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Week 12: Cancers (Basics (A primary tumour becomes malignant when it…
Week 12: Cancers
Basics
A primary tumour becomes malignant when it invades surrounding tissue
Uncontrolled proliferation
of genetically altered cells
Spread via blood or lymph to colonise distant organs (
metastasis
)
Origins
Background mutation rate i.e. genetic
Some paediatric tumours
Most rates vary greatly, i.e. environmental
Melanoma is 155x more common in Australia than Japan
Stomach cancer 8x more common in Japan than the US
Liver cancer 50x more common in China than Canada
Secondary to external factors, with exposure over time (many decades) causing cancer
Steps
Initiation
: mutation in a single cell (initiated cell)
Promotion
: initiated cell proliferates; normal cells undergo clonal expansion and accumulate additional mutations
Malignant conversion:
critical irreversible mutation
Progression
: malignant cells continue to mutate
Tumorigenesis
UV irradiation (>7200/year)
Poor diet (>7000/year)
Tobacco smoke
30% of all cancer deaths in developed world
15,500 cancers/year (AU)
Initiators: metabolic activation (
PAH/NNK
) leading to reactive forms, DNA adducts, gene mutations (cytosine to adenine
transversions
); also promoter: irritant leading to inflammation
60+ carcinogens:
volatile organics
(aldehydes e.g. acrolein, formaldehyde),
polycyclic aromatic hydrocarbons
(PAH – e.g. benzopyrene),
tobacco-specific nitrosamines
(e.g. NNK), and
heavy metals
(e.g. chromium, lead)
Infections (>3400/year)
Alcohol (>3200/year)
Progression
Eight capabilities gained through multiple mutations
Self-sufficient in growth signals
Insensitive to growth-inhibitory signals
Can evade cell death (apoptosis)
Can proliferate indefinitely (immortalised)
Can promote blood vessel growth (angiogenesis)
Can spread away from primary tumour (invasion and metastasis)
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Six stages of progressive tissue changes
Normal tissue
(e.g. epithelium)
Hyperplasia
(minimal change, increased proliferation)
Dysplasia
(cells no longer look normal)
Carcinoma
(adenoma or papilloma i.e. visible lump)
Local invasion
(breaching of basement membrane)
Metastasis
(colonies in distant organs)
Growth
Normal growth in
metazoan cells
Quiescent
until receive mitogenic signals
Growth factors instruct cells to proliferate, and they enter the cell cycle
Act via growth factor receptors (
GF-R
); receptor tyrosine kinases that convert
EC
to
IC
signal
Neighbouring cells also release growth inhibitory factors if the time isn’t right
Growth factor signalling
GF – ligand (
EC
)
GF-R –
RTK
IC signalling cascade
Phosphorylation (+++)
Activation of targets
Signalling can be co-opted at any steps in the signal transduction pathway, leading to uncontrolled proliferation
1. Self-sufficient for growth signals
Decreased growth factor dependency for growth
Oncogene activation
occurs when cells produce own growth signals
Autocrine GF production (
PDGF
– glioblastoma)
Overexpression of GF-R (
EGFR
– breast, stomach)
Constitutive activation of GF-R (
EGFR
)
Constitutive activation of
intracellular signalling
Ras/Raf/MAPK
proliferation pathway
PI3K/Akt
growth /survival pathway
2. Insensitivity to growth inhibition
Normal cells sense if appropriate for division to go ahead; signals routed through
tumour suppressors
, i.e. products of anti-oncogenes
Dozens of tumours suppressor genes (
TSGs
) limit cell proliferation
Familial cancers often due to inheritance of a mutated allele in a TSG
Retinoblastoma (Rb) – most extracellular anti-proliferative signals (e.g. TGF-beta) use the Rb pathway
Force cells out of the cell cycle and into G0
Induce cells to enter a post-mitotic state (i.e. undergo terminal differentiation)
Retinoblastoma protein
Hypophosphorylated Rb sequesters
E2F
to block G1/S cell cycle progression
Growth factors cause formation of
hyperphosphorylated
Rb, which releases
E2F
and enables cell to enter the cell cycle (i.e. G1 to S)
Familial retinoblastoma
_
Mutated Rb gene (one allele)
Second allele mutates during development
Uncontrolled proliferation; children present with
bilateral retinoblastomas
TSGs decrease proliferation or increase apoptosis
3. Evasion of cell death
Resistance
Increased expression of
hormone receptor (ER and AR)
, a survival signal
Increased expression of anti-apoptotic proteins, e.g. B cell lymphomas often show upregulation of
Bcl-2
Apoptosis
Programmed cell death, i.e. a carefully regulated process – cell structures are degraded, nucleus fragmented, cell corpse engulfed without scarring
Essential for normal development e.g.
