Ageing and cancer

Question 1

What is the definition of ageing?

Answer 1

The random change in the structure and function of
molecules, cells, and organisms that is caused by the passage
of time and by one’s interaction with the environment. Age`ing
increases the probability of death.

Question 2

What are the hallmarks of ageing?

Answer 2

genomic instability
telomere attrition
mitochondrial dysfunction
cellular senescence
epigenetic alterations
loss of proteostasis
deregulated nutrient sensing
stem cell exhaustion
altered intercellular communication

Question 3

What is Cancer?

Answer 3

Cancer is a problem of multicellular organisms
Cancer is a cellular phenomenon that occurs
because cells acquire certain abnormal
properties.
Cancer is a collection of different diseases
Cancer displays uncontrolled growth (core
feature)

Question 4

What is the lifetime risk of cancer in human populations?

Answer 4

1 out of 3

10 million cases each year

Question 5

What are characteristics of a malignant phenotype cancer cell?

Answer 5

loss of growth control (growth signal autonomy;
insensitivity to inhibitory signals)
resistance to apoptosis
unlimited replicative potential (telomere,
telomerase)
sustained angiogenesis
ability to invade the surrounding tissue
ability to colonize and survive in an ectopic
environment (metastasis)

Question 6

What are the differences between a normal cell and a malignant cancer cell in regards to growth signal autonomy

Answer 6

• Normal cells need external signals from
growth factor to divide
• Cancer cells are not dependent on normal
growth factor signaling
• Acquired mutations shorten circuit growth
factor pathways leading to unregulated
growth
o Autocrine signalling
o Deregulation of receptor firing

Question 7

What are the differences between a normal cell and a malignant cancer cell in regards to Insensitivity to growth inhibitory signals?

Answer 7

Normal cells respond to inhibitory signals to
maintain homeostasis
• Cancer cells do not respond to growth
inhibitory signals
• Acquired mutations interfere with the
inhibitory pathways

Question 8

What are the differences between a normal cell and a malignant cancer cell in regards to Unlimited replicative potential?

Answer 8

• Normal cells have an autonomous counting
device to define a finite number of cell
doublings after which they become senescent.
This cellular counting device is the shortening
of chromosomal ends, telomeres
• Cancer cells maintain the length the telomeres
• Altered regulation of telomere maintenance
results in unlimited replicative potential

Question 9

What are the differences between a normal cell and a malignant cancer cell in regards to Unlimited replicative potential-Telomeres?

Answer 9

• Telomeres are repetitive DNA sequences at the ends of
chromosomes
• Function as a molecular counter of the cell’s replicative
potential, protect the end of chromosomes
• Human telomeres contain 250-1500 copies of the repeat
sequence TTAGGG
• At each cell division, 50-100bp of telomeric DNA are lost due to
the limits of DNA polymerase
• Progressive shortening of the telomeres occurs with each
division
• When the chromosomes reach a threshold length, cells enter a
stable state. If cells bypass this stage, chromosomal instability
results apoptosis

Question 10

What are the differences between a normal cell and a malignant cancer cell in regards to Unlimited replicative potential-Telomerase?

Answer 10

• is a ribonucleoprotein, containing human
telomerase reverse transcriptase activity.
• maintain telomere length in certain cell types, such
as stem cells.
• 85% of tumours show upregulated expression of
telomerase
• telomerase transform normal fibroblasts to cancer
cells in vitro (tumourigenesis)
• several oncogenes have been demonstrated to
regulate the expression of telomerase.

Question 11

What are the differences between a normal cell and a malignant cancer cell in regards to Evasion of apoptosis?

Answer 11

• Normal cells are removed by apoptosis, often
in response to DNA damage
• Cancer cells evade apoptotic signals
• Loss of apoptotic regulators through mutation
lead to evasion of apoptosis

Question 12

What is apoptosis?

Answer 12

Apoptosis or programmed cell death, is a highly
regulated (genetically programmed) process that
allows a cell to self-degrade in order for the body to
eliminate unwanted or dysfunctional cells.
• Apoptosis is involved in embryonic development and
homeostasis in multicellular organisms
• Apoptosis is directly involved in degenerative
diseases, autoimmune disorders, vi

Question 13

What are key regulators of apoptosis

Answer 13

• P53, regulates cell cycle, DNA repair, apoptosis and genomic
integrity
• Bcl proteins (20 members).
Some are anti-apoptotic (pro-survival), others are proapoptotic).
Bcl2, B cell leukemia/ lymphoma 2
• Caspases (14 identified): cysteine-dependent asparate-specific
proteases; homologs of C.elegan ced-3
• Apaf-1: apoptosis protease activating factor 1; homolog of
ced-4, necessary for caspase (caspases 9,2) activation.
• IAPs: inhibitors of apoptosis; inhibit effector capspase activity
and promote degradation. 8 in human cells, also found in
viruses.

Question 14

What are the differences between a normal cell and a malignant cancer cell in regards to Sustained Angiogenesis?

Answer 14

• Angiogenesis: the formation of new blood vessels from
pre-existing vascular beds
• Tumour growth is limited by access to nutrients and
removal of metabolic waste mechanism
• Cancer cells induce angiogenesis; angiogenic molecules
are released by ECs and cells of the stroma
• Tumour stroma (connective tissue and mesenchymal
cells) is important in process
• Altering the balance between angiogenic inducers and
inhibitors can activate the angiogenic switch

Question 15

What are 3 anti-angiogenic cancer therapies?

