be essential in understanding how prostate cancer develops and, therefore, in designing new strategies to prevent it.