Biology of prostate cancer

Question 1

What are some prostate cancer stats

Answer 1

• rapidly becoming most common cancer type in males in the UK
• around 48,500 new prostate cancer cases every year

Question 2

What cells make up the prostate?

Answer 2

• luminal epithelial cells - prostatic fluid made here

Question 3

What type of gland is the prostate gland?

Answer 3

• 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

Question 4

Describe the stages involved in normal development of the prostate

Answer 4

• 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

Question 5

What are some prostate abnormalities?

Answer 5

• inflammation eg due to infection = prostatitis - linked to infertility
• dysregulated growth of prostate = benign - benign prostatic hyperplasia BPH, malignant = prostate cancer

Question 6

What are the main symptoms of prostate cancer?

Answer 6

• frequent trips to urinate
• poor urinary stream
• urgent need to urinate
• hesitancy whilst urinating
• lower back pain
• blood in urine

Question 7

Where does prostate cancer starts

Answer 7

• 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

Question 8

How is prostate cancer detected?

Answer 8

1. digital rectal examination (DRE)
2. PSA test
3. Ultrasound

Question 9

What is PSA?

Answer 9

• 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

Question 10

Describe the digital rectal examination (DRE)

Answer 10

• doctor feels prostate through wall of the rectum
• normal prostate = smooth, age appropriate size
• abnormal = hard texture, with rough surface

Question 11

How can an ultrasound be used?

Answer 11

• adenocarcinoma can be detected

Question 12

How is prostate cancer staged?

Answer 12

• TNM system for staging

- Gleason score system for grading

Question 13

Describe the TNM system for prostate cancer staging

Answer 13

• 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

Question 14

Describe the Gleason score

Answer 14

• 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*

Question 15

What are the prostate cancer treatments available?

Answer 15

• 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

Question 16

What are some other treatments available for prostate cancer?

Answer 16

• 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

Question 17

What are some of the risk factors of prostate cancer?

Answer 17

• 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

Question 18

What are the main prostate cancer genes involved?

Answer 18

• 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

Question 19

What are the 3 main types of hormones?

Answer 19

• steroids eg testosterone
• peptide/proteins eg insulin
• modified amino acids eg adrenaline

Question 20

Describe steroid hormones

Answer 20

• 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

Question 21

Describe the receptor mechanism of steroids

Answer 21

1. steroid hormones cross into the cell cytoplasm where they will bind to their receptor
2. binding to the receptor causes a conformational change in the nuclear receptor, causing it to become activated
3. nuclear receptors then translocate into the nucleus
4. nuclear receptors bind to specific DNA sequences called response elements located in the promoters of steroid responsive genes
5. steroid responsive genes are switched on and upregulated

Question 22

What are the characteristics of the the nuclear receptor?

Answer 22

• 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

Question 23

Describe the steps involved in ligand activated TF

Answer 23

1. ligand binding to the LB site = shift in an alpha helix activating receptor
2. receptor dimerises, moves into nucleus and binds to specific DNA sequences
3. receptor then recruits DNA modifying enzymes eg. histone deacetylases

Question 24

How does androgen ablation kill prostate cells?

Answer 24

• 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

Question 25

How can the androgen receptor be targeted in prostate cancer?

Answer 25

• 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

Question 26

How are 5alpha reductase inhibitors used in cancer treatment?

Answer 26

• stops the conversion of testosterone to DHT (more potent form)
• finasteride
• commonly used for BPH

Question 27

How are androgen blockers used?

Answer 27

• compete for active site
• prevent DHT from binding to AR
• bicalutamide

Question 28

What is hormone-refractory prostate cancer (HRPC)?

Answer 28

• 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

Question 29

What are some future prostate cancer therapies?

Answer 29

• 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

Question 30

How do anti-androgens work?

Answer 30

eg. enzalutamide blocks AR translocation to the nucleus

Question 31

What are the new radiation treatments that are being investigated?

Answer 31

• 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

Question 32

How can immunotherapy be used?

Answer 32

• 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