COD Cancer Flashcards
Name some changes in cellular properties that promote cancer
Resisting cell death Evading growth suppressors Sustaining proliferative signaling Inducing angiogenesis Enabling replicative immortality Activating invasion and metastasis
Normal cells require external stimulation from growth factors to promote entry into the cell cycle
How is this different from cancer cells?
They may have enhanced external stimulation eg mutations in gfr
They may have lost this dependency due to activating mutations in signal transduction components or mutations in cell cycle components
In order to maintain homeostasis, normal cells respond to inhibitory signals which regulate growth, differentiation and apoptosis
How have cancer cells lost this ability?
Loss of activity of tumour suppressor genes such as p53, PTEN & Retinoblastoma (Rb)
Aberration in developmental signalling pathways e.g. Hedgehog, Wnt and Transforming growth factor-b (TGF-b)
In order to maintain fidelity, normal cells with DNA damage are removed via apoptosis
How do cancer cells avoid apoptotic signals?
Via
Mutations that affect the intrinsic pathway of apoptosis i.e. Loss of p53 activity, upregulation of anti-apoptotic members of the BCL-2 family; down regulation of pro-apoptotic BCl-2 family members
Mutations that affect the extrinsic pathway e.g. aberrations in death receptor regulation
In normal cells & tissue, angiogenesis only occurs under very specific physiological conditions such as?
e.g. active periods of growth, female reproductive organs and wound healing.
What is the diffusion limit of oxygen through solid tissue?
200 micrometres
What is necrosis caused by?
hypoxia or lack of oxygen
True or false
Tumours require vascularisation to grow into a large mass and to prevent of necrotic cell death
True
Angiogenesis is regulated by a balance between the levels of angiogenic inducers and what?
angiogenic inhibitors
Many proangiogenic molecules are growth factors – key player is what?
vascular endothelial growth factor (VEGF)
What is VEGF expression regulated by?
hypoxia and over-activation of other growth factor signalling pathways
Normal cells shorten the ends of their chromosomes (telomeres) during every round of DNA replication which defines a finite number of cell doublings
Describe telomeres
Composed of repetitive DNA sequences (TTAGGG) and associated proteins
Protect ends of chromosomes and control chromosomal length
Shorten by 100-200 bp each DNA replication round due to limits of DNA polymerase needing an RNA primer
What is telomerase?
A form of reverse transcriptase that also contains the RNA template for the telomere repeat DNA (a)
Maintains telomere length
How do cancer cells and stem cells maintain telomere length and immortality
Produce telomerase
Cancer cells have gained the ability to invade and spread (metastasise) to distant sites by what?
Breaking cell- cell and cell –ECM attachment
Becoming more motile
Inducing angiogenesis to support ‘secondary’ tumour growth
Metastatic cells show preferential spread to particular sites - what is this known as?
organotropism
Where is the site of spread usually?
Close proximity to primary tumour
Direction of blood flow
Tumour cells get trapped in capillary bed
Distal/ non-obvious
Seed and soil hypotheses (Paget)
(cells need to match with optimum environment)
Premetastatic niche (Lynden) (distant site is prepared via circulating tumour derived fact
True or false
Less than 1:10,000 circulating tumour cells will survive to set up a secondary metastatic tumour
True
what helps mediate breakdown of cell:cell contacts and cell:ECM contact?
Src
EMT- Key regulators are transcription factors what?
SNAIL and TWIST
What are some Emerging Hallmarks and Enabling Characteristics of tumours?
Hallmarks: Avoiding immune destruction
Deregulating cellular energetics
Enabling characteristics: Tumor promoting inflammation
Genome instability and mutation
What is the rationale for cancer cells to utilise aerobic glycolysis?
Cancer cells are frequently hypoxic
Lack oxygen for oxidative phosphorylation
Process of glycolysis also generates intermediates for biosynthetic pathways such as growth
The immune system can recognise and eliminate cancer cells i.e. immune surveillance
T cells are key immune cells in cell killing
Name some T cells
cytotoxic T cells
Includes CD4, CD8, Natural Killer cells
Cytotoxic T cells can kill target cells by triggering apoptosis
How?
