24 - HDCs: Prostate Cancer

Question 1

function of prostate gland

Answer 1

produces prostatic fluid that creates semen when mixed with the sperm produced by the testes

Question 2

structure of prostate gland

Answer 2

an exocrine/apocrine gland composed of glandular tissue - tissue forms a system of ducts that produce and secrete prostatic fluid

tissue structure:
- luminal epithelial cells that line duct lumen
- basal epithelial cells
- stromal cells and muscle cells

Question 3

what are the stages of prostate development?

Answer 3

hormone-independent = from embryonic development up to puberty

enlargement during puberty – hormone dependent

hormone-dependent maintenance thereafter in adulthood

reactivation of prostate growth in old age – leading to hyperplasia and prostate cancer

Question 4

what is prostatits?

Answer 4

inflammation of the prostate due to infection or from an unknown origin

Question 5

symptoms of prostate cancer

Answer 5

frequent trips to urinate
poor urinary stream/ hesitancy
urgent need to urinate

lower back pain & blood in symptoms are rarer symptoms

Question 6

why is urination so affected in prostate cancer?

Answer 6

prostate is close and under the bladder - a large tumour growth/ hyperplasia increases volume of the prostate gland

presses on the bladder & compresses the urethra = affects urination

Question 7

describe the initiation and progression of prostate cancer

Answer 7

originates in luminal epithelial cells which hyper-proliferate and form prostate intra-epithelial neoplasia = then becomes an invasive adenocarcinoma

prostate cancer cells rapidly fill lumen and then begin invading outwards from the prostate

Question 8

what three tests can be used to detect prostate cancer?

Answer 8

digital rectal exam

testing for PSA/ prostate-specific antigen in blood

ultrasound - detecting tumour outside prostate capsule

Question 9

what is the TNM classification?

Answer 9

stating of prostate cancer based on:
T - size/extent of tumour
N - number of lymph nodes involved in cancer
M - metastasis

different staging for different letters

Question 10

describe T1-4 staging for prostate cancer

Answer 10

T1 = tumour is small, localised and confined to prostate

T2 = slightly larger, palpable by DRE

T3 = larger, may have started growing outside prostate gland capsule

T4 = growth outside prostate, involves other surrounding organs like the bladder and seminal vesicles

Question 11

describe N0-3 staging

Answer 11

NO = no cancer cells found in any lymph nodes

N1 = 1 positive lymph node < 2cm across

N2 = more than 1 positive lymph node or 1 tumour between 2-5cm across

N3 = any positive lymph node > 5 cm across

Question 12

describe M1a-c staging

Answer 12

metastasis to…
M1a = non-regional lymph nodes

M1b = bone

M1c = other sites

Question 13

what is the Gleason grading system?

Answer 13

used to help evaluate the prognosis and therapy of men using prostate biopsy samples
- higher Gleason score = worse prognosis

• normal prostate has clear, ordered tissue and glandular morphology
• high grade carcinoma has a change in orderly structure, duct lumen are filled with cells

Question 14

what are the different treatments for men with prostate cancer?

Answer 14

watchful waiting & active surveillance, radical prostatectomy, radical radiotherapy or hormone therapy

watchful waiting
= for older patients with low-grade tumours where more advanced therapy won’t be that useful, patient often has no/few symptoms
= will likely die before the cancer has any serious effects
= active surveillance follows with regular tests to monitor progression

radical prostatectomy
= for T1/2 stage cancer confined to the prostate gland

radical radiotherapy
= for up to T3 cancer, spread past the prostate capsule

hormone therapy
= often combined with radiotherapy/ prostatectomy for metastatic cancer

Question 15

what are the risk factors for prostate cancer?

Answer 15

age
race/ethnicity - more in African-American and Caribbean men

geography - more in Western countries, increases with migrating to Western countries

family history - inherited genetic factor, higher risk

inherited gene changes
= inherited BRCA1/2 gene mutations - involved in DNA damage repair
= men with Lynch syndrome - inherited condition
= loss of PTen
= TMPRESS2 and ERG fusion
= during cancer progression, more gene mutations can be induced in other genes or oncogenes

diet and obesity

chemical exposures

inflammation of prostate - e.g. STIs

Question 16

how does the loss of PTen contribute to prostate cancer?

Answer 16

PTen is a phosphatase that antagonises the P13K pathway and leads to normal cell growth

loss of PTen = increased growth factor signalling = inappropriate cell growth and proliferation

Question 17

how does the TMPRESS2-ERG fusion contribute to prostate cancer?

