SAMPLE NOTES, FULL EDITION IS ORDERED AND COMPLETE. … · Seminal vesical, sac like lateral to...
Transcript of SAMPLE NOTES, FULL EDITION IS ORDERED AND COMPLETE. … · Seminal vesical, sac like lateral to...
SAMPLE NOTES, FULL EDITION IS ORDERED AND COMPLETE.
TOPIC LIST:
Week 1 Core themes
Week 1 Male reproduction 1
Week 2 Male reproduction 2
Week 2 Male Reproductive Endocrinology
Week 3 Ovarian Physiology
Week 4 The reproductive brain I
Week 4 The reproductive brain 2
Week 5 The pituitary gland
Week 5 Reproductive Neuroendocrinology: - revision
Week 6 Human pregnancy and some of its problems
Week 8 Reduced fertility: trauma and disease
Week 9 IVF Assisted reproduction
Week 9 Endocrine Disruptors and Reproduction
Week 10 Nutrition and Reproduction
Week 10 Inhibin and related proteins TGF-β proteins in reproduction
Week 11 Stress and Reproduction
Week 11 Reproductive Cancer – Prostate
Week 12 Environmental control of reproduction
Week 1- Male reproduction 1
Hypothalamic-pituitary axis
Hypothalamus, production of Gnrh which
releases FSH and LH from the pituitary gland.
GnRH is released a pulsatile (received also.)
Anterior pituitary:
• Gonadotrophs → LH, FSH, activin
• Lactotrophs → Prolactin, activin
• Somatotrophs → Growth hormone,
activin
• Adrenocorticotrophs → ACTH
• Thyrotrophs → TSH
• Folliculostellate cells → Follistatin
Note: testicular steroids REDUCE frequency of GnRH impulses. So the increase of
testosterone can depress of GnRH.
Luteinizing hormone →leydig cells, which produces testosterone and estrogen. Mostly
testosterone FSH →Seminiferous tubule or the sertoli cells, this produces inhibin and a
steroid, 5 alpha di hydro testosterone. Inhibin directly acts on the pituitary and has negative
feedback which reduces FSH.
Large testosterone causes a reduction in LH and GnRH and testicular functions.
Effect of castration, removal of testis causes an increase of FSH as inhibin is not present.
This can be uses to diagnose infertility in male. With LH takes a longer to increase as the
testis removes testosterone, which acts on the hypothalamus.
Testosterone – important negative feedback hormone in male via actions at the
hypothalamus (GnRH) Castration also removes the Sertoli cells – source of negative
feedback hormone inhibin ( ↑FSH)
HORMONAL CONTROL FAILS
Testis may be smaller than normal as
they are missing germ cells.
Secondary failure may occur due to
additional failure in Hypothalamus of
pituitary axis. This causes a reduction in
FSH and LH. This can be treated with
GnRH injections.
Epididymis
Essential for sperm maturity and motility. Membrane wont bind to the egg.
Testis and epididymis is outside the body to allow for testicular descent. Development
testis start inside the abdomen, attached to the Gubernaculum testis which directs the
scrotum to pass the Inguinal canal. 3 month foetal. The babies relative size increases where
as the Gubernaculum becomes smaller which pull the testis down. Peritoneal cavity and
scrotal sac fuses after development.
SCROTAL CONTROL OF TESTICULAR TEMPERATURE
• specialised spermatic blood supply with a single artery (dranage through a plexis)
• counter current heat exchange (can’t function at body temperature) by artery and
Venus exchange
role of cremaster:
• high temp stops spermatogenesis and increases cancer risk
• Dartose muscle in the skin crinkles up to protect testis.
Heat stress takes 8 weeks to recover from.
Not all mammals have testicular descent.
Sperm production
White coat, tunica albuginea encloses the testis.
Inside, the storage of sperm is collected in the
mediastinum and forced out by tunica albuginea
contraction (smooth muscles).
