Biology of prostate cancer Flashcards
1
Q
What are some prostate cancer stats
A
- rapidly becoming most common cancer type in males in the UK
- around 48,500 new prostate cancer cases every year
2
Q
What cells make up the prostate?
A
- luminal epithelial cells - prostatic fluid made here
3
Q
What type of gland is the prostate gland?
A
- specialised type of exocrine gland = apocrine gland
- exocrine gland - secrete substances out onto a surface or cavity, via a ductal structure
- endocrine gland - secrete substances directly into the bloodstream
- apocrine gland - specialised exocrine gland which a part of the cells’ cytoplasm breaks off releasing the contents
4
Q
Describe the stages involved in normal development of the prostate
A
- hormone independent from embryonic development up to puberty
- enlargement during puberty
- hormone-dependent maintenance hereafter in adulthood
- and reactivation of prostate growth in old age = hyperplasia and prostate cancer
5
Q
What are some prostate abnormalities?
A
- inflammation eg due to infection = prostatitis - linked to infertility
- dysregulated growth of prostate = benign - benign prostatic hyperplasia BPH, malignant = prostate cancer
6
Q
What are the main symptoms of prostate cancer?
A
- frequent trips to urinate
- poor urinary stream
- urgent need to urinate
- hesitancy whilst urinating
- lower back pain
- blood in urine
7
Q
Where does prostate cancer starts
A
- originates in the cells that line the lumen - lumen epithelial cells
- hyper-proliferate = prostate intraepithelial neoplasia (PIN)
- develop into invasive adenocarcinoma
- fill the lumen and invade outwards from the prostate
8
Q
How is prostate cancer detected?
A
- digital rectal examination (DRE)
- PSA test
- Ultrasound
9
Q
What is PSA?
A
- 34KDa glycoprotein, discovered in 1979
- a serine protease
- clears seminal vesicles by lysing the seminal coagulate
- transcriptionally regulated by androgens
- when tumour grows it breaks down structure and destroys basement membrane = PSA escapes to bloodstream
- elevated levels suggests disruption to prostate
- normal levels <4ng/ml
- PSA level correlates well with clinical staging of the disease
10
Q
Describe the digital rectal examination (DRE)
A
- doctor feels prostate through wall of the rectum
- normal prostate = smooth, age appropriate size
- abnormal = hard texture, with rough surface
11
Q
How can an ultrasound be used?
A
- adenocarcinoma can be detected
12
Q
How is prostate cancer staged?
A
- TNM system for staging
- Gleason score system for grading
13
Q
Describe the TNM system for prostate cancer staging
A
- standard for classifying the extent of cancer spread
- T = size and extent
- N = nearby lymph nodes associated with cancer
- M = metastasised or not
- T1 : small, localised tumour
- T1a = small tumour found in prostate tissue but undetectable through DRE
- T1b = >5% of the sample contains cancer
- T1c = found during biopsy due to investigation for prostate cancer
- T2: palpable tumour
- T2a = tumour suspected from rectal exam confined to <1/2 of one of the prostate lobes
- T2b = tumour contained in >1/2 of one of the prostate lobes
- T2c = tumour involving both lobes of the prostate gland
- T3 = escape from prostate gland
- T3a = tumour extends beyond the prostate capsule into surrounding tissue
- T3b = tumour involved seminal vesicles
- T4 - local spread to pelvic region = involve bladder
14
Q
Describe the Gleason score
A
- used to examine prognosis
- looks at biopsy samples
- normal prostate = clear luminal structure, and orderly glandular tissue
- prostate hyperplasia = abnormal growth of glandular tissue
- high grade carcinoma = glandular structure is broken down, mass of proliferating cancer cells
- COPY GLEASON PATTERN PIC*
15
Q
What are the prostate cancer treatments available?
A
- watchful waiting - low grade tumour, older patients
- radical prostatectomy - stage T1 or T2 = surgical removal of prostate gland
- radical radiotherapy - external up to T3 = kill cancerous cells
- bilateral orchidectomy - metastatic cancer + hormone therapy
- hormone therapy - prostatectomy or radical radiotherapy
- brachytherapy - radiation dose is delivered inside the prostate gland through tiny radioactive seeds implanted into tumour
16
Q
What are some other treatments available for prostate cancer?