Answer 17

TMPRESS2 is normally driven by antigen receptor transcription factors

promoter of TMPRESS2 gene is fused with gene coding for proto-oncogene ERG

strong proliferation signals induced by testosterone cause inappropriate gene activation

Question 18

describe the mechanism for androgen receptor signalling

Answer 18

circulating testosterone passes through cell membrane into cytoplasm

androgen receptor is a nuclear receptor protein – binds testosterone with high affinity

AR activates and dimerises – complex translocates to nucleus

complex binds to androgen response elements = specific DNA seqs in promoter regions of androgen target genes

recruit in gene transcriptional machinery and co-activators needed for expression of target genes

leads to target gene protein expression and cell growth

Question 19

mechanism of action of abiraterone acetate?

Answer 19

inhibits the production of androgen precursors by inhibiting the main enzymes used to produce them - e.g. 17-alpha-hydroxylase = inhibits testosterone synthesis

abiraterone acetate has a similar structure to cholesterol and steroid intermediates - can switch off adrenal androgen precursor production

Question 20

mechanism of action of Goserelin and Abarelix?

Answer 20

Goserelin = super agonist
Abarelix = antagonist

both shut down HP signalling to the testes = reduced GnRH, FSH and LH production = reduce testosterone production

Question 21

examples of 5-alpha-reducase inhibitors?

Answer 21

Dutasteride, Finasteride

Question 22

mechanism of action for finasteride?

Answer 22

Finasteride structure resembles an androgen intermediate - can inhibit 5-alpha-reducase activity = inhibit testosterone to DHT conversion

DHT is the more potent form of testosterone - preventing its production reduces the growth of pre-cancerous benign prostate hyperplasia

Question 23

examples of competitive androgen antagonists?

Answer 23

Bicalutamide, Enzalutamide, Flutamide, Nilutamide

Question 24

mechanism of action of Bicalutamide?

Answer 24

acts as a competitive androgen antagonist - competes with testosterone for the ligand binding domain of the androgen receptor

normally when androgens bind to AR - it causes movement of AR helix 12 to fold over and create an active transcription factor

Bicalutamide binding to LBD of AR as an androgen antagonists prevents AR helix 12 from folding over = keeps receptor inactive

Question 25

what are the four drug mechanisms for preventing androgen signalling? give an example for each

Answer 25

inhibiting testosterone synthesis - e.g. abiraterone acetate

controlling hormone production/HPT axis - e.g. Goserelin, Abarelix

inhibiting 5-alpha-reductase activity & testosterone conversion to DHT - e.g. Finasteride

inhibit androgen binding to receptor with competitive androgen antagonists - e.g. Bicalutamide

Question 26

describe the 8 mechanisms of resistance for cancer cells against hormone therapy

Answer 26

1. hormone overproduction or local synthesis
   = tumours can upregulated biosynthetic genes and enzymes to synthesise their own hormones
   = cause autocrine stimulation for growth regardless of systemic hormone levels
2. ligand binding site mutations
   = promiscuous receptors - acquire ligand binding site mutations where they become less specific
   = mutations allow other ligands/hormones to bind
3. receptor amplification
   = genes expressing steroid receptors become amplified - increased receptor presence causes increased sensitivity & signal amplification
4. receptor phosphorylation/ activation in the absence of ligand
   = some growth factors phosphorylate and activate steroid receptors inappropriately in the absence of a ligand - activates target genes for cell growth despite no ligand
5. androgen receptor transcript variants – activation in the absence of a ligand
   = in high grade prostate cancers degeneration of androgen receptor variants can occur, prodcuing a shorter transcript/ truncated version lacking certain domains
   = can still bind and trigger target gene activation without a ligand
6. receptor bypass – independence from steroid hormone
   = cancer cells rely less on nuclear receptor activation via hormones, can rely on oncogenes to drive growth forwsrd
   = become independent from the original hormone used for growth
7. receptor co-factor amplification
   = co-factor amplification amplifies signal from steroid receptors in response to low hormone levels
8. antagonists become agonists via LBD mutations
   = acquired mutations in ARs allow androgen antagonists often used for hormone therapy to function as agonists - drive disease forward instead

Question 27

how and why do cancer cells develop resistance to hormone therapy?

Answer 27

homogenous cancer cells develop various mechanisms to overcome hormonal starvation

resistance mechanisms in cancer cells are quickly selected for = cancer cells become adapted to low hormone levels, and less sensitive to treatments