Two main functions of the testis
• Spermatogenesis/sperm production – seminiferous
tubule Sertoli cells, germ cells, peritubular myoid,
cells (contractile)
• Hormone synthesis and secretion – interstitium
Sertoli cells (in green)
• population established prior to puberty
• sustentacular or supportive cells
• create an unique environment for spermatogenesis
• germ cells develop in contact
• blood testis barrier
• limit the capacity to produce sperm. The number of sertoli cells developed at
puberty controls the amount of sperm that is produced.
Sertoli cells bunches up to the germ cells to control environment of sperm development
• FSH receptors in basal cell membrane of Sertoli cells
• FSH acts with T to support spermatogenesis
• stimulates: mRNA and protein synthesis, glucose transport, lactate production, inhibin,
synthesis of androgen-binding protein (ABP), Synthesis of Mullerian inhibiting hormone
inhibits female development (MIH), transferrin, aromatase, mitosis (in immature Sc)
Tight junction join adjacent sertoli cells. Hence spermatozoa is exposed to what blood brings
in but the cells above is controlled by sertoli cells as they are controlled by tight junctions.
These were discovered by injecting fluorescent protein and observing movement, (not in
tubule).
• Sertoli cells: differentiate prior to puberty, support cells for germ cells development, form
blood-testis barrier, synthesized androgen-binding protein (ABP), synthesized Mullerian
inhibiting hormone (MIH)
• Germ cells – spermatogenesis and production of spermatozoa
GERM CELLS
• Undergo meiosis to produce sperm
• 2 processes that we have to go through are mitosis and meiosis (eggs and sperm)
• Mitosis occurs first where the cell type changes in structure and in function slightly
• Mitosis produces Type A spermatogonia which then turns into Type B spermatogonia
• Type B spermatogonia undergoes meiosis to produce Primary Spermatocytes (takes 24days) Secondary Spermatocytesearly spermatids and then late spermatids
SPERMIOGENESIS
• This is the final stage in spermatogenesis in which the spermatids matures into fully formed spermatozoa
• In this process there is no cell division that takes place
• This process happens in 5 main stages, 1. DNA compaction and nuclear shaping 2. Formation of acrosome(important for fertilization) 3. Development and specialization of the tail 4. Loss of the cytoplasm 5. Formation of the residual body
Week 2-MALE REPRODUCTION 2
Two main functions of the testis
• Spermatogenesis/sperm production – seminiferous tubule Sertoli cells germ cells
Hormone synthesis and secretion – interstitium
NTERSTITIAL TISSUE Components:
Leydig cells
• Steroidogenesis:
responsive to LH as have the receptors
and communications to the setoli cells
2-way paracrine interactions with Sertoli cells
• highly vascular which carries LH signals
• well-developed lymphatics
• loose connective tissue and macrophages
-Testis has small connective tissue. And are associate with blood supply as hormones
are introduced back into circulation.
LH from blood→ LH
receptor→ cyclic amp
pathway→ androgen
production.
Androgen production needs
cholesterol to form
testosterone in the leydig
cells. It can make cholesterol
from acetate, stores or food.
Leydig cells can push
testosterone into the sertoli
cells. The androgen binding
protein can carry this into the lumen of the epididymis to maintain functions. It can also be
converted by 5alpha reductase reduces testosterone to a functional androgen (3 times)
more potent in maintaining secondary sex organs.
Steroid producing cells contain smooth ER, this causes the cells to stand up well.
Estrogen in the male derives from aromatases converting testosterone to produce estrogen
in males it goes to the blood stream. This has been shown occur in the leydig cell.
LH importance in testosterone production. LH pulse is associated with peak in testosterone.
STEROIDOGENESIS IN THE MALE
The difference in the pathways
of cholesterol→pregnenolone
→Androstenediol→Tesostrone
In the pathway to the right the
starting point is the only thing
that differs.
If 3B-HSD is present than it is
converted to progesterone.
