Week 7 Flashcards
In general, why does prostate cancer occur?
Prostate cancer occurs due to the uncontrolled proliferation of cells found in the prostate ducts.
What are the 2 histological types of prostate cancer.
Acinar adenocarcinomas
Non-acinar adenocarcinomas
In terms of early and late stage prostate cancer, which is androgen independent and which is androgen dependent?
Early = dependent Late = independent
Who does prostate cancer most commonly affect?
Men over 50
What are the symptoms of prostate cancer?
- Frequent urination during the night (nocturia)
- Feeling urgency to urinate
- Difficulty starting to urinate
- Straining/ taking a long time to urinate
- Weak flow
- Bladder feeling full
- Blood in urine or semen
Can be symptomless
What main molecule controls prostate cancer?
Androgens
What are the main purpose of androgens?
Androgens are crucial for male sexual and reproduction function and are also responsible for development of secondary sexual characteristics in men including factors such as body hair growth and voice change.
What are the 3 main zones of the prostate gland?
CZ - Central Zone
PZ - Peripheral Zone
TZ - Transitional Zone
What is the purpose of the central zone of the prostate gland?
Contains ductal tube from seminal vesicle
Where does the majority of cancer and prostatic intraepithelial neoplasia arise in the prostate gland?
In the peripheral zone
Where does BPH occur?
Transitional zone
What is BPH?
Benign Prostatic Hyperplasia
What type of organ is the prostate?
An exocrine gland
What is the main purpose of the prostate ?
It is an exocrine gland involved in the secretion of components which help to liquefy seminal fluid.
How do the acini of the prostate gland work and what is their purpose?
Each acinus is lined with epithelial cells which secrete fluid into the acing lumen, flowing to the prostate gland itself.
Describe the structure of a normal prostate acinus.
It is comprised of a bilayer of epithelial luminal, basal cells and neuroendocrine cells which are all surrounded by stromal tissues.
What are the 3 main cell types of the basal layer of normal prostate acinus?
Stem cells
Transit Amplifying Cells
Committed Basal Cells
What characterises a cancerous acinus?
Hyperproliferation of the luminal cells, loss of basement layer, basement membrane breakdown and immune cell infiltration.
The stroll cells also become reactive.
Outline the stages that an acinus goes through from having a normal structure to becoming cancerous
Normal
PIA - Proliferative Inflammatory Atrophy
PIN - Pre-cancerous hyperplasia of luminal cels
Cancer
What happens to change an acinus from normal to PIA (Proliferative inflammatory atrophy).
Oxidative stress
Inflammation
Luminal and stroll cell proliferation
What happens to change an acinus from PIA to PIN (Pre-cancerous hyperplasia of luminal cells).
Luminal cell hyper proliferation
Telomere shortening
Stromal reactivity
What happens to change an acinus from PIN to cancer?
- Luminal cell hyper proliferation
- Loss of basal epithelial cells
- Breakdown of basement membrane
- Immune cell infiltration
- Stromal reactivity
What causes prostate cancer to be misdiagnosed often?
It’s heterogeneity.
Outline the clonal progression of prostate cancer.
- Benign mosaic sub-clonal populations arise during organogenesis due to accumulation of genomic changes.
- Local tumour progression
(Additional genomic drivers product district sub-clonal populations) - Metastatic dissemination
(Sub-clones evolve further, replacing other tumour cell populations)
(Selection of adapted/ resistant cells).
How is prostate cancer traditionally diagnosed?
Looking at symptom presentation
- Digital rectal examination (DRE)
- PSA Test
- Biopsy of prostate to allow grading
How do prostate biopsies work?
Transrectal needle biopsy
- A biopsy needed is attached to an ultrasound probe and inserted into the rectum to image the prostate
- 10-12 fires of the gun are required to allow core sampling.
Transperineal needle biopsy
- A biopsy needed attached to ultrasound is inserted into the perineum
What are the 2 options for prostate biopsy?
Transrectal needle biopsy
Transperineal needle biopsy
Describe the tissue / cells seen in stages 1-5 of prostate cancer
1 - small, uniform glands
2 - more space between glands
3 - infiltration of cells from glands at margins
4 - Irregular cases of cells with few glands
5 - Lack of glands, sheets of cells
The cells become more poorly differentiated from stages 1-5 of cancer tissue grading
What measurement is often used to diagnose prostate cancer and why?
PSA levels - prostate specific antigen
- Invasion and destruction of tissue architecture by cancer cells allows measurements of PSA.
What family is PSA in?
The Human Kallikrein 2 gene family
hK3
What is PSA secreted by and what is its purpose in the prostate?
Secreted by prostate epithelium to liquefy seminal fluid
Where and how does PSA exist?
Exists both as free protein and is also bound to other proteins
If PSA is found to be elevated, what will be carried out?
A biopsy of the prostate will be taken.
Outline some of the roles of PSA in prostate cancer.
- Kallikrien’s can cleave pro-PSA and release active PSA
- PSA cleaves proteins leading to the ECM remodelling
- PSA may lead to metastasis of primary tumour
- PSA may inhibit bone resorption
- PSA inhibits angiogenesis
- PSA-specific epitopes can activated cytotoxic T lymphocytes
Do all individuals with elevated PSA have prostate cancer?
No, some people with elevated PSA do not have prostate cancer and this leads to un-necessary biopsies.
Some individuals with advanced prostate cancer do not have elevated PSA at all.
What is an alternative biomarker to PSA to test for prostate cancer?
Prostate Cancer Antigen 3 (PCA-3)
What is the molecule PCA-3 and where is it expressed?
It is a small, non-coding RNA molecule which is expressed specifically in prostate cancer cells.
In prostate cancer, how is the expression of PCA-3 altered? And how is this identified?
It is over expressed 60-100 times.
Identified by differential expression analysis (normal prostate vs prostate cancer)
What are the advantages of having PCA3 as a biomarker for prostate cancer?
PCA3 score correlates with positive PCA biopsies
PCA£ score is a better indicator than PSA
What treatments can be used to treat early stage prostate cancer?
Watchful waiting Active surveillance Anti-androgen (AA) treatment Surgery Radiotherapy Brachytherapy Cryotherapy Ultrasound
What treatments can be used to treat late stage prostate cancer?
Radiotherapy Bisphosphonates Pain relieving drugs Chemotherapy Second generation AAs
How does Enzalutamide work for treating metastatic prostate cancer (name some mechanisms).
- Competitively inhibits androgen binding to AR
- Inhibits nuclear translocation of the AR
- Inhibits AR binding to DNA and coactivator recruitment
