Prostate Cancer Lecture 1.doc

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Western University
Anatomy and Cell Biology
Anatomy and Cell Biology 4461B
Geordie Shepherd

JL Lecture 1: Overview of Prostate Cancer Prostate Cancer Quick Facts • Most common cancer in Canadian men; afflict 1/7, 1/27 will die Has one of the highest survival rates (5 year survival is 100% for localized and 30% for • metastatic cancer in North America) The Prostate • Exocrine organ • Consists of lobular tubulo-alveolar glands that secrete fluid through ducts that empty into the prostatic urethra • Produces some seminal fluid and may facilitate sperm motility; fluid comprises the bulk of seminal emissions and is rich is prostate-specific antigen (PSA) • PSA is produced from terminally differentiated luminal cells • Treatment of prostate cancer place urinary, sexual and bowel function at risk. Prostate Anatomy • Peripheral Zone • Bulk of normal gland • Most cancers originate here • Central Zone • Surrounds the ejaculatory ducts • Very few cancers originate here • Anterior Fibromuscular Stroma • Anterior band of fibromuscular tissue contiguous with the bladder smooth muscle and external sphincter • Transition Zone Located centrally and surrounds the urethra • • Enlarges as males grow older and becomes the dominant zone of the prostate • 15% of cancers originate here Prostate Cancer Initiation • Proliferative inflammatory atrophy (PIA) is likely the first histologic step in carcinogenesis; characterized by reduced cellular volume and rapid cycling • Prostatic intraepithelial neoplasia (PIN) is a histologic precursor of invasive malignancy; defined by cytologically atypical epithelial cells within architecturally benign-appearing acini • Separated into low and high-grade PIN • Only high-grade PIN (HGPIN) is considered a precursor of invasive carcinomas; may proceed the development of cancers by 10 years or more Risk Factors for Prostate Cancer Age • Most important risk for prostate cancer, rarely occurs in men under 40 Ethnicity • Black men have the highest incidence, Asian men have the lowest Family History • Men with a brother or father diagnosed with prostate cancer at age 50 are 2-fold more likely, men with more than one first degree relative diagnosed are 8-fold more likely to get prostate cancer. Diet and Lifestyle • Increased risk is associated with high-saturated fats, red meats, low fruits, low veg- etables, low fish and low soy. Vitamin D, omega-3, calcium and non-steroidal anti- inflammatory agents are implicated in reduced incidence. Obesity • Associated with high-grade cancers because of lower testosterone Gene Alterations • Develop from an accumulation of genetic alterations resulting in increased cell pro- liferation and reduced cell death • Linkage analysis has identified areas of susceptibility on multiple chromosomes • Genes of interest include: RNaseL, macrophage scavenger receptor-1 (MSR1) and ELAC2/HPC2 • Increased frequency of TMPRSS2:ERG oncogenic gene fusion occurs in moderate to poorly differentiated prostate cancers. Evidence suggests that this gene fusion may contribute to androgen independence through disruption of androgen-receptor signaling. This androgen driven promoter causes an overexpression of ETS tar- gets. • PTEN: tumor suppressor gene that suppresses the Akt pathway. 100% of prostate cancers have mutations in the Akt pathway, especially this gene. A deficiency of PTEN overactivates Akt. Prostate Cancer Symptoms • Frequent urination, weak, interrupted urine flow, pain or burning during urination. • Blood in the urine or semen • Pain in the back, weight loss, fatigue for spreading cancer • Could also be caused by an enlarged prostate, a condition called benign prostate hyperplasia (BPH) Detection and Diagnosis PSA Level (Blood Test) • Excellent sensitivity but low specificity; benign prostatic hypertrophy and pro- statitis cause false-positive PSA elevation • Using a PSA threshold of 4ng/nL, 70-80% of tumors detected, cancer rates range from 4-9% • Positive predictive value for a single PSA level greater than 10ng/mL results in >60% specificity for prostate cancer • Positive predictive value for a PSA level between 4-10ng/mL results in approx. 30% specificity for cancer • PSA velocity is a better measure of high risk patients; a rate >0.75/year in- crease warrants biopsy • Almost 5% of prostate cancers have undetectable PSA Digital Rectal Examination (DRE) • Low sensitivity and specificity for diagnosis • Biopsy of a nodule or area of induratio
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