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7 replicative immortality Flashcards

1
Q

What is replicative immortality, and why is it essential for cancer cells?

A

Replicative immortality refers to a cancer cell’s ability to divide indefinitely, bypassing normal cellular limits such as senescence and crisis. This is essential for tumour formation and growth.

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2
Q

What are the two main barriers to replicative immortality?

A

The two main barriers are senescence, where cells enter a non-proliferative but viable state, and crisis, which leads to cell death.

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3
Q

Who discovered the concept of replicative senescence, and what is it called?

A

Leonard Hayflick discovered that normal human cells have a limited number of divisions before becoming senescent, known as the Hayflick limit.

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4
Q

How is replicative senescence linked to telomeres?

A

Replicative senescence occurs due to telomere erosion, where repeated cell divisions progressively shorten telomeres until they trigger a permanent cell cycle exit.

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5
Q

Why is replicative senescence considered an anti-cancer mechanism?

A

It prevents uncontrolled cell proliferation by stopping the division of aged or damaged cells, reducing the risk of mutations that could lead to cancer.

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6
Q

What are telomeres, and why are they important?

A

Telomeres are specialised DNA-protein structures at chromosome ends that maintain genetic integrity and prevent chromosomal ends from being recognised as damaged DNA.

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7
Q

What is the hexanucleotide sequence found in human telomeres?

A

The sequence is 5’-TTAGGG-3’, repeated thousands of times.

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8
Q

What is the function of the shelterin complex?

A

Shelterin is a six-protein complex that binds and protects telomeres, preventing them from being mistakenly recognised as DNA damage.

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9
Q

Name the six proteins in the shelterin complex and their roles.

A

TRF1 & TRF2: Bind double-stranded telomeric DNA
POT1: Binds single-stranded telomeric DNA
TIN2, TPP1, RAP1: Structural roles, aiding in protection and regulation

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10
Q

What is the “end replication problem,” and how does it contribute to ageing?

A

DNA polymerase cannot fully replicate chromosome ends, causing telomeres to shorten with each cell division. Eventually, this triggers senescence or apoptosis, contributing to ageing.

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11
Q

How do cancer cells bypass telomere shortening?

A

Most (~85–90%) upregulate telomerase, an enzyme that extends telomeres, while ~10–15% use Alternative Lengthening of Telomeres (ALT).

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12
Q

What are the two key components of telomerase?

A

hTERT (telomerase reverse transcriptase): Catalytic subunit
hTR (telomerase RNA): Provides the template for telomere extension

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13
Q

In which types of cells is telomerase normally active?

A

Telomerase is highly expressed in stem cells, progenitor cells, and germ cells but is absent in most normal somatic cells.

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14
Q

What are C-circles, and what do they indicate?

A

C-circles are extrachromosomal telomeric DNA found in ALT-positive cells, serving as a marker of Alternative Lengthening of Telomeres.

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15
Q

What is apoptosis, and why is it crucial for cancer prevention?

A

Apoptosis is a programmed cell death mechanism that removes damaged or unnecessary cells. It prevents cells with DNA damage or oncogene activation from proliferating.

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16
Q

What are the key morphological features of apoptotic cells?

A

Blebbing, chromatin condensation, nuclear fragmentation, and DNA fragmentation.

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17
Q

How does p53 regulate apoptosis?

A

p53 induces pro-apoptotic genes (e.g., PUMA, NOXA, BAX, APAF1) and suppresses anti-apoptotic factors, ensuring damaged cells undergo apoptosis.

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18
Q

How does MYC activation lead to apoptosis?

A

Hyperactive MYC upregulates ARF, which inhibits MDM2, leading to p53 activation and apoptosis via PUMA, NOXA, and BIM.

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19
Q

What is the role of the Bcl-2 family in apoptosis?

A

The balance between pro-apoptotic (e.g., BAX, BAK, PUMA) and anti-apoptotic (e.g., BCL-2, BCL-XL) proteins determines whether apoptosis occurs.

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20
Q

What are caspases, and how do they function?

A

Caspases are cysteine proteases that drive apoptosis. Initiator caspases (e.g., Caspase-8, Caspase-9) activate effector caspases (e.g., Caspase-3, Caspase-7), which dismantle the cell.

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21
Q

What is genomic instability, and why is it a hallmark of cancer?

A

Genomic instability refers to an increased rate of mutations and chromosomal abnormalities, leading to tumour evolution and resistance to therapy.

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22
Q

What are the two types of genomic instability in cancer?

A

Chromosomal instability (CIN) (structural/numerical changes) and microsatellite instability (MIN) (DNA-level defects).

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23
Q

What is chromothripsis?

A

A catastrophic event causing extensive chromosomal rearrangements in a single step, often seen in cancer.