Injecting granzymes into the target cell – directly cleave and activate effector caspases
Initiating the extrinsic route of apoptosis by activating death receptors
How do cancer cells evade the immune system?
Loss of tumour antigens
Downregulation of antigen-presenting molecules (APCs)
Over-expression of immune checkpoint proteins and anti-apoptotic proteins
What is an embryonic stem cell?
from inner mass of early embryo that can differentiate into different cell types during development
What is an adult stem cell?
in regenerative tissue, replaces cells that mature and die
What are CSCs?
Cancer stem cells
Describe CSCs
Are are subpopulations within a tumour that are thought to initiate and maintain the cancer
May be responsible for:
Heterogeneity of tumours
Tumour plasticity
Migratory abilities
Can be identified (and isolated) through various and/or tissue specific stem cell markers e.g. CD44 (breast and pancreas), CD133 (colon, prostate, brain)
More likely to survive anti-cancer treatments
May arise from deregulation of self-renewal pathways e.g. Wnt and Hedgehog
What is a driver and passenger mutation?
Driver mutation: confers growth/survival advantage
Passenger mutation: does not confer any advantage!
What are some Carcinogenic agents and cancer risk?
Radiation Chemicals Infectious pathogen Endogenous reactions Mutations arise due to both DNA damage caused by carcinogens and additionally, errors/malfunctions in DNA repair mechanisms
Describe direct and indirect DNA damage
Direct DNA damage
Ionisation of atoms comprising DNA
Indirect DNA damage Radiolysis of H2O and ROS generation Hydroxyl radical H2O2 Superoxide radical
Describe UV radiation
eg wavelengths
UVA - (wavelength 320-380 nm)
UVB - (wavelength 290-320 nm) * most effective carcinogen
UVC - (wavelength 200- 290 nm)
Describe UVB
Most effective carcinogen
Mutations induced cause bends in the DNA which are misread by DNA polymerase
Causes 80% of skin cancers - squamous and basal cell carcinomas (some melanoma)
p53 tumour suppressor commonly affected
Risk factors – over exposure to the sun i.e. sunburn, sunbeds
What is the general mechanism of action for a chemical carcinogen?
An electrophilic (or electron deficient) form reacts with the nucleophilic sites (sites that can donate electrons) in the purine and pyrimidine rings of nucleic acids.
Direct acting carcinogens (uncommon)
Indirect acting carcinogens (common)
Describe Direct acting carcinogens (uncommon)
Reactive electrophiles
Interact with nitrogen and oxygen atoms in DNA
Examples include dimethyl sulphate and nitrogen mustards
Describe Indirect acting carcinogens (common):
Unreactive and water soluble
Electrophilic centre produced by enzyme modification e.g. via processing by cytochrome p450 enzymes
Interact with bases in DNA forming adducts
Examples include polycyclic aromatic hydrocarbons (PAHs) (cigarette smoke) & aromatic or heterocyclic amines (cooked meats)
Risk: smoking, diet high in cooked or processed meat, preservatives in processed food
What is an oncogenic virus?
A virus that can cause cancer
DNA tumour viruses
RNA tumour viruses (retroviruses)
Describe DNA tumour viruses
Encode viral proteins that block tumour suppressor action
Example: Human papillomavirus (HPV) degrades RB tumour suppressor leading to constitutive activation of the cell cycle
oncogenic virus
RNA tumour viruses (retroviruses)
Encode mutated forms of normal genes
Example: Human T-cell lymphotropic virus (HTLV-1) (only virus known to be linked with human leukaemia)
oncogenic virus
Describe bacteria as an infectious agent
Cause chronic inflammation that helps promote cancer e.g. Helicobacter pylori infection can initiate gastric cancer
Bacterial proteins affect cell signalling proteins that regulate cell proliferation, survival and invasion
What are Proto-oncogenes?
