Cancer 2 Flashcards
Understand the molecular reasons for underpinning the formation of cancer (hallmarks)
A
Understand why cancer can be difficult to treat
- We don’t know all the mutations that cause cancer and/or we don’t have accurate tests for them
- even if we do know the mutation we don’t have drugs to treat all mutations
- if we have a drug.. Tumours are genetically unstable, they develop new mutations, bypass therapy
- primary tumour may have different characteristics to secondary tumours
- multiple drug combinations are toxic
Hallmark : Self sufficiency in growth signals
-normal cells need growth signals to proliferate
With help of growth factors, components of the extracellular matrix(ecm), cell-cell adhesion
-Cannot grow in absence of these stimuli
-Cancer cells are able to grow independently
WK- cancer 4, page8
-Key words:-
Ligands bind,physiological signalling, cells divide, growth factor is produced, receptor causes internal signalling, autocrine signaling, cells co-express PDGFR (platelet-derived growth factor), ie overexpress the message and the messenger, overexpresssion of the receptor allows the cells to be hyper-responsive to normal levels of gf , direct mutation of receptor, ligand independent signaling
Hallmark: insensitivity to anti-growth signals
- “off switch “
- checkpoints in cell cycle are ignored
- G1 - cellular contents, excluding the chromosomes are duplicated
- S each of the 46 chromosomes is duplicated by the cell
- G2 the cell “double checks” the duplicated chromosomes for error, making any needed repairs
- Mitosis
CHECKPOINT AFTER METAPHASE
Determines whether all the sister chromatids are correctly attached to spindle microtublees
CHECKPOINT DURING G1
External signals.: cell decides whether to proliferate or not
CHECKPOINT DURING G1/S
Cell look for DNA damage try to fix themselves before progressing with the cell. Managed by p53
CHECKPOINT DURING G2
Cell assess whether the chromosomes replication has been successfully. Decides whether to continue with the cell cycle or not.
ALL OF THESE SIGNALS SENSED BY THE RETINOBLASTOMA PROTEIN (Rb)
Hallmark: evading apoptosis
- “cell suicide program” after all previous chemical signals stop
- The ability of cancer cell numbers to increase = cell divison>cell death ( tumour will grow when cell division is more than cell death)
- large number of cancer cells die
- programmed cell death (AKA apoptosis)
- how do cancer cells evade it p53 in quality control of cell cycle
- p53 is a tumour suppressor (there to stop cells from dividing out of control)
- describe as the “guardian of the genome” If DNA damage is identified it will halt the cell cycle (G1/S), it activates DNA repair proteins when DNA has sustained damage, it initiates apoptosis of the damage can’t be repaired
- the loss of p53 is the most common mutation in cancer
- mutation or deletion seen in over50% of human tumours
- can be caused by mutagens, inherited gene mutation,pathogens eg virus
Hallmarks:Limitless replicative potential
X prb and p53
Senescence
Crisis
- this happens due to telomeres (signal at the end of DNA that tells the cell how many divisions it has)
- abnormal telomere maintenance can be seen in most malignant cells
- up-regulation telomerase which adds the 6bp repeats onto the ends
- the telomere is kept above critical threshold allowing unlimited replication of cells
Hallmarks: sustained angiogenesis
-More info on slides
Summary:
-Angiogenesis is tightly controlled in normal cells
- tumours hijack angiogenesis to grow the vessels they need to continue expanding.
-Critical step in all tumour growth - 1mm3 max without it
Hallmarks: tissue invasion and metastasis
- In most cancers, cell move away from the primary tumour and colonise a distant site= metastasis
- metastasis are the cause 80-90% cancer deaths
- First tumour cells invade beyond the tumour margin= invasion
- second they escape the primary site (lymph blood) and colonise a secondary site (s) = metastasis
- pre-requisite for the spread of cancer
- cell adhesion molecules stop invasion and metastasis their loss may be responsible for this phenomenon
Treating cancer
Surgery:
- Not always possible, dependant on site and blood supply
- if localised disease it can be fully curative
- unfortunately metastasis can be microscopic which makes them hard to defect, eventually flourish despite primary tumour removal
Radiotherapy:
- uses directed X-rays
- not always feasible treatment dependent on cancer site
- proton beam is the latest technology, limits toxicity to the surrounding tissue, only one in the Uk - Manchester
- can be used alone
- often used in combination with other modalities
- can be used to de-bulk for surgery, prime the immune system for immune-targeted anti-cancer drugs
DISADVANTAGES
- residual cells are often more aggressive than ore-treatment
- normal tissue damage is major inhibitor of efficacy e.g. in lung cancer or brain cancer
Chemotherapy:
- Targets a central hallmark of cancer Uncontrolled growth
- works in 3 main ways
Bind to DNA to stop DNA replication
Inhibit the DNA replication machinery
Binds to and disrupts cell components needed for cell division
- targets cells with rapid cell growth
- (also hits normal tissues/cells that grow rapidly)
- so hair loss, sickness and diarrhoea, weakened immune system, infection prone
Targeted therapy:
- exploits the hallmarks
- determine specific drivers of hallmarks in individual patients
Personalised cancer therapy
