W8 Hallmarks of cancer (GN) Flashcards
What is a Tumour/Neoplasm?
how does a tumour originate?
benign means?
malignant means?
➢Abnormal new growth of tissue that possess no physiological/purposeful
function and derived from by uncontrolled and disorganised cell proliferation
- Tumour is initiated in a single cell by the progressive accumulation of mutations
in genes that are crucial in cell proliferations, survival and invasion. - Not all tumours are cancerous
Benign tumour growth
▪ Slow, limited and localised
Malignant/Cancer growth
▪ Invasive and malignant
Benign tumour vs malignant cancer?
Benign
* Non-cancerous cells
▪ Slow growth rate
▪ Encapsulated → stay localized
▪ No invasive
▪ Retention of cell specialisations
▪ Cells with normal shape
▪ Rarely fatal (good prognosis)
Malignant (CANCER)
* Cancerous → invasive
▪ Rapid growth rate
▪ Invade tissues
▪ Metastasise to other far organs
▪ Poorly differentiated/specialised
▪ Larger cells with darker shape
▪ Life-threating, (bad prognosis)
The 4 main classes and relative suffixes of tumours are?
-
Carcinomas
-cells that cover external and internal organs or glands -
Sarcomas
-cells in the supporting tissues: bone, cartilage, fat, connective tissue, muscle -
Lymphomas
-start in the lymph nodes & tissues of the immune system -
Leukemias
-start in the immature blood cells that grow in the bone marrow
What are some types of tumours do not fit into the major classifications
- Gliomas, Neuroblastoma, Schwannomas
and Medulloblastomas, Melanoma
-specific cells of the Central and Peripheral
nervous system
What are the different kinds of cancer prefixes?
adeno- gland
chondro-cartilage
erythro- red blood cell
hemangio- blood vessels
hepato- liver
lipo- fat
lymph- lymphocyte
melon- pigment cell
myeloma- bone marrow
mayo- muscle
osteo- bone
What are the Different Kinds of Cancer?
Incidence of cancer in UK – both sexes and all ages in 2017:
➢ breast (15%),
➢ prostate (13.5%),
➢ lung (13.1%)
➢ bowel (11.5%) cancers
* together account for 53% of all new cancer cases
Mortality from cancer in UK – both sexes and all ages in 2017
➢ lung (21%),
➢ bowel (11%),
➢ prostate (7%)
➢ breast (7%) cancers
What are the traditional hallmarks of cancer? (6)
- Sustaining proliferative signalling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Introducing angiogenesis
- Resisting cell death
What are the Complementary hallmarks of cancer? (4)
- Deregulating cellular energetics
- Genome instability and mutation
- Avoiding immune destruction
- Tumor-promoting inflammation
What is the ‘normal’ cell cycle?
- 3 cell cycle checkpoints
- Checkpoint progression depends on
cyclically activated Cyclin-dependent
protein kinases (Cdks) bound to cyclin - Proliferative signals stimulates the
synthesis of cyclins that activate CDKs - Cyclin/CDKs phosphorylates key proteins
Normal cell proliferative signalling:
- Growth factors, Intracell., Factors =
- Cyclin/CDKs activation, Activation of protooncogenes
= Pathways for checkpoint progression - Anti growth factors, DNA damage
- = Activation of tumor suppressor genes
- = Pathways to block cell cycle, Enter G0 phase or apoptosis
Cancer Hallmark 1 – sustaining proliferative signalling
How are the first 2 cell signalling steps reprogrammed?
Cancer cells acquire growth factor-proliferation autonomy in a variety of ways, reprogramming the first two cell signalling steps
- Key mutations in oncogenes to stimulate and sustain cell division
Reception → Cancer cells become hyperresponsive
▪ release of extracellular growth factors
(autocrine/paracrine activation → positive feedback)
▪ Overexpression of extracellular receptors of those signals
Transduction → alteration of signalling components (i.e. RAS oncogene)
▪ Constitutive activation of downstream signalling pathways
▪ Defective activation of negative feedback regulatory mechanisms (off-switches)
Cancer Hallmark 2 – evading growth suppressor:
What do ca cells become irresponsive to?
What signalling components are altered?
What are inactivated?
- DNA changes to evade cell progression inhibition
➢ Reception
Cancer cells become irresponsive to antiproliferative signals
▪ Inactivation or down expression of receptors sensing these signals
* DNA changes to evade cell progression inhibition
➢Transduction → alteration of signalling components (e.g. p53 and other tumour suppressor proteins inactivation)
▪ Tumour suppression inactivation activated by growth suppressor signals → Blocking transition to G0 phase or cell cycle transition
Apoptosis in normal tissue?
