W8 Hallmarks of cancer (GN)

Question 1

What is a Tumour/Neoplasm?

Answer 1

➢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

Question 2

Benign tumour vs malignant cancer?

Answer 2

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)

Question 3

The 4 main classes and relative suffixes of tumours are?

Answer 3

• 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

Question 4

What are some types of tumours do not fit into the major classifications

Answer 4

• Gliomas, Neuroblastoma, Schwannomas
  and Medulloblastomas, Melanoma
  -specific cells of the Central and Peripheral
  nervous system

Question 5

What are the different kinds of cancer prefixes?

Answer 5

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

Question 6

What are the Different Kinds of Cancer?

Answer 6

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

Question 7

What are the traditional hallmarks of cancer? (6)

Answer 7

• Sustaining proliferative signalling
• Evading growth suppressors
• Activating invasion and metastasis
• Enabling replicative immortality
• Introducing angiogenesis
• Resisting cell death

Question 8

What are the Complementary hallmarks of cancer? (4)

Answer 8

• Deregulating cellular energetics
• Genome instability and mutation
• Avoiding immune destruction
• Tumor-promoting inflammation

Question 9

What is the ‘normal’ cell cycle?

Answer 9

• 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

Question 10

Normal cell proliferative signalling:

Answer 10

• 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

Question 11

Cancer Hallmark 1 – sustaining proliferative signalling

Answer 11

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)

Question 12

Cancer Hallmark 2 – evading growth suppressor

Answer 12

• 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

Question 13

Apoptosis in normal tissue?

Answer 13

• Apoptosis → physiological and neat process inducing a programmed cell death induced by external and internal stimuli

Intrinsic pathway:
▪ Internal signals realising cytochrome C
from mitochondria into the cytosol
➢ Extrinsic pathway
▪ External signals (e.g. TNF-α) recognised
by death receptors

Anti-apoptotic (survival) stimuli = low
Pro-apoptotic stimuli = high

Question 14

Cancer Hallmark 3 – resisting cell death

Answer 14

• Driver mutations to evade apoptosis:
  ➢INC anti-apoptotic regulators (e.g. Bcl-2)
  ➢ DEC pro-apoptotic regulators
  ➢Inactivating apoptotic signalling proteins
  (caspases – cleaving multiple substrates)

Question 15

Telomeres and senescence
What are telomeres?

Answer 15

• 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)

Question 16

Cancer Hallmark 4 – enabling replicative immortality
What does this mean?

Answer 16

• Cancer cells express telomere-extending enzymes (telomerases) to prevent senescence
• 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

Question 17

Cancer Hallmark 5 – inducing angiogenesis
Why do tumours do this?

Answer 17

• Expanding tumour masses lead to hypoxia (low/no O2 inducing apoptosis) and reduced access to nutrients
• To further grow, tumours require O2 and nutrients supply and remove waste from the
  blood (by angiogenesis → sprout of new vessels from quiescent vasculature

Question 18

Cancer Hallmark 6 – invasion and metastasis

Answer 18

• 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.

➢ Dictation 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

Question 19

Other hallmarks – Deregulating cellular energetics

Answer 19

• 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

Question 20

Other hallmarks - avoiding immune destruction

Answer 20

• 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

Question 21

Other hallmarks – genome instability

Answer 21

• 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

Question 22

Other hallmarks – promoting inflammation

Answer 22

• Infiltration of immune cells causes inflammation supplying factors
  ➢ enhance cancer hallmarks, establish a tumour microenvironment and accelerate genome instability

Question 23

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

Answer 23

=D

Question 24

RECAP and Comparison between normal and tumoral cells:

Answer 24

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- Immature-no differentiation
Cell differentiation-
Genomic stability-
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