Structure of steroid hormones
• NOT constructed of amino acids like protein hormones STRUCTURE of STEROID
HORMONES • Ring structure typical of all steroids • Hydrophobic (lipophilic) • Synthesised
by steroidogenic cells • Synthesis via complex pathway with cholesterol as precursor. Hence
they can pass through cell membranes. Most receptors for these are in cells.
Common steroid hormones
• Androgens Testosterone, dihydrotestosterone (DHT) Spermatogenesis, male sexual
function, behaviour
• Oestrogens Oestradiol, oestrone Female sexual function, behaviour (both sexes),
bone
• Progestagens Progesterone Menstrual (oestrous) cycle, pregnancy
• Corticosteroids Glucocorticoids, mineralocorticoids Carbohydrate metabolism,
stress, blood pressure
PROCESSING
• Less potent steroids can be converted to more potent forms • Integral component of
steroid action. In males:
Type of enzyme present affects precursor being converted into androgens,
oestrogens or progestogens. These enzymes regulate type of steroid found in tissue and its
potency.
I.e strong estrogen response Weak estrogen response
STEROID HORMONE RECEPTORS
Receptors are intracellular • Receptors are often bound to other proteins (bioavailability) •
Steroid molecules diffuse into cells and bind to receptor • Dimerise with androgen,
phosphorylate and allows it to go through nucleus • Bind to response elements in
promoters of various genes
The testosterone I converted to DHT and bind to androgen receptor by displacing
HSP→then dimerization and pass to nucleus to activate gene expression.
Androgens in high levels depresses the immune system and testicular function i.e steroids,
aggressive behaviour, muscle definitions and hypertrophy, Adams apple- deeper voice,
secondary sex characteristics.
EPIDIDYMIS
Collect sperm from testis. Note changes in duct
structure and luminal content between head
(caput), body (corpus) and tail (cauda)
The motility occurs from the head to the body
and to the tail. In the head they are infertile.
95% of fluid is removed by the head, which is
less dense. In the tail, there has a larger density
of sperm.
Functions:
• secretion – various specific proteins
• absorption – water (fluid), proteins
• sperm transport (caput epididymis)
• sperm maturation (corpus epididymis)
• sperm storage – requires androgens and<body temperature (cauda
epididymis)
Prostate
Underneath the bladder with muscular coat with glandular component. During ejaculation,
there is contraction of smooth muscle into the urethra. Bladder sphincter closes to prevent
urine entering.
In cancer the is outgrowth of transformed cells in the glandular epithelium. This can be
treated with antiandrogens. Castration of testis can make the prostate cease function
Seminal vesical, sac like lateral to vasdefrence which empties this joins with the duct of the
seminal vesical which empties into prostatic urethra. Remission is when sperm merge into
prostatic uretha →ejaculation. At the base of the epithelium is where seminal vesical is
produced.
Emission
COMPONENTS of SEMINAL PLASMA
• Fructose – energy substrate for sperm
• Phosphorylcholine – associated with membrane structure and sperm maturation
• Prostaglandins – principally PGE; source - seminal vesicle – affects sperm motility,
cervical mucus, vaginal/uterine contractions
• Proteins – glycoproteins, enzymes, immunoglobulins , – prostate-specific antigen
(PSA, assists in motility initiation; liquifaction enzyme) (prostate) – semenogelins I
and II (bind Zn2+) (seminal vesicles)
• Zinc – high levels in prostatic fluid – bacteriostatic effects in vagina – inactivates
proteases (eg PSA)
BULBOURETHRAL GLANDS (lubrication)
Paired glade on either side of prostate and produced a fluid High in sylic acid, a lubricant.
Human Ejaculate: Testis/Epididymis - ~10%; Prostate - ~30%; Seminal Vesicles - ~60%
QUIZ AT THE END OF THIS LECTURE.