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24
Q

What are the main sources of DNA damage?

A

Endogenous: Replication errors, oxidative stress.
Exogenous: UV radiation, ionising radiation, genotoxic chemicals.

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25
What are the major DNA repair pathways?
MMR (Mismatch Repair): Fixes replication errors BER (Base Excision Repair): Removes damaged bases NER (Nucleotide Excision Repair): Repairs bulky DNA lesions NHEJ & HR (Double-Strand Break Repair): Fixes DNA breaks
26
What is Lynch syndrome, and how is it related to MMR?
Lynch syndrome (HNPCC) is caused by mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) and increases colorectal cancer risk.
27
How do BRCA1/2 mutations contribute to cancer?
BRCA1/2 are involved in homologous recombination (HR). Mutations impair DNA repair, increasing the risk of breast and ovarian cancer.
28
How do cancer cells resist apoptosis?
TP53 mutations (~50%) MDM2/MDMX overexpression (inhibiting p53) BCL-2 upregulation (anti-apoptotic)
29
What are telomerase-targeted therapies?
hTERT inhibitors (targeting telomerase activity) Immunotherapies (e.g., vaccines against hTERT)
30
What is oncogene-induced senescence?
A state of permanent growth arrest triggered by oncogene activation, acting as a tumour-suppressing mechanism.
31
What is telomerase?
A ribonucleoprotein enzyme that extends telomeres, counteracting telomere shortening.
32
What are the two key components of telomerase?
hTERT (telomerase reverse transcriptase) and hTR (human telomerase RNA template).
33
In which types of cells is telomerase highly expressed?
Stem cells, germ cells, and progenitor cells but is absent in most normal somatic cells.
34
What percentage of cancers rely on telomerase reactivation?
85-90% of cancers upregulate telomerase to maintain telomere length.
35
What is the Alternative Lengthening of Telomeres (ALT) mechanism?
A telomerase-independent mechanism using homologous recombination to maintain telomeres.
36
What are the key markers of ALT-positive cancers?
C-circles and ALT-associated promyelocytic leukaemia (PML) nuclear bodies.
37
What gene mutations are associated with ALT activation?
ATRX and DAXX mutations, affecting chromatin remodelling.
38
What is apoptosis?
A programmed cell death mechanism crucial for embryogenesis, tissue homeostasis, and cancer prevention.
39
hat are the key morphological features of apoptosis?
Blebbing, chromatin condensation, nuclear fragmentation, and apoptotic body formation.
40
How does p53 regulate apoptosis?
It induces expression of pro-apoptotic proteins (e.g., PUMA, NOXA, BAX) to trigger cell death.
41
What is the Bcl-2 family?
A group of proteins that regulate apoptosis, with both pro-apoptotic (BAX, BID, BAK) and anti-apoptotic (BCL-2, BCL-XL) members.
42
How do cancer cells evade apoptosis?
By overexpressing anti-apoptotic BCL-2 proteins, mutating p53, or downregulating death receptor signalling.
43
What are caspases?
A family of cysteine proteases that execute apoptosis.
44
What are the two apoptosis pathways?
Intrinsic (mitochondrial) pathway and extrinsic (death receptor) pathway.
45
What is genomic instability?
A hallmark of cancer involving increased mutation rates, chromosomal abnormalities, and DNA repair defects.
46
What are the two types of chromosomal instability (CIN)?
Numerical (aneuploidy) and structural (chromosomal rearrangements).
47
What is chromothripsis?
A catastrophic event causing massive chromosomal rearrangements in a single event.
48
What are the key DNA repair pathways?
Mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), non-homologous end-joining (NHEJ), and homologous recombination (HR).
49
Which DNA repair defect is associated with Lynch syndrome?
Mismatch Repair (MMR) deficiency leading to microsatellite instability (MIN).
50
What is the role of BRCA1 and BRCA2 in DNA repair?
They facilitate homologous recombination repair (HRR), and mutations increase breast/ovarian cancer risk.
51
Which hereditary syndrome is associated with TP53 mutations?
Li-Fraumeni syndrome, increasing susceptibility to multiple cancers.
52
What cancer syndrome is caused by ATM gene mutations?
Ataxia telangiectasia, leading to increased lymphoma and leukaemia risk.
53
How do oncogenes contribute to genomic instability?
By inducing replication stress and promoting DNA damage.
54
What are the four main phases of the cell cycle?
G1 (growth), S (DNA synthesis), G2 (preparation for mitosis), and M (mitosis).
55
What is the function of cyclin-dependent kinases (CDKs)?
They regulate cell cycle progression by phosphorylating target proteins, activated by cyclins.
