“Everything You Need to Know About Prostate Cancer

“Everything You Need to Know About Prostate Cancer: Basic Research, Causes, Diagnosis, and Treatment” University of Chicago Urology Research Laboratory Donald Vander Griend Ph.D. University of Chicago 2005 Huggins Lectureship NOTES: • Lectures and information are posted on the Ben May Institute for Cancer Research Website. URL: http://ben-may.bsd.uchicago.edu/bmi/presentations/3rd/research.htm • Next Time (Feb 5th, Lecture 4) is in Room 120 in this building. • UofC Section of Urology: 773-702-1860 Lecture Outline 1. Jan 15 - The Problem, The Prostate, and The Man 2. Jan 22 - What is Cancer? 3. TODAY - The Causes of Prostate Cancer 4. Feb 5 - Diagnosing Prostate Cancer 5. Feb 12 - Treating Prostate Cancer 6. Feb 19 - Prostate Cancer Metastasis 7. Feb 26 - Hormones and Prostate Cancer 8. March 5 - Emerging and Novel Treatment Techniques - Hope for the Future  Cellular division is a common and tightly regulated process.  Many genes encode proteins that regulate cell division. Oncogenes promote cell division and Tumor Suppressor Genes block cell division.  Changes (mutations) in these genes can cause uncontrolled cell division and the formation of a tumor.  Metastasis is the process whereby tumor cells move to other organs and form secondary tumors.  Cancer is a difficult disease to eradicate. If You Recall…Lecture 2 What Is Cancer? The Causes of Prostate Cancer Risk Deciphering risk studies Age Race and Ethnicity Genetic Factors Diet Hormones Reducing the Risk of Prostate Cancer What Really Causes Cancer?  Abnormal cell proliferation.  These changes occur because the genes controlling cell division become damaged or mutated.  Thus, anything that causes DNA damage can cause cancer. 1. Physical damage to DNA 2. Blockage of DNA repair enzymes 3. Disallow DNA error-checking by abnormally accelerating cell division “Causing” Cancer  Agents that cause cancer are really agents that cause DNA damage and increase the risk of developing cancer. Determining Risk Etiology – the study of causes or origins of disease. Purpose: to identify, understand, and quantify factors or agents that have a role in the development of disease. Establish an association between two factors. Assign a relative risk number (normal non-risk = 1) Example of Relative Risk: Smoking and Lung Cancer Observed Deaths from Lung Cancer in Smokers Expected Deaths from Lung Cancer in Non-Smokers = = Relative Risk of Dying From SmokingInduced Lung Cancer 20/day b/4 age 18; 643 deaths Current smoker 40 deaths Age 60-64 Quit between age 30-34 126 deaths 40 deaths 16.1 Relative Risk = 3.2 Relative Risk Evaluating Prostate Cancer Risk Studies I Sample size and distribution: How many people participated? What ages? Where were they from? Event: Did they measure incidence or mortality? Readout: How did they measure it? PSA alone, DRE, biopsy? Evaluating Prostate Cancer Risk Studies II  Time: Over how long did they look? Three years minimum, ideally 5-10 years.  Comparison: What were their controls? Should be aged-matched. Young men and women are poor controls for prostate cancer.  How Much: What is the relative risk? How strong was the association? Evaluating Prostate Cancer Risk Studies III What other parameters where taken into consideration? Geography and environment Before vs. after PSA test How closely patients were monitored Details, Details, Details…. Criteria For a Strong Association A high relative risk. Consistency between different studies. A graded response to a graded dose. That is, the greater amount of agent, the greater the risk. Establishing a cause and effect (i.e. exposure must precede cancer). A plausible mechanism to explain how the agent causes cancer. ? Factors that Increase the Risk of Developing Prostate Cancer Rates differ as much as 90-fold among populations. These differences can be used to discover risk factors. Risk factors include: Age, Race & Ethnicity, Diet, and Hormones Age and Prostate Cancer Besides gender, age is the most established risk factor for prostate cancer. 