A
- high intensity focused ultrasound (HIFU) - sound waves kill cancer cells by heating them up to a high temp
- chemotherapy - docetaxel - stabilise microtubules preventing cell division
- cryotherapy - killing cancer cells by freezing them
17
Q
What are some of the risk factors of prostate cancer?
A
- age
- race/ethnicity - african american men are more likely to develop
- geography - more prevalent in western countries
- family history - father or brother = doubles risk
- genes/inherited - BRCA1/2,
- diet
- obesity
- chemical exposure
18
Q
What are the main prostate cancer genes involved?
A
- BRCA1/2, PTen
- PTen = phosphatase that antagonises the PI3K signalling pathway
- loss of PTen = increased growth factor signalling
- TMPRSS2-ERG fusion - most frequent, present in 40-80% of prostate cancers = strongly driven by testosterone
19
Q
What are the 3 main types of hormones?
A
- steroids eg testosterone
- peptide/proteins eg insulin
- modified amino acids eg adrenaline
20
Q
Describe steroid hormones
A
- all steroid hormone are synthesised from cholesterol
- multi-ring structure, small lipophilic molecules
- once they enter the cell they bind to unique receptor
- work systemically having effects on several tissue
- testosterone controls reproductive and supportive organs, development of sexual characteristics eg. deepening of voice, body hair
21
Q
Describe the receptor mechanism of steroids
A
- steroid hormones cross into the cell cytoplasm where they will bind to their receptor
- binding to the receptor causes a conformational change in the nuclear receptor, causing it to become activated
- nuclear receptors then translocate into the nucleus
- nuclear receptors bind to specific DNA sequences called response elements located in the promoters of steroid responsive genes
- steroid responsive genes are switched on and upregulated
22
Q
What are the characteristics of the the nuclear receptor?
A
- ligand binding domain (LBD) - binds specific steroid molecules with high affinity
- DNA binding domain (DBD)- binds specific DNA sequences
- activation function domain (AF1 & 2) - recruits gene activation machinery
23
Q
Describe the steps involved in ligand activated TF
A
- ligand binding to the LB site = shift in an alpha helix activating receptor
- receptor dimerises, moves into nucleus and binds to specific DNA sequences
- receptor then recruits DNA modifying enzymes eg. histone deacetylases
24
Q
How does androgen ablation kill prostate cells?
A
- testes grow in the presence of testosterone, surge in puberty drive growth of prostate
- when testosterone is removed, prostate shrinks = death of majority of prostate cells
25
Q
How can the androgen receptor be targeted in prostate cancer?
A
- the prostate gland is an androgen sensitive and dependent tissue
- prostate cancer cells retain this sensitivity and dependency
- therefore, this can be used as an inherent vulnerability that can be exploited for treatment
- switch off AR signalling, switch of cancer growth
26
Q
How are 5alpha reductase inhibitors used in cancer treatment?
A
- stops the conversion of testosterone to DHT (more potent form)
- finasteride
- commonly used for BPH
27
Q
How are androgen blockers used?
A
- compete for active site
- prevent DHT from binding to AR
- bicalutamide
28
Q
What is hormone-refractory prostate cancer (HRPC)?
A
- despite initial rates of 80-90%, nearly all men treated for advanced prostate cancer develop hormone-resistant prostate cancer after 18-24 months
- these hormone-refractory prostate cancer cells can grow in the absence of androgens
29
Q
What are some future prostate cancer therapies?
A
- selective androgen receptor modulators (SARMs) - target AR in prostate but not in bone or muscle
- non-androgen targeted pathways eg. PTen
- personalised treatment based on mutational events in patients tumours
30
Q
How do anti-androgens work?
A
eg. enzalutamide blocks AR translocation to the nucleus
31
Q
What are the new radiation treatments that are being investigated?
A
- prostate-specific membrane antigens (PSMA) is a type II membrane protein expressed in all forms of prostate tissue, including carcinoma
- PSMA protein has a unique structure which can be detected using an antibody
- PSMA gene is located on the short arm of chr 11 in a region commonly deleted in prostate cancer
- has glutamate carboxypeptidase II activity that can be selectively bound
32
Q
How can immunotherapy be used?
A
- sipuleucel-T
- patients WBC are extracted and incubated with a fusion protein antigen consisting of prostatic acid phosphatase (PAP_ and GM-CSF
- activated blood product is returned and reinfused into the patient
- this trains the immune system to attack the prostate cancer cells
