Hallmarks

Question 1

original 6 hallmarks

Answer 1

Sustaining Proliferative Signaling:
Evading Growth Suppressors:
Resisting Cell Death:
Enabling Replicative Immortality:
Inducing Angiogenesis:
Activating Invasion and Metastasis:

Question 2

2 enabling characteristics + 2 new generation hallmarks

Answer 2

Enabling Characteristics:
Genome Instability and Mutation:
Tumor-Promoting Inflammation:

Emerging Hallmarks:
Deregulating Cellular Energetics: (Warburg effect).
Avoiding Immune Destruction:

Question 3

what is the warburg effect

Answer 3

Favouring glycolysis even in the presence of oxygen

cancer cells predominantly produce energy by glycolysis followed by lactic acid fermentation in the cytosol, even in the presence of sufficient oxygen to support oxidative phosphorylation

less ATP yield but generates ATP quickly and provides metabolic intermediates for the synthesis of nucleotides, lipids, and proteins, which are essential for rapid cell proliferation.

contributes to the acidic microenvironment of tumors, which promotes invasion and metastasis while evading immune responses

Question 4

Resistance to cell death:
Analyse the role of apoptosis resistance in cancer.

Answer 4

BCL-2 family overexpression - BAK/BAX antagonists (within P53-activated pathway)
- impaired response to DNA damage

TRAIL pathway mutations. (FADD mutations, receptor downregulation, decoy upregulation)
…

Question 5

BCL-2 overexpression

Answer 5

BCL-2 family overexpression - BAK/BAX antagonists (within P53-activated pathway)
- prevent their oligomerisation
- impairs the release of cytochrome C from the mitochondrial membrane because caspase 8 is not activated, meaning caspase 3 and 7 are not activated and these are responsible for forming mitochondrial membrane pores, allowing cytochome c to be released from the membrane into the cytosol.
- Usually Cytochrome C would degrade the extracellular materials to initiate apoptosis.
- impaired response to DNA damage

Question 6

TRAIL pathway

Question 7

TRAIL pathway mutations

Answer 7

FADD mutations, receptor downregulation, decoy upregulation

Question 8

PI3K/AKT/mTOR

Question 9

9) Activating Invasion and Metastasis:

Explain the processes involved in tumour invasion and metastasis.
What are the roles of epithelial-to-mesenchymal transition (EMT) and the extracellular matrix in this hallmark?

Answer 9

MMPs, CAFs, and TAMs.
MMP-2 and MMP-9 - degrade type IV collagen (component of the basement membrane BM)
- MMPs for ECM degradation,
- CAFs for ECM remodeling and signalling,
- TAMs for immune evasion and guidance,

EMT - endothelial-to-mesenchymal transition
endothelial cells acquiring mesenchymal traits
- EMT for generating mesenchymal cells that support metastasis

Question 10

Explain the methods of detecting MMP activity, used in practical 3

Question 11

How do MMPs degrade the ECM?

Answer 11

• Cancer cells secrete enzymes such as matrix metalloproteinases (MMPs) and cathepsins to degrade the ECM.
• allows tumor cells to breach the basement membrane and invade nearby tissues and blood vessels.
• cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) enhance ECM remodeling, creating paths for invasion.

TGF-β and VEGF -

MMP-2 and MMP-9 over-expression - observed in metastatic melanoma and colorectal cancer.

Question 12

Sustaining Proliferative Signalling:

Explain how cancer cells sustain proliferative signalling. Provide examples of specific pathways or mutations that enable this hallmark.

Answer 12

PI3K

Question 13

Evading Growth Suppressors:

Discuss the mechanisms by which cancer cells evade growth suppressors. How do alterations in tumor suppressor genes like TP53 and RB contribute to this process?

Answer 13

evading P53:

Question 14

Enabling Replicative Immortality:

How do cancer cells achieve replicative immortality? Discuss the role of telomerase and other mechanisms in this process.