finger webs
; important in adult homeostasis – cell damage sensors look for abnormal/stressed cells and induce apoptosis
Most common pathway affected include mutations of the
p53
tumour suppressor gene
p53 is a key
DNA damage sensor
(activates apoptosis in cells with severe DNA damage or metabolic problems)
Dominant negative (interfere with
WT
protein) or inactivating p53 mutations are seen in around half of tumours
4. Cell immortalisation
Normal cells divide a finite number of times (
Hayflick number
)
While
telomerase
is normally expressed only in the embryo,
re-expression
is used to immortalise cells into experimental cell lines
Mitotic ‘counting devices’ with multiple TTAGGG repeats (100-1000s). 50-100bp are lost per cell division; DNA polymerases can’t replicate 3’ ends of chromosomes
Telomere loss leads to
senescence
and/or
apoptosis
, so
telomerase
– specialised DNA polymerase with a template to transcribe 6bp telomere repeats – acts to maintain telomeres in the embryo
Associated with 85-90% of tumours (increased telomerase expression)
UV radiation induces
ETS factor
binding to
TERT promoter
, forming melanocytes
5. Angiogenesis
All cells need nutrients and oxygen to remove waste (<100 micromoles from blood vessel)
Early tumours lack the ability to promote
angiogenesis /neovascularisation
, but can 'flick the switch' to grow
Complex process involving many positive vascular endothelial GF (
VEGF
) and basic fibroblast GF (
bFGF
) signals, plus negative thrombospondin-1 (
Tsp-1
) and
angiostatin
signals
Results in a shift in balance of signalling proteins, triggering angiogenesis
Tumour cells and
stromal
cells contribute to altered balance
6. Tissue invasion & distant metastasis
Colonisation of multiple distant sites causes around 90% of cancer deaths (as opposed to primary tumour growth)
Metastatic cascade
Carcinoma in situ moves and degrades basement membrane, resulting in
intravasation
Cells stick to blood vessel walls,
extravasate
, and survive and proliferate in the new environment
Colorectal cancer (
CRC
) metastasises to liver (portal circulation)
Breast cancer
spreads to bone, lungs, liver, and brain
7. Evading the immune system
The immune system patrols tissues and routinely eliminates the vast majority of abnormal cells
Successful tumours evade the immune system by co-opting immune cells to increase growth and encourage invasion, e.g.
TAMs, Tregs, DCs
Melanoma
Progression
: benign nevus, dysplastic nevus, radial-growth phase, vertical-growth phase, metastatic melanoma
Sequential mutation
s: MAPK pathway, telomerase upregulation, G1/S checkpoint override, chromatin modulation, further MAPK activation, further cell cycle dysregulation, p53 pathway disruption, PI3K pathway activation
Familial cancers
(Pre-existing mutation)
TSGs
Retinoblastoma
(Rb) – controls progress through cell cycle
Li-Fraumeni
syndrome (TP53) – controls entry into apoptosis
Neurofibromatosis
(NF1) – RasGAP
Von HIppel-Lindau
disease (VHL) – controls HIF-1 levels
Familial Adenomatous Polyposis
(APC) – controls beta-catenin levels
Genome maintenance/DNA repair genes (caretakers)
Lynch syndrome
(HNPCC) – MSH2, MLH1, MSH6, PMS2, PMS1
Breast
and
ovarian cancers
– BRCA1 and BRCA2
Chemotherapy
Overview
History
Surgery (excision or debulking)
1950s
: radiotherapy appeared as a result of the development of megavoltage linear accelerators
1940-60s
: drug-based therapies first developed as systemic treatments that aimed to selectively kill tumour cells
Initially, chemotherapy developed to treat
leukaemia
&
lymphoma
; used in combination with surgery, radiotherapy, biological therapy (bone marrow transplants)
WW1
Mustard gas victim autopsies revealed
myelosuppression
and
lymphoid hypoplasia
WW2
Bombing of Allied ships released mustard gas – survivors developed severe
myelosuppression
Nitrogen mustard
thus developed for treatment of lymphoid malignancies
Folic acid
Low in
megaloblastic anaemia
, but high proliferation in acute lymphoblastic leukaemia
Folate analogues (
anti-folates
) were synthesised for A.L.L. remission
Terminology
Neoadjuvant
Given before surgery to shrink tumour and make surgery less extensive
Adjuvant
Given after surgery to destroy remaining cells and prevent recurrence
Induction
Given to reduce remission, commonly used in the context of leukaemia treatment
Consolidation
Given once remission is achieved
Definitive
Curative, e.g. for an early stage tumour that is chemotherapy sensitive – testicular cancer
Palliative
Not curative; used for symptom management