Prostate Cancer + Reproduction and Environment

Question 1

What is the most common genetic mutation involved in prostate cancer?

Answer 1

• The TMPRSS2:ERG mutation in which the ERG gene becomes abberantly expressed

Question 2

What are the 10 hallmarks of cancer?

Answer 2

1. Cancer cells stimulate their own growth (proliferation)
2. Cancer cells resist inhibitory signals
3. Resist apoptosis
4. Stimulate angiogenesis
5. Have replicative immortality
6. Metastasise
7. Genome instability and mutation
8. Deregulate cellular energetics
9. Avoid immune destruction
10. Promote tumour-promoting inflammation

Question 3

What is therapy resistance?

Answer 3

• Occurs when cancers that have been responding to therapy suddenly begin to grow and proliferate
• Occurs because the cancer cells adapt to the pressures of chemotherapy
• A number of factors contribute including:
  1. Gene amplification
  2. Pumping of drug out using p-glycoproteins
  3. Generating mechanisms to inactivate drug
  4. Stopping uptaking the drug

Question 4

What is the most common cancer in Australian men?

Answer 4

• Prostate cancer
• 1 in 5 men will develop it
• Second most common cause of cancer death in men (after lung cancer)

Question 5

Where does prostate cancer usually occur?

Answer 5

• Prostate cancer usually arises in the peripheral zone from glandular epithelial cells
• They arise as adenocarcinomas

Question 6

How is prostate cancer detected?

Answer 6

1. Rising prostate specific androgen (PSA) levels: requires regular blood tests
2. Digital rectal examination
3. TRUS biopsy

Question 7

What is the standard histopathological progression of prostate cancer?

Answer 7

1. Early neoplastic changes occur in the prostate leading to a PIN (prostatic intraepithelial neoplasia) lesion- this is a pre-malignant lesion in the prostate
2. PIN lesions can progress and develop into an adenocarcinoma which is typically indolent (slow growing)
3. Indolent adenocarcinomas can develop into aggressive adenocarcinoma (and some men will progress rapidly from PIN to aggressive adenocarcinoma)
4. Aggressive adenocarcinoma has a high likelihood of resulting in metastasis

Question 8

How is the Gleason score calculated?

Answer 8

• Tissue pathology is graded from 1-5 based on morphology (1 being normal)
• The Gleason score is calculated from the most common Gleason grade + the highest Gleason grade
• A score of over 8 indicates aggressive prostate cancer

Question 9

What is the typical timeline of prostate cancer treatment?

Answer 9

1. Indolent prostate cancer is actively surveilled
2. If indolent prostate cancer becomes aggressive (localised) it will be treated with surgery/radiation to remove and the tumour and/or prostate
3. Usually there will be a recurrance marked by increasing PSA. This recurring cancer is usually treated with androgen ablation
4. Eventually the cancer may adapt and recur as castration resistant prostate cancer (not androgen independent but simply synthesises its own androgens) CRPC is very serious and usually causes death but new treatments involve blocking steroid metabolism

Question 10

What are pheromones?

Answer 10

• Small chemical substance that affect the behaviour of another animal

E.g. the Ram effect, introduction of a Ram has an excitory effect on the HPG axis of ewes leading to increases LH secretion- this is mediated by pheromones

Question 11

How is the action of pheromones mediated?

Answer 11

1. Pheromones are sensed by the vomeronasal organ
2. This signals via the accessory olfactory bulb and amygdala to the hypothalamus
3. The action of pheromones in activating the HPG axis is mediated by kisspeptin

Question 12

How does seasonality affect reproduction?

Answer 12

1. Photic input is detected by the eye in the retinal ganglion cells
2. This is relayed to the suprachiasmatic nucleus (region of the hypothalamus)
3. This is relayed to the pineal gland
4. This increases the secretion of melatonin
5. Melatonin targets the hypothalamus and posterior pituitary

• CLOCK genes also play a role

Question 13

Why do animals in the non-breeding season become anestrous?

Answer 13

• During the non-breeding season ewes become highly sensitive to negative feedback effect of estrogen
• There is a down regulation of kisspeptin in the ARC
• There is an upregulation of GnIH secretion in the hypophyseal portal blood