Week 2- Male Reproductive Endocrinology
Definition: Collection of glands synthesise & secrete hormones into the bloodstream where
they act on target organs/tissues. The endocrine system has no ductal system (as such are
sometimes referred to as ductless glands) straight into blood stream. i.e testis. Contrast to
the exocrine glands, which secrete their products using ducts i.e prostate
The HPG axis: GnRH→gonadatrope
1. Hypothalamus → GnRH synthesis
2. Median eminence → GnRH storage/release
3. Portal blood vessels → GnRH transport (rapid)
4. Anterior pituitary → GnRH action
5. LH & FSH release into bloodstream
These are released in periodical pulses (GnRH,
and LH)
FSH is released passively (steady state), but is
still depended on GnRH amp and frequency.
Within the testis FSH→ sertoli cells which
nourish developing sperm cells to
spermatagonia→ spermatid. This produces
inhibin
LH→ leydig cells which are the steroidogenic
cells→ aromatases and testosterone.
Testostrone feedback to Hypothalamus to
↓GnRH.
Estrogen feedback to both Hypothalmus
and anterior pituitary ↓LH and GnRH
Inhibin feedback only to the anterior
pituitary ↓FSH.
Classes of Hormones.
• Peptides (eg GnRH) – Short chains of linked amino acids 10 amino acids
• Proteins/glycoproteins (eg LH & FSH) – Long chains of linked amino acids- FSH (2
polypeptide units, 96+110 amino acids)
• Steroids (eg testosterone & estradiol) – Derived from cholesterol
• Amino acid derivatives (eg norepinephrine) – Amino acids with modified groups
Steroid hormones
- 4 ring (tetracyclic) molecule
- Lipid soluble, enables passive diffusion into membrane
- All derived from cholesterol during steroidogenesis
All begins from cholesterol→ progestogens→androgens→estrogens
Note the enzymes: aromatase converts androgen into estrogen. 5 alpha reductase converts
testosterone into 5 alpha dihydro-tesostrone which is potent.
- Sex steroids: - androgens, oestrogens and progestogens - Have important roles in a range
of reproductive functions in both sexes - Feedback effects on the secretion and actions of
GnRH
Testosterone effects are mediated by the interaction with the androgen receptors.
Estradiol can signal through 2 different
receptors. ERbeta or ERalpha.
• Testosterone: levels decline at > 50
years of age
• LH: basal levels increase in older men
this is in response to less negative feedback
form testosterone at level of hypothalamus;
LH pulsatility is blunted (less effective)
• Leydig cells: steroidogenic capacity
decreases
• Spermatogenesis: lower fecundity at >40 years, 50% lower probability of achieving
pregnancy w/in 1 yr compared to men
In adulthood, there are variations across the year. Daily there is a diurnal secretion pattern,
highest in the morning and lowest in evening.
Male hypogonadism
Classical: testicular failure associated with androgen deficiency
Revised: decreased testicular function, as compared to what is expected for age, involving
impaired hormone secretion by Leydig cells
(androgens) and/or Sertoli cells (AMH, inhibin
B) and/or a disorder of spermatogenesis.
Primary (hypergonadotropic) hypogonadism –
Testicular disorder (eg, leydig cell hypoplasia)
Ethane dimethane sulphonate (EDS) Kills off
leydig cells – HIgh (hyper) gonadotrophin
levels
Central (hypogonadotropic) hypogonadism –
Disorder in hypothalamus/pituitary – Low
(hypo) gonadotrophin levels, error within the brain (understand the effects and mechanism
is important)
T feedback:
No evidence of direct T feedback on pituitary in humans (only hypothalimis), this because it
occurs animal models (rodent vs human)
Indirect via in situ T→E conversion in aromatase. Anterior pituitary and hypothalamus both
produce aromatase, potentially T in AP is converted to estrogen which is having a -ve effect
Testicular E synthesis. In human males, Leydig cells are the main source of testicular
estrogens. Sertoli cell only produce a small amount compared to leydig cells.