Answer 15

Anti-VEGF mAb
Anti-VEGFR1
Anti-VEGFR2

Question 16

What are the differences between a normal cell and a malignant cancer cell in regards to Invasion and metastasis?

Answer 16

• Normal cells maintain their location in the body and
generally do not migrate
• The movement of cancer cells to other parts of the
body is a major cause of cancer deaths
• Mutations alter the activity of enzymes involved in
invasion and alter molecules involved in cell-cell and
cell-extracellular adhesion

Question 17

What causes cancer?

Answer 17

• acquisition of mutations
o inborn zygotic mutations, somatic mutations
o viruses, chemicals and radiation
• abnormal tissue microenvironment
o blood and lymphatic vasculature, fibroblasts,
immune cells, extracellular matrix and
signalling molecules
o characterized by hypoxia

Question 18

What processes are effected by mutations?

Answer 18

STRUCTURAL
• Amino Acid composition (nucleotide substitutions, Amino Acid
substitutions)
• Gene duplications, deletions; Chromosome duplications,
deletions
• Secondary, Tertiary, Quaternary structure
REGULATORY
• Gene/Protein expression (transcription, RNA processing,
translation, etc)
• Protein activity (allosteric control, conformational changes,
receptors)

Question 19

What are two tumour suppression mechanisms?

Answer 19

Caretakers and Gatekeepers

Question 20

What are caretakers?

Answer 20

Tumour-suppressor genes or proteins that act to
protect the genome from damage or mutations.
Many caretaker genes encode proteins that
recognize or repair DNA damage.

Question 21

What are gatekeepers?

Answer 21

Tumour-suppressor genes or proteins that regulate
cellular responses that prevent the survival or
proliferation of potential cancer cells. These
responses are known as apoptosis and cellular
senescence

Question 22

What are the types of DNA repair relating to ageing and cancer?

Answer 22

 Single strand break repair: DNA ligase
 Base Excision Repair (BER): involves the removal of
bases damaged by ionizing radiation.
 Nucleotide Excision Repair (NER) removes an
oligonucleotide containing a pyrimidine dimer. DNA
polymerase and ligase fill in the removed section.
 Homologous recombination repair of DS breaks
involves using homologous DNA as a template for
repair.

Question 23

What is a result of failing caretaker systems?

Answer 23

Causes a predisposition to certain cancers

eg. Failure of NER place a predisposition to UV induced skin cancer (Xeroderma
pigmentosum)

Question 24

What characterises Xeroderma

pigmentosum?

Answer 24

an autosomal recessive genetic
disorder of DNA repair (NER)
• mutated XPA-XPG
• sensitive to UV-light and have a
1000-fold increased risk of
developing skin cancer
• involves both sexes and all races,
with an incidence of 1:250,000
• symptoms include
o irregular dark spots on the skin
o development of many freckles at an early
age
o severe sunburn when exposed to only
small amounts of sunlight
o eyes that are painfully sensitive to the sun
o Spidery blood vessels

Question 25

Describe a gatekeeper example in regards to cancer and ageing

Answer 25

Gatekeeper example: p53 in cancer and ageing
• Transcription factor – regulates expression of other
genes. In humans is encoded by the TP53 gene
•One of the most commonly mutated genes in human
cancers: e.g. Li-Fraumeni syndrome
• Regulates the cell cycle; DNA repair, increases
apoptosis; thus, functions as a tumor suppressor that
is involved in preventing cancer
• Regulates genes involved in metabolism (glucose
utilization and mitochondrial respiration)

Question 26

What are two facts relating to gatekeepers and caretakers?

Answer 26

• Inactivation of caretakers (molecules involved in
DNA repair) and gatekeepers may reduce life
span, by increasing cancer risk.
• Increasing gatekeeper activity may be
antagonistically pleiotropic: diminishes cancer
risk, accelerate age-related pathologies.

Question 27

How can treatment of cancer effect ageing?

Answer 27

• Once cells have become immortal, there is a tradeoff
between killing the cancer cells and accelerating ageing
in normal cells
• Radiation and chemotherapy kills cancer cells but will
age normal cells (and induce mutations)
• Cancer is a byproduct of ageing; yet, cancer
protection/treatment could accelerate ageing

Question 28

What are final conclusions relating to ageing and cancer?

Answer 28

• Cancer is a problem of multicellular organisms. Cancer is a collection of
different diseases.
• Cancer displays malignant phenotypes, uncontrolled growth is the core
feature
• Tumour-suppressor genes act to prevent or repair genomic damage
(caretakers) or inhibit the propagation of potential cancer cells
(gatekeepers) by permanently arresting their growth (cellular senescence)
or inducing cell death (apoptosis).
• Some caretaker tumour suppressors seem to postpone the development of
ageing phenotypes
• The gatekeeper tumour-suppressor mechanisms (apoptosis and cellular
senescence), by contrast, might promote certain ageing phenotypes
• Metabolic aging is characterized by aerobic glycolysis; oxygen consumption
declines with aging; cancer cells rebel against metabolic aging.
• Two distinct metabolic compartments within a tumour: glycolytic and
oxidative.