1000 Rate Per 100,000 800 600 400 200 0 Prostate Cancer Incidence in 1995 50-59 60-69 70 and over Age and Prostate Cancer Approximately 75% of new prostate cancer patients are older than 65 years of age. However, the incidence of diagnosis in men age 50-59 has increased significantly since the 1970s. Attributed to PSA and is considered a screening effect. Prostate Cancer Incidence 150 Rate per 100,000 125 100 75 50 25 0 Age-Adjusted Incidence Why the Large Differences Between Race and Ethnicity? Caused by a combination of underlying differences: 1. Genetic 2. Exposure to factors in environment 3. Cultural and dietary differences 4. Fear of doctors and medicine 5. Cancer registration and differences in health care What About Asian-Americans? Asian-American men have a higher incidence of prostate cancer than Asian men. Rate per 100,000 50 40 30 20 10 0 Age-Adjusted Incidence Tianjin, CHINA Chinese Hiroshima, Japanese Los Ang. JAPAN Los Ang. USA USA Rate per 100,000 100 150 200 250 300 50 0 Incidence Prostate Cancer in American Men Average Mortality Incidence Mortality Black White Incidence Mortality Why The Difference Between White and Black Americans?  Not entirely clear.  Some observations: • Still true after adjusting for socioeconomic, clinical, and pathologic variables (i.e. disease status at diagnosis, access to health care). • African American men received aggressive treatment for advanced prostate cancer less often. • Post-surgical survival was lower (1.8 years).  Suggest some as yet undefined predisposition for an increased risk of developing prostate cancer. Hereditary Factors Affected first degree relative (brother or father) increases risk 2 to 3 fold. Men with two or three affected first degree relatives have a 5 to 11 fold increase risk. Strong association of developing prostate cancer between monozygotic twins. Genes and Prostate Cancer These hereditary associations point to a gene or set of genes that may have a role in prostate cancer. Scientists have conducted many large and genome-wide studies of these families. No single gene or chromosomal region has been implicated. However, some hot-spots have been identified. Prostate Cancer Chromosomal Hot Spots  A chromosome is a large molecule of DNA that contains many genes.  Humans have 23 chromosome pairs received from each parent (46 total).  Hotspots for prostate cancer have been identified on chromosomes 1, 8, 17, 20, and X.  The gene(s) responsible is (are) either unknown or intensely debated. Chromosome Insulin-Like Growth Factor 1 (IGF-1)  What is it? A secreted and circulating protein that stimulates cell proliferation and protects cells from death (apoptosis).  Binds to IGF-1 Receptors on cells.  Highly variable between individuals.  Men with very high levels of circulating IGF-1 have an increased risk of developing prostate cancer (RR=4.3) IFG-1 (ligand) IFG-1R (receptor on cell surface) Cell Ligand activates Receptor – Signals to promote cell division and block apoptosis. Diet  Increased risk is associated with a “Western Lifestyle”.  High intake of fat, meat, and dairy products.  Fatty acids are the major player. Fat and Prostate Cancer Strong world-wide correlation between prostate cancer and levels of fat consumption. Men on a high fat diet have an increased risk of developing prostate cancer. Red meat and animal fat were the two strongest factors. Calculated Relative Risk of 1.6. May also be due a lack of vegetables. What is Fat? Water in-soluble hydrocarbon chains. Also called lipids or fatty acids. Many varieties in nature Many important functions: energy storage, protection (myelin), cellular barriers and membranes. H HO H H O=C-C-C(14-20)-C-H H HH Saturated: All Single C-C bonds Unsaturated: Double C=C bonds Triple C C bonds Fatty Acid How Does Fat Cause Prostate Cancer? COOH Fat Molecule Raises Androgen Levels Source of Free Radicals Carcinogenic Fat Metabolites Accelerated Proliferation of Prostate Cells Damage of DNA Accelerated Proliferation of Prostate Cells Androgens and Prostate Cancer  Clearly, androgens are important for the growth and survival of prostate cells.  