Signalling depends on the protein
polypeptide protein→signal via cell surface
Steroid→within nucleus or cell cytoplasm
Androgens (testosterone & DHT) – Androgen receptor
Estrogens (estradiol & estrone) – Estrogen receptors ERα ERβ
Each have a A/B, C, E, D and alpha has a F
domain. D contains the nuclear
localisation signal (brings receptor into
nucleus.) E domain location of ligand
binding to receptor. Variation is in A/B, relating to interaction with transcription. Signalling
is by classical signalling pathway.
Classical Nuclear receptor signalling
Steroid passes membrane encounters nuclear receptor bound to a HSP (originally to
protect it) disassociates in ligand presentsLigand and receptor dimerises and pass in
nucleases reacts with transcriptions causing an effect on the cell.
Note change of gene transcription and protein factors do not present for a while.
This pathway can be inhibited at any step. MDV3100 can be used to stop ligand from
binding. i.e in prostate cancer. Or the use of finasteride to block 5alpha reductase. Or target
HPG axis by using a GnRH agonist.
Non-classical nuclear response
Ligand binds to its receptor and the receptor is locked into the cell membrane. Or estrogen
can signal different receptor (g protein). This causes an effect on cytoplasmic kinases causes
rapid mediated effects (minutes.)
Hormone action is complex
• Administration of hormones to whole animals effect the endocrine system
– Reduction of other hormones and subsequent effects on target organs
• Also direct effects on target tissues themselves
Formally prostate cancer would be treated by estrogen to supress HPG axis (reducing
androgens) however this has local effects also. (rapid proliferations of epithelial cells).
(reduced testosterone hence smaller prostate???
Determining receptor may be to uses
- Stimulate with agonist
- Block with antagonist
- Knock-out (& transgenic) mice - (full, conditional, tissue specific)
Transgenic models
For estrogen effects in an animal
ArKO – no aromatase
AROM+ - excess aromatase
• αERKO – no ERα
• βERKO – no ERβ
• αβERKO – no ERα or ERβ
• NERKi – membrane signalling only
• AF2ERKi – AF2 mutation (ligand dependent transcription activation domain)
• UtEpiαERKO - Uterine epithelial-specific ERα knockout (for specific tissue)
Testis:
Testis:
-Reproductive tract undergoes normal pre- and neonatal development
-Age-related phenotype of attenuated fluid resorption in efferent ducts leads to dilation
of Rete testis
-Atrophy of the seminiferous epithelium, and decreasing sperm counts
-Disrupted sperm function illustrated by an inability to fertilize
-Age-related decreases in testis weight
Prostate:
-Age-related increases in seminal vesicle weight
-proliferation
-inflammation
-stimulation of ERα leads to squamous metaplasia
βERKO
-Undergoes normal pre- and neonatal development with no apparent defects in
spermatogenesis that impede fertility
Prostate:
-Stimulation of ERβ leads to apoptosis and decrease in proliferation (beneficial actions)
-Lack of ERβ signalling leads to prostate hyperplasia in adulthood
Androgen receptor is mostly expressed in the epithelium and the stroma, Estrogen receptor
α is largely just within the stromal tissues, and estrogen receptorβ is the epithelium and
stroma.
this shows the importance of receptor localisation. Highlights that the androgen in the
epithelium does not affect prostate growth, rather that androgen in the stroma that DOES.
• Steroids have preferred action at receptor subtypes:
– Estradiol is selective for ERα
– Genistein is selective for ERβ
– Some steroids are mixed agonists / antagonists
• Utility for therapeutic activity (blocking negative effects and stimulating positive
effects)
• Or stimulating AR / ER in specific tissue types (i.e. in breast or prostate, but not brain
or bone)
• Or blocking steroid production (aromatase inhibitors)
Week 3-Ovarian Physiology
Gap between the ovary and infundibulum causes egg to be lost resulting in atopic
pregnancy.