56
What are the key CDK-cyclin pairs involved in the cell cycle?
Cyclin D-CDK4/6 (G1), Cyclin E-CDK2 (G1-S), Cyclin A-CDK2 (S), and Cyclin B-CDK1 (G2-M).
57
What is the restriction (R) point in the cell cycle?
A checkpoint in late G1 where the cell commits to division, regulated by Rb protein and E2F transcription factors.
58
How does the retinoblastoma (Rb) protein control cell cycle progression?
When hypophosphorylated, Rb binds to E2F, preventing transcription of genes needed for S phase. Phosphorylation by CDK4/6-Cyclin D releases E2F, allowing progression.
59
What are CDK4/6 inhibitors, and how do they work?
Drugs that selectively inhibit CDK4 and CDK6, preventing Rb phosphorylation and blocking G1-S transition, leading to cell cycle arrest.
60
Name three FDA-approved CDK4/6 inhibitors used in cancer treatment.
Palbociclib, Ribociclib, and Abemaciclib.
61
What types of cancer are CDK4/6 inhibitors primarily used for?
Hormone receptor-positive (HR+), HER2-negative breast cancer and certain other cancers with Rb pathway deregulation.
62
What are common resistance mechanisms to CDK4/6 inhibitors?
Loss of Rb function, upregulation of cyclin E-CDK2, and activation of alternative survival pathways (e.g., PI3K/AKT).
63
What is p53, and why is it called the ‘guardian of the genome’?
A tumour suppressor protein that responds to DNA damage by inducing cell cycle arrest, DNA repair, or apoptosis, preventing mutations from propagating.
64
What happens when p53 is mutated?
It loses its tumour-suppressive functions, leading to genomic instability, uncontrolled cell growth, and cancer development.
65
What percentage of human cancers have TP53 mutations?
Over 50% of cancers have inactivating p53 mutations.
66
What is the MDM2-p53 feedback loop?
MDM2 is an E3 ubiquitin ligase that degrades p53, keeping its levels low under normal conditions. When DNA damage occurs, MDM2 is inhibited, allowing p53 accumulation.
67
How do cancers overexpressing MDM2 resist p53-mediated apoptosis?
MDM2 overexpression leads to excessive p53 degradation, preventing cell cycle arrest and apoptosis.
68
What are p53-reactivating drugs, and how do they work?
Drugs like Nutlins, APR-246, and ONC201 restore p53 function by blocking MDM2-p53 interaction or stabilising mutant p53.
69
What are tumour suppressor genes?
Genes that restrain cell proliferation and promote apoptosis (e.g., p53, Rb, PTEN).
70
What is the ‘two-hit hypothesis’ of tumour suppressor gene inactivation?
Both alleles of a tumour suppressor gene must be inactivated (mutated or deleted) for cancer development.
71
How does the loss of PTEN contribute to cancer?
PTEN is a tumour suppressor that inhibits the PI3K-AKT pathway; its loss leads to uncontrolled cell growth and survival.
72
What is angiogenesis, and why is it important for tumours?
Formation of new blood vessels, essential for tumours to receive oxygen and nutrients.
73
What is the main pro-angiogenic factor in cancer?
Vascular Endothelial Growth Factor (VEGF).
74
How do tumours induce angiogenesis?
By upregulating VEGF and hypoxia-inducible factor-1α (HIF-1α) in response to low oxygen levels.
75
What are angiogenesis inhibitors, and how do they work?
Drugs like Bevacizumab (anti-VEGF antibody) block blood vessel formation, starving tumours of nutrients.
76
How do tumours develop resistance to anti-angiogenic therapy?
By activating alternative pro-angiogenic pathways or increasing tumour invasiveness.
77
What is metastasis?
The spread of cancer cells from the primary tumour to distant sites via blood or lymphatic systems.
78
What is the epithelial-mesenchymal transition (EMT)?
A process where epithelial cells lose adhesion and gain migratory properties, aiding metastasis.
79
What are circulating tumour cells (CTCs)?
ancer cells in the bloodstream that can form secondary tumours in distant organs.
80
What role does the tumour microenvironment play in cancer progression?
It includes stromal cells, immune cells, fibroblasts, and extracellular matrix, influencing tumour growth and metastasis.
81
What are immune checkpoint inhibitors, and how do they work?
Drugs like anti-PD-1 (pembrolizumab, nivolumab) and anti-CTLA-4 (ipilimumab) remove immune suppression, allowing T cells to attack tumours.
82
What are CAR-T cells?
Genetically engineered T cells with chimeric antigen receptors (CARs) that target specific cancer antigens, used in blood cancers.
83
How do tumours evade immune detection?
By upregulating PD-L1, secreting immunosuppressive cytokines, and inducing regulatory T cells (Tregs).

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