Cancer Cell Biology ☺️ Flashcards
Cancer
- what is it
- what causes it
Disease where abnormal cells
- divide without control
- invade nearby tissues via blood and LN
Environmental/lifestyle affects genome
- infection - HPV=> cervical
- carcinogens - smoking=> lung
- diet - alcohol
Genetics
- inherited - BRCA
- somatic - RAS
How does RAS work
GTPase - can be ON/OFF
GDP bound protein - OFF
GTP bound protein - ON => bind to effector proteins
RAS cannot be switched off in cancer
-most common in pancreatic tumours
RAS activates many pathways needed for cancer cells
- transcription, cell cycle progression
- cell survival, growth, migration
Describe the cell cycle
Interphase -G0/1 = quiescent/organelles replicate Rb phosporylated => transition from G1 to S -S = DNA replication -G2 = growth of structural elements
Mitosis
- M = nuclear division and cytokinesis
- mitotic checkpoints present
If cell cycle too fast, DNA replication more likely to have mistakes
How do cyclins affect the cell cycle
Cyclins - bind to cyclin dependent kinase => move cell through cell cycle
-regulate the checkpoints between each stage of the cell cycle
Phosphorylates Rb gene => G1 to S
How does TGFb affect tumour progression
Roles include
- tumour suppressing responses
- environmental modifying responses
- cause changes in phenotype
Cancer cell does not respond to TGFb due to
- lack of TGFb receptor
- lose response to TGFb but TGFb still being produced
CAN STILL ACT
- changes in phenotype of integrins and ecadherins => easier to metastasise
- stimulate release of angiogenetic factors (VEGF)
- stimulate connective tissue formation
- stimulate chemokines and cytokines that make it easier for the metastasised tumour to grow in a distant organ
- increase immunosuppression against tumour
What is genomic instability
Increased tendency of genome alteration during cell division due to
- increased frequencies of base pair mutations
- microsatellite instability
- chromosomal structural variation
Resisting apoptosis
- when does apoptosis happen
- how do we get resistance
Induced in response to DNA damage or oncogene activation
-mediated by p53
Resistance achieved by
- loss of p53 signalling (non functioning/too much MDM2/inactivation of DNA damage kinase)
- upregulation of prosurvival factors like Bcl2
How does p53 work
A gatekeeper gene -directly regulates tumour growth by inhibiting growth/induce apoptosis
If no DNA damage present
-p53 degraded by MDM2
If DNA damage present
- DNA damage kinase detects this => phosphorylates p53
- MDM2 inactivated
- cell cycle arrest/sensence/apoptosis
Caretaker/stability genes
- how does MMR (mismatch repair gene) work
- what happens if you lose this function
- examples
Correct base mispairs
Accummulation of spontaneous errors
-BRCA1, 2
Importance of BRCA1, 2
-significance of BRCA1, 2 mutations
How can we exploit BRCA1, 2 mutations in cancer treatment
Caretaker gene - encode proteins that stabilise genome, by repairing breaks
Proteins act as scaffolds that allows for repair
-BRCA1 - recognises double breaks
-BRCA2 - supports repair
BRCA1/2 needs double hit to not function
If BRCA1, 2 ability lost => cells still have PARP activity
-key in DNA single strand break repair
Synthetic lethality
-By using PARP inhibitors => cell can no longer repair DNA damage adequately to survive
Enabling replicative immortality
-avoiding telomere shortening
What happens in a normal cell
How does this differ to cancer cells
Normal cells
- telomere repeat sequences
- polymerase doesn’t transcribe the ends of DNA => lose telomeres instead of useful DNA
- if telomeres lost => p53 triggered => senescence
Cancer cells
-telomerase lengthens telomeres so cell senesence cannot be achieved
Inducing angiogenesis
Activating invasion and metastasis
When tumour gets larger, normal vasculature cannot supply the increased metabolic demand