Ovary formation
Surrounded by germinal epithelium
Middle medullary region is heavily
vascularised. Usually stroma,
fibroblast cells. However there is
cellular and less matrix in the ovaries.
Outer cortex is less vascularised, this
is important in follicular development
(less O2).
The GREL cells in the primordial ovary which give rise to the granulose and the surface
epithelium. The stroma cell play a role when they move and break up Oregonia.
Tunica albuginea is the connective tissue which underlays epithelium.
Oogenesis – development in the fetal ovary
Production of female germ cells Primordial germ cells migrate to the coelomic epithelium of the gonadal ridges. After embryonic sexual differentiation primordial germ cells proliferate and become oogonia. By week 20 of pregnancy ~7 million oogonia present. the oocytes are able to stay as a Primary oocyte for up to 50 years. Only one follicle per a cycle is selected to continue meiosis The polar body forms from cytoplasm which contains equal number of chromosomes, but will eventually degenerate to form a diploid number. Oocyte mutation is out of phase with follicular genesis.
The ovary at birth Most follicles remain in the resting stage This pool of follicles constitutes the ovarian reserve including:
• Primordial oocyte – surrounded by flattened granulosa cells
• Transitory follicle – oocyte surrounded by a mix of flattened and cuboidal granulosa cells
• Small primary follicle – oocyte surrounded by a single layer of cuboidal granulosa cells
The ovarian reserve does not divide so it is a set number, at birth there at 1000000, but at menopause is reached when there is <1000 left in ovary.
Follicles
• Basic unit of female reproduction
• Roughly spherical cellular structure Comprises: Oocyte (egg) Granulosa cells Theca cells
Develop from primordial follicle to ovulation by a number of different stages Many different stages of development can be seen in ovary at any one time. Secondary follicles have more than 1 layer of granulose cells. Multiple sections of follicular development can be seen as it takes more than 3 months for primary follicles to develop into secondary follicles and more to develop into dominate follicle (<6cycles) Primordial follicle
The most basic follicle Can only observe oocyte Surrounded by flattened layer of cells Follicle recruitment is by factors which signal development, why one particular one us recruited over another is unknown. Primary follicle Small primary follicle Cuboidal epithelial cells surrounding oocyte
Large primary follicle Epithelial cells start to proliferate and form many layers, become known as granulosa cells Thick glycoprotein layer – zona pellucida - forms between oocyte and granulosa Stroma around follicle develops into theca Definitive theca layers only appear when follicles have 3-6 layers of granulosa cells Antral follicle (from secondary follicle) Surrounding theca differentiates into: 1.Theca interna – rounded cells which secrete androgens and follicular fluid – important for production of steroid hormones 2.Theca externa – spindle shaped The antrum forms within the growing follicle to cushion and filled with follicular fluid which maintains osmolality and nutrients. This fluid that is released with the egg at ovulating to assist with transition to fallopian tube. Graafian follicle Named after Reinier de Graaf Follicular fluid fills the space now called the antrum – this is surrounded by the granulosa cells The granulosa cells specifically surrounding the oocyte now called the cumulus oophorus which signal back to oocyte to develop whereas the outer layer is called the mura granulosa cells. One transitions to become the dominant follicle Dominant follicle A selectable follicle is 2-5mm During the late luteal phase they respond to increasing FSH Selectable follicles respond to FSH to stimulate granulosa cell proliferation but not estrogen production The selected follicle – which becomes the dominant follicle is the one which grows most rapidly in response to FSH Steroidogenesis in the dominant follicle From the time it is selected the follicle destined to ovulate shows marked changes in steroidogenic activity – enhanced androgen production, aromatase activity (only detected in follicles >10mm) The selected follicle initiates estrogen production – this differentiates it from other follicles Positive correlation between granulosa cell aromatase activity, the number of granulosa cells and the estradiol concentration in the follicular fluid This follicle will ovulate – others will disappear by atresia