It is thought that abnormally elevated androgen levels result in accelerated proliferation of prostate cells and prostatic tumorigenesis.  Factors that affect androgen levels: high fat consumption, obesity, heavy alcohol usage.  Several studies have shown that men with very high levels of testosterone have a relative risk of ~2.3-2.6 of developing prostate cancer. Regulation of Testosterone Hypothalamus GnRH Pituitary (Gonadotropins) LH & FSH (Gonadotropin Releasing Hormone) Some agents abnormally interfere Testosterone Testes Prostate Growth and Function Occupation and Prostate Cancer Risk Men with heavy cadmium exposure (welders and electroplate workers) have a weakly increased risk of developing prostate cancer. Mechanism: cadmium interferes with zinc, a crucial element for many DNArepair proteins. Sexual Activity and Vasectomy Sexual Activity: No consistent association with prostate cancer risk. Vasectomy: No significant association with prostate cancer risk (Debated Relative risk = 1.1 – 1.2) ? Reducing the Risk of Prostate Cancer 1. Vitamin E 2. Phyto-estrogens 3. Lycopene 4. Selenium Vitamin E Vitamin E and Prostate Cancer  Vitamin E is a potent anti-oxidant found in vegetable oils, seeds, grains, nuts, and other foods.  Also called alpha-tocopherol.  Discovered in a large Finnish Study while testing Vitamin E supplements for effects on lung cancer.  No noticeable effect on lung cancer, but a 32% decrease in prostate cancer incidence and a 41% decrease in prostate cancer mortality.  No clear mechanism of preventative action. Phyto-Estrogens  Estrogen-like compounds found in nature.  Block androgen production just like estrogen.  Less potent than estrogen.  Most studied are the Flavonoids found in soybeans and red clover.  High level of consumption in Asia. Estrogen Flavone Estrogens and Phyto-Estrogens Block Testosterone Production Hypothalamus GnRH LH & FSH Estrogen Pituitary Testosterone Prostate Growth and Function Testes Lower Testosterone production and decrease prostate cell proliferation Lycopene  Potent anti-oxidant present at high-concentrations in tomatoes.  In a comparison between men who consumed large vs. small quantities of tomato sauce, there was a 36% lower incidence of prostate cancer.  No effect from tomato juice. Lycopene Lycopene Mechanism  Protect prostatic epithelial cells from DNA damage.  Block the effects of IGF-1 on prostate cell proliferation. Lycopene DNA Damage Prostate Cell IFG-1 (ligand) IFG-1R (receptor on cell surface) Ligand activates Receptor – Signals to promote cell division and block apoptosis.  Trace mineral component in water and soil.  Interest in selenium stemmed from the observation that mortality from certain cancers was lower in states with high soil selenium concentrations.  Discovered a role for prostate cancer from a large study investigating selenium supplements and skin cancer.  Prostate cancer incidence was 66% lower in the selenium group compared to the placebo group. Selenium Selenium Mechanisms  Anti-oxidant to prevent DNA damage.  Enhance immune system to detect and destroy cancer cells.  Promotes cancer cell death.  Decrease levels of androgen. Negligence: The Greatest Risk Prostate cancer mortality has decreased as greater numbers of men are screened for prostate cancer. If caught at an early stage, prostate cancer is not necessarily lethal. If someone is at a higher risk, they should be regularly screened. Currently there is no curative treatment for metastatic prostate cancer. ? Next Time – Room 120 DETECTING PROSTATE CANCER  PSA  Kallikrein Tumor Markers  Digital Rectal Exam  Biopsy STAGING PROSATE CANCER  The TNM staging system  Histologic Grading: The Gleason Score  Post-Surgical Evaluation  Imaging Bone Metastases Sources Used  Epidemiology, Etiology, and Prevention of Prostate Cancer. Reiter RE and deKernion JB. Campell’s Urology, 8th Edition.  Risk Factors for Prostate Cancer. Brawley OW. UpToDate.com  Prostate Cancer Epidemiology. Grönberg H. The Lancet, 361: 859-864, 2004.