-hypoxia triggers angiogenic switch (VEGF)
Form own vessels to maintain high metabolic rate
-increased pathways to the vasculature
Must be able to
- alter cell adhesion
- increase motility - downregulation of ecadherin (no longer attached to other cells) and changes in type of integrin (detach cell from BM)
- degrade matrix with metalloproteinases - form a pathway to the vessels
- intravasate, survive in the circulation, arrest, extravasate
Describe locations and patterns of metastasis
Different primary cancers have specific patterns and locations of metastasis
- prostate => bone
- lung => v early mets to liver
Seed and soil hypothesis
-if a local/distant organ secretes a cytokine/chemokine that the tumour has a receptor to, the tumour will preferentiatlly migrate to that organ
How do cancer cells avoid immune destruction
Tumour cells can dowregulate MHC => reduced tumour antigen presentation
Tumour cells produce chemokines that
- attract Tregs
- TGFb converts CD4 => Tregs
Tumour cells express PDL1 => inhibit programmed cell death to suppress Tcell response
Describe tumour promoting inflammatory processes
- macrophages
- describe the relationship between the 2
Tumour microenvironment promotes emergence of M2 macrophages
Functions
- produce immunosuppresive molecules
- secrete growth factors => tumour cell proliferation
- secrete angiogenetic factors => promote angiogenesis
- support invasion
Costimulatory relationship => may aid intravasation
M2 secretes EGF needed by cancer cells
Cancer cells secrete CSF1 needed by M2
M1-kill tumour cells
M2-promote antiinflammatory functions => promote tumour progression
Types of genetic alterations
Chromosomal imbalance
Single gene - tumour suppressors and oncogenes
Epigenetic abnormalities
Somatic mutations vs germline mutations
Driver mutations vs passenger mutations
Somatic
- in non germline tissues
- cannot be inherited
Germline
- in egg/sperm
- can be inherited => all cells in offspirng affected
Driver - positively selected due to growth advantage
- causally implicated in oncogenesis
- often 2-8 driver mutations
Passenger - not selected for
-does not contribute to cancer
Protooncogenes => oncogenes
Tumour suppressors => non functional tumour suppressors
Regulate cell proliferation Gain of function dominant mutation => oncogenes that promoted proliferation -only 1 copy needed to be faulty -Her2 - breast -KRas - colorectal -BRAF - melanoma
Inhibit tumour formation
Loss of function recessive mutation => cell proliferation increases
-both copies must be faulty (2hit hypothesis)
-TP53 - LiFraumeni
-RB1 - retinoblastoma
Common hereditary cancer syndromes
- HBOC
- LiFraumeni
- Lynch
- FAP
- MEN2
- Familial retinoblastoma
- phaechromocytoma syndrome
HBOC - breast, ovarian
LFS (SBLA) - sarcoma, breast, lymph/leukemia, adrenals
Lynch syndrome (MMR genes) - colorectal
FAP (APC gene) - colorectal
MEN2 (RET gene) - medullary thyroid
Familial retinoblastoma (RB1 gene)
Phaechromocytoma syndrome (SDHx gene) - phaechormocytoma
Red flags suggestive of hereditary cancer
Multiple tumours, associations between different tumours
Inheritance pattern
Young age, ethnicity (BRCA1, 2 in Ashkenazi)
Lynch syndrome
- pathophysiology
- possible treatments
Germline mutation in MMR genes - microsatellite instability => colorectal, ovarian cancer
Leads to formation of neoantigens => stimulate antitumour response of host
Tumour upregulates PD1 => avoid immune surveillance
PD1inhibitors target this to restore immune function
EGFR in sporadic non small cell lung cancer
- function of gene normally
- what happens when it mutates
Epidermal growth factor receptor - regulates signal pathways to control cellular proliferation
Becomes oncogene with driver mutations
Tyrosine kinase inhibitors can block this pathway to reduce signalling
