Biology 2 How do Cancers Grow? Flashcards
What are the 6 hallmarks of cancer?
Sustained proliferative signalling Evading growth supressors Activating invasion and metastases Enabling replicative immortality Inducing angiogenesis Resisting cell death
What are telomeres?
The repetitive regions at the end of chromosomes, each time a cell divides, the telomere gets shorter (unless telomerase is active to restore them).
What is telomerase?
It is not normally active in cells apart from in germ cells and stem cells.
Around 90% of malignant cells express telomerase. This enables telomeres to be restored and cell division to continue unrestricted.
What is senescence and when does it occur?
cellular old age - occurs when telomeres have reduced to an inactive size/been used up after X no. of cell divisions.
What happens if p53 is lost?
If normal cell checkpoints are lost or disrupted then cell division continues until the cell reaches “crisis”.
In some cases cells escape crisis by activating telomerase or by alternative telomere lengthening (ATL) –> this is a way in which cancer cells become immortal as according to hallmarks of cancer.
Which of the 6 Hallmarks of Cancer are relevant in this lecture?
Replicative immortality
How is replicative immortality ensured?
Telomerase or Alternative Telomerase Lengthening to allow cell division to continue (for example in absence of p53).
What is ATL?
Alternative telomerase lengthening
In cells that don’t express telomerase, recombination or fusion between the ends of different chromosomes occurs. The cells that survive ATL then have chromosome rearrangements (fused, deletions, amplifications)
Some of these changes may be oncogenic
How do cells know what to do?
How do they know how to divide, grow, rest, die, differentiate, move etc
They sense the environment and respond accordingly from stimuli transduced to nuclei which can lead to changes in gene expression etc
Receive chemical messages (growth factors, mitogens, cytokines, hormones). If this foes wrong it can lead to uncontrolled proliferation and cell survival.
Name two oncogenes
MYC and RAS
Name two tumour suppressors
p53 and Rb
What is the effect of Myc and Ras on the cell cycle?
Inhibits checkpoints in the cell cycle that are regulated by p53 and Rb. These checkpoints would normally repair any damages to DNA or abnormalities etc or programme cell death (apoptosis) but without them, damaged DNA etc goes on to proliferate.
Three S’s of receptors
Specificity (ligand-protein and protein-protein)
Signal amplification
Signal convergence
What types of receptors are there?
Receptor tyrosine kinases, (RTKs i.e. EGFR, VEGFR)
Steroid hormone receptors (nuclear receptors) e.g. estrogen receptor.
G-protein coupled receptors - despite being common drug target, not many anti-cancers use this as a target.
What is EGFR?
Epidermal growth factor receptor, senses growth signals and leads to an increase in proteins needed for cell division.
What is the EGFR signalling pathway and what does it lead to?
Two proteins bind to the EGF receptor and activates RAS (oncogene). This leads to downstream signaling to RAF–> MEK and switches on genes for proliferation via EKR (kinase transcription factor).
PI3K is also activated and leads to AKT; normally this leads to cell apoptosis, p53 or protein synthesis. In cancer cells, apoptosis and TP53 is downreglated and protein synthesis/cell division proliferates.
EGFR mutations
Cancers are caused by mutations and EGFR is frequently mutated in cancer;
changes in DNA, protein sequence, protein function. In this mutation EGFR is permanently activated, as if bound to EGF which causes the cell to divide.
Which drugs target the EGFR and how do they work?
Cetuximab is an antibody that binds to the receptor and blocks it
Erlotinib and Gefitinib look like ATP and stop EGFR activation by blocking functional ATP.
How do Erlotinib and Gefitinib fair against mutant EGFR?
The same EGFR mutations that promote cancer also make EGFR more sensitive to erlotinib and gefitinib. A patient’s cancer DNA sequence is determined to decide which drug is used - personalised medicine example.
What is the mechanism behind tyrosine kinase inhibitors?
Competitive inhibition of ATP binding
What are steroid hormone receptors?
Steroid hormones are derived from cholesterol (a lipid membrane component). They can diffuse into cells so there is no need for cell surface receptors.
Steroid hormone receptors are part of the same nuclear receptor superfamily. They are transcription factors that become activated by steroid hormones e.g. estrogen receptor, androgen receptor, progesterone receptor, retinoic acid receptor.
What is an estrogen receptor and how is it activated?
An exmaple of a type I steroid hormone receptor that is activated in the cytoplasm. Estradiol is the ligand that diffuses into the cell. Binds to the receptor, displacing associated chaperone proteins e.g. HSP90. The ER dimerizes and migrates to the nucleus. ER dimer associates with co-activators or co-repressors to modify transcription of target genes.
What kind of drug is tamoxifen?
It is a pro-drug
Metabolised to active metabolite CYP2D6
Binds to the ER with much higher affinity than estrogen
It is therefore an estrogen antagonist (with some unexpected agonism).
Known as a selective-ER-modifier (SERM)
What is Fulvestrant?
A pure anti-estrogen (without the agonism that is associated with Tamoxifen).
Prevents dimerisation and therefore activation of ER
Known as a selective-ER-down regulator (SERD)
