Cancer And Apoptosis

Question 1

Definition of cancer

Answer 1

A group of diseases generally characterised by genomic instability and uncontrolled cell division and leading to invasion of surrounding tissue and eventual dispersal to distant sites
Genomic instability underlies all cancers- individual mutations or at chromosome level
Uncontrolled cell division can be useful in diagnosis as you can stain for cell proliferation

Question 2

Metastasis

Answer 2

Cancer spreading through different organs within the body
Start with localised tumour, break through basal lamina, invade capillary and travel in blood stream, adhere to blood vessel wall, escape blood vessel, proliferate to form new tumour
Important to diagnose before this
Tumours secrete factors that recruit cells from circulatory system to generate new blood vessels throughout the tumour mass

Question 3

Benign tumour

Answer 3

Shows excess proliferation but doesnt invade surrounding tissue

Question 4

Malignant tumour

Answer 4

Proliferate, genomic instability, can invade and start ti metastasise

Question 5

Carcinoma

Answer 5

Epithelial cell derived

Question 6

Lymphoma

Answer 6

Cancer of lymphatic system

Question 7

Leukaemia

Answer 7

White blood cell derived

Question 8

Sarcoma

Answer 8

Cancer of connective tissue or bone

Question 9

Clonal origin of cancer

Answer 9

Founder cell has accumulated sufficient mutations to proliferate in an uncontrolled manner
Needs at least 2 mutations, usually around 10
First population likely to be benign
Further mutations in cancer cells may make them invade tissues or be genomically unstable
Creates second population of tumour cells with additional attributes
Process repeats where the cells now all have different genomes
Cells compete for space, nutrients and oxygen
Results in selection of malignant cells as they divide faster, can invade more space and can distribute themselves by metastasis

Question 10

Overview of causes of cancer

Answer 10

Genetic change- mutation e.g. delaminating of cytosine makes it into a uracil, if not corrected can permanently change dna base sequence or chromosomal level changes, translocations, deletions
Inheritance- can pick up less active alleles from parents that predispose you to cancer e.g. BRCA 1 or 2 genes involved in dna repair increase risk of breast cancer
Viral infections- retrovirus can cause tumourgenesis either benign or malignant

Question 11

Aneuploidy

Answer 11

An altered genome

Question 12

Polyploidy

Answer 12

Multiple copies

Question 13

Rat sarcoma virus (oncogenes and tumour suppressors)

Answer 13

3 genes encoded, one for protein shell, one for receptor proteins, one reverse transcriptase, benign virus
One variant has extra gene, Ras
Ras converts cells to tumour cells, viral oncogene
Cellular version of Ras isn’t an oncogene, difference is one amino acid at N terminus that stops Ras hydrolysisng GTP to GDP so it is locked in active form
Viral Ras is locked in active form
Ras is a signalling molecule
Many viral oncogenes enforce cell proliferation on infected cells to extend viral spread and enable for replication
Viral versions are constitutively active
Cellular equivalents can mutate and cause cancer, usually single mutations that have a dominant action, can no longer be switched off so everything downstream can no longer be switched off

Question 14

DNA tumour viruses

Answer 14

E.g. HPV causes cervical carcinoma
Complex genome compared to retroviruses
Multiple genes, E or L for early or late expression in life cycle
DNA genome
Only E6 and E7 required for transformation of a normal cell into cancer cell
Both have no homology with human proteins
E7 binds to Rb, freeing up E2F to drive expression of genes required for S phase
E6 binds to transcription factor p53, destroying it by acting as a marker so it is degraded

Question 15

What is p53

Answer 15

Key regulator of apoptosis, causing apoptosis or cell cycle arrest
Activated by stress, breakages in genome, ROS
Binds to promoter region of Bax, pro apoptotic member of Bcl2 family
Also binds to promoter of p21cip1 which inhibits G1 cyclin cdks so no Rb phosphorylation, no E2F released, no cascade, wont enter s p[hase

Question 16

Tumour suppressors

Answer 16

Genes whos proteins have a normal function to stop cancer cells from developing
E.g Rb and P53
Commonly mutated in human cancers, usually loss of function mutations e,g. Premature stop codons causing truncation of protein

Question 17

Cancer causing mutations

Answer 17

Overactivity mutations- single mutation event creates oncogene
Under activity mutation - mutation even, both copies mist be mutated, inactivates tumour suppressor gene
Some people inherit one mutated copy from parents so cancer more likely to develop as only one copy left to mutate
Big issue in therapeutics is loss of function of tumour suppressors as you can’t drug deleted genes
Cancer has unstable genome which makes it a moving target to hard to treat as genome changes

Question 18

Apoptosis intrinsic pathway

Answer 18

Cell senses DNA damage and causes apoptosis
Cytochrome c is released from mitochondria and binds to adaptor protein Apaf 1 causing it to oligomerise and bind to initiator caspases
Bcl2 family proteins can suppress apoptosis when expressed as they control the release of cytochrome c into the cytosol, can be pro apoptotic or anti apoptotic and can bind to each other to inhibit each other
Bad and Bak are the main effector Bcl2 family proteins
Bak is a transmembrane protein in outer mitochondrial membrane
Bcl2 proteins can bind to Bak to prevent movement of cytochrome C

Question 19

Apoptosis extrinsic pathway

Answer 19

External signals cause cell to carry out apoptosis
Extracellular signal proteins bind to cell-surface death receptors
E.g. Fas ligand on surface of a killer lymphocyte
When ligand binds to Fas protein receptor, cytosolic tails of the protein bind to intracellular adaptor proteins which bind to initiator caspases
Initiator caspases cleave each other as they have a low level of activity then go on to trigger a caspase cascade

Question 20

Caspases

Answer 20

Cleave target proteins C terminal into aspartame residues
Typical target site is Asp-Glu-Val-Asp
Kept inactive until required as bound to a pro domain, very low level of activity
Cleavage site is cleaved by an active caspase, removing the pro domain and activating the caspase
Active caspase made up of large subunit and small subunit
One molecule of initiator caspase can cleave multiple copies of an executor caspase- caspase cascade- signal amplification
Caspase can cleave structural proteins, enzymes and renders cell non functional
Also activated caspase activated DNase which cleaves DNA between nucleosomes (CAD) , caspase degrades CAD inhibitor

Question 21

Adaptor proteins

Answer 21

Bind to caspases, holding them all together in one area so they are more likely to cleave each other

Question 22

Regulator proteins

Answer 22

Control movement of cytochrome c out of mitochondria
E,g. Bak accumulates and forms a pore in outer mitochondrial membrane
E.g. Bcl2 inhibits Bak to prevent apoptosis

Question 23

Features of apoptotic cells

Answer 23

Phosphatidylserine moves to outer layer of phospholipid bilayer
Signals to be engulfed by macrophage
Cell contents partially degraded and released in membrane bound blebs
Apoptotic bodies vesicles are engulfed by phagocytosis then lysosomal enzymes complete digestion

Question 24

Clinical relevance

Answer 24

Excessive numbers of cells undergoing apoptosis causes tissue damage e.g, heart attacks and strokes where many cells die by necrosi and some less affected cells die by apoptosis, drugs that block apoptosis could save these cells
Mutations that inactivate genes encoding for Fas death receptor prevent apoptosis of some lymphocytes, causing them to build up in spleen which caused autoimmune disease, drugs stimulating apoptosis could help with this and with cancers