Answer 14

evading cell cycle arrest:

telomerase:

Question 15

Inducing Angiogenesis:

Describe how cancer cells induce angiogenesis. What is the significance of VEGF in this process, and how does it support tumor growth?

Answer 15

Response to cellular stress - wound healing
Response to nutrient deprivation
balance between VEGF and thrombospondin-1

Angiopoietin/tie
- ANGPT1 binds to tie2
- triggers Grb2 - MAPK pathway
- promotes vascularisation
- ANGPT2 destabilises existing vasculature
compliments VEGF

VEGF/PI3K
- VEGF binds to VEGFR (an RTK)
- triggers PI3K/AKT/mTOR/eNOS

• provides intravasation routes for metastasis
• delivering nutrients and o2 -
  interstitial pressure - barrier for drugs
  grow faster + metastasis = poor prognosis
• SOFAFENIB + BEVACIZUMAB - VEGF inhibitors
• angiopoetin inhibitors + combination approach

Question 16

how is RAS/RAF/MEK/ERK pathway dysregulated in cancer?

Answer 16

• Mutations in RAS keeping it constantly activated
• Over-expression of RTKs
• Over-production of GFs from tumour cells

Question 17

RAS/RAF/MEK/ERK pathway
(ERK=type of MAPK)

Answer 17

• growth factors such as EGF bind to complimentary RTK receptor (such as EGFR)
• autophosphorylation of tyrosine residues
  recruits GRB2 adaptor protein to bind to SOS
• SOS-mediated phosph. of GDP to GTP on RAS, activating RAS
• Phospho cascade RAF/MEK/ERK
• In cytoplasm: inhibits BAD - anti-apoptosis and regulates warburg effect
• In nucleus: phosph. MYC and FOS trascription factors
  ^Cyclin D1 \/CDK inhibitors

(hallmarks: avoiding cell death, proliferation (cell cycle deregulation), angiogenesis)

Question 18

how does angiogenesis link to the RAS/ERK pathway?

Answer 18

from angiogenesis, angiopietin/tie2 complex upregulates GRB2 adaptor protein

Question 19

cell cycle deregulation
- sustaining prolif signalling

Answer 19

overexpression of cyclins like cyclin D

Mutations in CDK4

TP53 mutations - vulnerable to DNA damage

Question 20

11 Therapeutic Implications of the Hallmarks of Cancer:

How can an understanding of the hallmarks of cancer guide the development of targeted therapies? Provide examples of drugs that exploit specific hallmarks.

Question 21

12 Immune System Evasion in Cancer:

Discuss how cancer cells evade immune destruction. What role do immune checkpoints, such as PD-1/PD-L1, play in this process?

Question 22

13 Energy Metabolism in Cancer:

Cancer cells often exhibit altered energy metabolism. Describe the Warburg effect and its implications for cancer growth and survival.

Question 23

14 Genomic Instability and Mutation:

Analyse the importance of genomic instability in cancer. How does it drive tumour evolution and heterogeneity?

Question 24

15 Inflammation

How does chronic inflammation contribute to the development and progression of cancer? Discuss the role of inflammatory cytokines and signalling pathways.

Answer 24

normally protective - tissue repair
in cancer - persistent and unregulated
TME promoting genetic instability, DNA damage, angiogenesis, and immune evasion

inflammatory cytokines IL6/TNF-a/IL1B
activate NF-kB and STAT3
produced by both tumour and infiltrating cells, creating a feedback loop that promotes tumour growth

signalling pathways
STAT3
VEGFR

UNIQUE - continuous source of mutagenic agents like ROS and Nitrogen species
vital to TME

TREATMENT

Question 25

STAT3 PATHWAY

Question 26

VEGF PATHWAY

Question 27

discuss how the hallmarks of BREAST cancer manifest uniquely

Question 28

discuss how the hallmarks of PANCREATIC cancer manifest

Question 29

discuss how the hallmarks of LUNG cancer manifest uniquely

Question 30

discuss how the hallmarks of COLORECTAL cancer manifest