Theca cells respond to LH the granulosa to FSH and produce estrogen. Follicle that is destined to ovulate enlarges to ~18mm during late follicular phase Shows changes in steroidogenic activity - ↑ androgen production by thecal cells, ↑ aromatase → ↑↑↑ estrogen Granulosa cells can now bind LH – this replaces FSH as the steroid hormone stimulus At mid-cycle gonadotropin surge the follicle switches to progestin production – essential for ovulation (progesterone receptor antagonist prevents ovulation, progesterone receptor knockout animals do not ovulate) LH increases progesterone receptor expression in granulosa cells. Oocyte dying- Initial recruitment prior to puberty die as they do not survive the antrum start (lack of hormones). Polycystic ovary syndrome- due to a hormone imbalance, high LH, and follicles do not mature and will develop into cysts. This leads to high inulin and high testosterone leading to infertility. Week 11 Reproductive Cancer – Prostate
Cancer-
Cancer is a disease of the body's cells
Caused by a mistake in the genetic profile,
causing loss of controlled cell growth
Genes that regulate cell growth and
differentiation are altered, tumour
suppressor genes or oncogene mutation
Cells undergo ‘malignant’ transformation
Arises from almost any type of tissue.
Treatment resistance is the largest killer.
Defining feather of cancer is the ability to
spread to surrounding areas, or different
parts of the body. (metastasize, moving from
sight of origin) Cancer cells that do not
spread beyond the immediate area in which
they arise are said to be benign ie. they are
not dangerous.
Hallmarks of Cancer
1. Cancer cells stimulate their own growth (proliferation) 2. They resist inhibitory
signals that might otherwise stop their growth 3. They resist their own programmed
cell death (apoptosis) 4. They stimulate the growth of blood vessels to supply
nutrients to tumors (angiogenesis) 5. They can multiply forever (immortality) 6. They
invade local tissue and spread to distant sites (metastasis)
There are now 10 hallmarks with the update.
In prostate cancer, there are lots of cells presents.
It is inside stroma tissue where all
microenvironment cells can be found. i.e cancer
associated fibroblasts, immune cells and blood
vessels.
Germline Mutations
• Family History • Tumour susceptible genes • BRCA1/BRCA2. They occur within the germ
cells and hence will be passed on.
Somatic Mutations
• No Family History • Tumour susceptible genes • TMPRSS2:ERG fusion. These arise in every
other cell in the body due to specific mutation in tumour suppressor genes.
Mutation in DNA ultimately changes to gene expression and RNA.
Breast cancer subtypes- grouped based on estrogen receptor alpha gene. Which defines the
tumours ability to respond to estrogens. ER negative tumours → treatment is more limited.
ER positive tumours-can respond well to estrogen hence treatment can be used to target
this → better outcomes.
Personalised Medicine: At the heart of the change: an emerging ability for researchers to
use genetic information to match drugs to the biological drivers of tumors in individuals.
BRAF Inhibitors in Melanoma
Standard treatment for skin cancer has shown limited success – 5% response rate Skin-
cancer patients with a mutation in a gene called BRAF, 48% responded to a targeted
treatment. Use of a BRAF inhibitor have been shown to cure melanoma.
Treatment Resistance
Therapy resistance occurs when cancers that have been responding to a therapy suddenly
begin to grow. In other words, the cancer cells are resisting the effects of the
chemotherapy. “Cancer chemotherapy failed" Drugs need to be changed
There are several possible reasons for therapy resistance: – Some of the cells that are not
killed by the therapy mutate (change) and become resistant to the drug. Once they multiply,
there may be more resistant cells than cells that are sensitive to the therapy.
– Gene amplification. A cancer cell may produce hundreds of copies of a particular gene.
This gene triggers an overproduction of protein that renders the anticancer drug ineffective.
– Cancer cells may pump the drug out of the cell as fast as it is going in using a molecule
called pglycoprotein.