They promote cell proliferation or cell survival
Examples: components of signalling pathways driving cell proliferation ; anti-apoptotic proteins
Effect of mutation – GAIN of function
Dominant mutation
Converts proto-oncogenes into oncogenes
What are tumour suppressors?
Inhibit cell survival and/or negatively regulate cell proliferation
Examples: apoptosis promoting proteins; CDK inhibitors; cell cycle checkpoint regulators
Effect of mutation – LOSS of function
Recessive mutation
What are some genetic events that can cause loss of function in tumour suppressor genes?
Loss of entire chromosome
Region containing normal gene is deleted
Mutation in coding sequence which results in non-functional protein
Chromosomal rearrangements – gene is disrupted
Gene activity silenced by epigenetic changes
Mutations in genes coding for chromatin-remodelling complexes e.g. SWI/SNF
Describe what could happen if you inherit mutations in tumour suppressor genes
Predisposition to develop cancer Hereditary retinoblastoma (loss of RB TS gene results in childhood retinal tumours and other tumours later in life) Familial adenomatous polyposis (FAP) (loss of APC gene – formation of colon polyps which if untreated could develop into malignant colon cancer
What are caretaker genes?
Repair or prevent DNA damage
Examples: DNA repair enzymes
Effect of mutation – LOSS of function
Recessive mutation
Arise by deletion, point mutation or methylation Repair mechanisms affected DNA mismatch repair Nucleotide excision repair Double stranded DNA breaks
Can get inherited defects
Passage through the cell cycle is regulated by cyclins and cyclin-dependent kinases (CDKs)
Describe cyclins and CDKs
The concentration of different cyclins varies in different stages of the cell cycle
Cyclin is the regulatory subunit of the CDK
Pairing of cyclins and CDKs is specific
Examples: Cyclin D /CDK 4/6
CDKs are serine threonine kinases
Cyclins are divided into four classes defined by their activity in the cell cycle
What are these 4 classes?
G1 cyclins
G1/S cyclins
S phase cyclins
M phase cyclins
What is CDK activity influenced by?
Cyclin binding
Phosphorylation & dephosphorylation
Binding to CDK inhibitors e.g. p15, p16, p21 and p27
What is p53?
Guardian of the genome Transcription factor Multi-functional TS that can promote: Arrest in G1 and G2 phase Via production of p21 and p27 cdk inhibitors Apoptosis DNA repair with respect to DNA damage
True or false
Mutations in p53 promote the formation of the malignant phenotype and they are the most common mutations found in tumours
Nearly all p53 mutations are located in its DNA binding domain
True
What are the two Mechanisms leading to abnormalities in EGFR signalling?
- Increased ligand production
EGFR ligands particularly EGF are frequently over-expressed in cancer
Occurs via autocrine stimulation - Increased EGFR receptor levels
Can occur due to:
Gene amplification
Defective gene promoter activity (binding of p53 proteins)
Defective receptor downregulation (inability to bind c-Cbl)
*****What is a mechanism leading to abnormalities in erbB signalling?
*****Mutations giving rise to constitutively active variant receptors
A variety of mutations are known to exist and can be found in all areas of the receptor i.e. both extracellular and intracellular
Example: EGFR variant III
Loss of most of the extracellular binding domain
Constitutively active (in absence of ligand)
Prominent in the very aggressive brain tumour glioblastoma
Strongly and persistently activates the PI3 kinase/Akt signalling pathway
Increased cell survival, proliferation and motility
Resistance to treatment
Apoptosis can be triggered by two routes
What are these?
Intrinsic / mitochondrial route or extrinsic (death receptor mediated) route
Intrinsic route most commonly disrupted in cancer
Whether the intrinsic pathway is activated depends upon the release of what?
cytochrome c from the mitochondria
Regulated by a balance between molecules that promote apoptosis and those which inhibit apoptosis
Give examples of pro apoptotic and anti apoptotic molecules
pro - BAK, BAK, BAD
anti - BCL-2, BCL-XL = L is small