What is apoptosis? (simple)
What is the intrinsic pathway?
extrinsic pathway
- Apoptosis → physiological and neat process inducing a programmed cell death induced by external and internal stimuli
Intrinsic pathway:
▪ Internal signals releasing cytochrome C from mitochondria into the cytosol
Extrinsic pathway::
▪ External signals (e.g. TNF-α) recognised by death receptors
Anti-apoptotic (survival) stimuli = low and Pro-apoptotic stimuli = high
Cancer Hallmark 3 – resisting cell death
What are the Driver mutations to evade apoptosis?
inc in?
dec in?
what are inactivated?
➢INC anti-apoptotic regulators (e.g. Bcl-2)
➢ DEC pro-apoptotic regulators
➢Inactivating apoptotic signalling proteins
(caspases – cleaving multiple substrates)
Telomeres and senescence
What are telomeres?
What happens to telomeres after each DNA replication?
What happens when telomeres become too short? (2)
- Regions of repetitive DNA sequences at chromosome ends
- Each DNA replication shortens telomeres (25-200 bps)
- When telomeres become too short, chromosomes can no longer be replicated → Senescence (cell arrest) → and Crisis (apoptosis)
What are the functions of telomeres? (2)
- Prevent DNA replication and cell division of aged/damaged cells
- Prevent chromosomes from sticking to each other (fusion/recombination) & gene loss
Cancer Hallmark 4 – enabling replicative immortality
What do telomerases do?
What does this mean?
- Cancer cells express telomere-extending enzymes (telomerases) to prevent senescence (cell growth arrest)
- Add nucleotides repeats at the end of telomeric DNA, every time DNA is replicated
- Telomerases → maintenance of the length of telomeres above the critical point
- Bypass the limited replicative potential of a cell – allowing replicative immortality
What is senescence? (extra info)
-When cells age and stop dividing, they do not die but they enter a state of permanent growth arrest (cell arrest)
-Tumour suppressive process as it prevents cancer cell proliferation.
Cancer Hallmark 5 – inducing angiogenesis
Why do tumours do this?
- Expanding tumour masses lead to hypoxia (low/no O2 inducing apoptosis) and reduced access to nutrients
- To further grow, tumours require O2 and nutrient supply and remove waste from the
blood (by angiogenesis → sprout of new vessels from quiescent vasculature
Cancer Hallmark 6 – invasion and metastasis:
Tumour cells can acquire break away to do what?
What are the 3 differences between benign and malignant tumours to allow invasion and metastasis?
- Tumour cells can acquire break away from their site of origin to invade surrounding tissue or spread to distant site, resulting in the development of secondary tumour.
➢ Difference between benign and malignant
▪ Loss of adhesion junctions (e.g. integrins, E-cadherin)
▪ Change of morphology and increased motility
▪ Matrix-degrading proteases to facilitate invasion
- Entering the bloodstream or lymphatic system can reach distant sites/organs (metastasis)
-Facilitated by angiogenesis
Other hallmarks – Deregulating cellular energetics- glycolysis enzymes:
What can promote invasion and metastasis?
- Glycolysis enzymes are overexpressed inducing cells to undergo aerobic glycolysis and lactic fermentation, rather than cellular respiration
- Less efficient → energy/g of glucose → 2 vs 30/32 ATP
- Quicker glucose intake & glucose consumption (20x)
- Glycolysis intermediates → nucleotide and amino acid synthesis
- Fermentation releases lactic acid → acidification of the microenvironment → promoting invasion & metastasis
Other hallmarks -
How do ca cells avoid immune destruction?
- Cancer cells evade immune cells detection and activation:
▪ Low immunogenicity → No/rare tumour-specific antigens or restricting oncovirus-specific antigen synthesis
▪ Dec MHC molecule expression
▪ Induction of local immunosuppression
Other hallmarks
How do ca cells cause genome instability?
- Cancer cells inactivate DNA repair systems causing genome instability
▪ BCRA1 and BCRA2 play a central role in cancer development - Type/degree of genomic instability influence the clinical features and prognosis of cancer.
- Cancer cells have different numeric/structural chromosome abnormalities
Other hallmarks
How do ca cells promote inflammation?
- Infiltration of immune cells causes inflammation supplying factors
➢ enhance cancer hallmarks, establish a tumour microenvironment and accelerate genome instability
Which of the following are NOT hallmarks of cancer?
A) Reprogramming energy metabolism
B) Stimulation of angiogenesis
C) Invasion and metastasis
D) Induction of cell death
E) Evasion of growth inhibitory signals
=D
RECAP and Comparison between normal and tumoral cells:
Normal cell Vs Cancer Cell:
Cell division:
N- Tightly controlled and regulated (factor-dependent)
C- Uncontrolled and unregulated (factor-independent
Apoptosis activation
N- Regulated and physiological
C- Inhibited
Cell differentiation-
N- Specialised cells
C- Immature-no differentiation
Genomic stability
N- Stable and monitored
C- Instable
Tissue
N- Organised
C- Disorganised and inflammed
Replicative power:
N- Limited until senescence
C- Cell immortality
Cell invasiveness
N- No
C- Yes (only malignant cells)
New blood supply
N- Only for tissue repair
C- Tumour angiogenesis