– Cancer cells may stop taking in the drugs because the protein that transports the drug
across the cell wall stops working.
– The cancer cells may learn how to repair the DNA breaks caused by some anti-cancer
drugs.
– Cancer cells may develop a mechanism that inactivates the drug. Research is underway
to investigate ways of reducing or preventing chemotherapy resistance.
Prostate Cancer
• Most common cancer in Australian men – 1 in 5 Australian men will develop in their
lifetime – Second most common cause of cancer death in men (after lung cancer)
• Aetiology largely unknown, but is age and
hormone related – Androgen deprivation is
primary therapy.
• Vast majority are adenocarcinomas (arise from
glandular epithelium)
Histologically graded using the Gleason
system/score
The Prostate Gland
3 zones PZ = peripheral zone TZ = transition zone
CZ = central zone
Prostate cancer primarily arises from peripheral zone.
Detection of Prostate Cancer
Blood Test looking for prostate specific antigen (PSA) which is produced by prostate
epithelia cells • Rising PSA best indicator (regular testing)
Digital Rectal Examination (DRE) (feels tumour nodule) TRUS Biopsy
Screening Debate – Pro-PSA
• Early and regular PSA testing detects earlier stage prostate cancer • Reduces morbidity
and mortality of incurable prostate cancer • Rising PSA best indicator (regular testing) •
Circumstantial data suggesting cancers detected on screening are more likely to be
localised, and are of significant volume and grade
Screening Debate – Anti-PSA
• Accurate screening & diagnosis – false
positives • Predictive value of
information – latent or aggressive •
Resultant effects of treatment, including
surgery compared to watchful waiting
(Lack of evidence that early detection
and treatment leads to mortality (death)
reduction) • Cost to the community -
appropriate use of resources?
Gleason score = most common Gleason
grade + highest Gleason grade Gleason
score ≥ 8: treatment Gleason score ≤ 7:
ambiguous Gleason score/grade 3+3 = 6
4+3 = 7 3+4 = 7 4+4 = 8
This alludes to the patient outcomes.
Patients are first caught in a indolent stage
and then surveyed (active surveillance)
until it starts to change.
Major clinical challenge: Distinguishing between indolent and aggressive disease
Surgery – Radical Prostatectomy –
Complications: incontinence,
impotence External-beam
radiotherapy Brachytherapy –
Implanting radioactive pellets or seeds
containing iodine 125
Second Line Management for
Advanced Disease
Hormonal control – Androgen
ablation therapy – GnRH agonists
[positive-feedback; overrides pulsatile secretions] – Anti-androgens [blocking AR or
androgen synthesis] – Leads to androgen-independent disease – Complications: Loss of
sexual interest, impotence Chemotherapy – Docetaxel [cell-spindle stabliser; stops cell
division] – Mitozantrone [anthrocycline; anti-tumour antibiotic] – Cyclophosphomide
[alkylating agent]
Androgen independent (non-responsive to androgens) is not the same as castrate resistant
(still requires androgens to control growth, cells begin to shift and express different
enzymes) a drug being developed, Abiraterone Acetate – Enzyme Inhibitor, block pathway,
preventing the cancer from making its own androgens.
Enzalutamide (MDV3100) – AR Antagonist- stops interaction with testosterone preventing
changes in gene transcription.
Steroid Production in Castrate-Resistant Prostate Cancer (CRPC)
Androgen-independent does not = castrate-resistant prostate cancer • Tumours failed ADT
adapt to low androgen environments and make their own steroids i.e. prostate cancer is still
reliant on androgens • New drugs try to further block steroid metabolism
OBJECTIVES
1. Understand the basic cellular and molecular events associated with cancer – Hanahan
and Weinberg Interactions between cancer cells and microenvironment
2. Describe the disease progression of prostate cancer – Understand treatment resistance.
Genetic changes in the cancer cell and/or the tumour microenvironment. – Castrate-
resistant prostate cancer