Common Signalling Pathways of Development and Cancer

Question 1

What causes cancer?

Answer 1

• > 200 forms of cancer
• caused by environmental, viral and genetic factors
• causes either activation of oncogenes or loss of TSGs

Question 2

What common processes occur during development and tumourigenesis

Answer 2

• proliferation
• migration
• invasion
• apoptosis
• angiogenesis

Question 3

How does mis-regulation of developmental signalling pathways cause cancer in embryogenesis?

Answer 3

• TGF-b and Fgf are major molecular mechanisms that control embryonic development
• they function as morphogenetic that are secreted from one cell type to another to regulate cell proliferation, survival or differentiation during normal embryogenesis
• they are evolutionarily conserved
• during development, the signalling systems are tightly regulated
• if they escape control, they cause diseases and cancer

Question 4

What are signalling pathways that are common targets for cancer therapies?

Answer 4

• driver genes can be classified into 1 or more of 12 pathways
• they all confer a selective growth advantage
• these pathways can be further organised into 3 core cellular processes:
  1. Cell survival
  2. Cell fate
  3. Genome maintenance

Question 5

What does the TGF-b signal pathway use?

Answer 5

• receptors type l/ll single-pass transmembrane receptor kinases
• ligands in the TGFb superfamily

Question 6

What is the mechanism of the TGF-b pathway?

Answer 6

• TGF-b ligands bind to a type ll receive which recruits and phosphorylates a type l receptor
• the type l receptor phosphorylates Smad2/3 which can now bind Smad4
• the Smad2/3/4 complex enters the nucleus and allows gene expression by binding to a DNA sequence

Question 7

What is the function of the TGF-b pathway?

Answer 7

• it’s involved in many cellular processes including cell growth, differentiation, apoptosis, homeostasis, inflammation and immunity
• it inhibits the cell cycle however as the tumour progresses, cells develop resistance to TGF-b inhibition so it becomes tumour promoting
• mutations of TGF-b is found in many cancers, eg pancreatic and colorectal cancer

Question 8

What does the Hedgehog signalling pathway use?

Answer 8

• transmembrane receptor protein Ptch1/2
• ligand hedgehog protein (hh) and there are 3 types:
  1. Sonic (Shh)
  2. Indian (Ihh)
  3. Desert (Dhh)

Question 9

What is the mechanism of the hedgehog signalling pathway?

Answer 9

• in the absence of the ligand, Ptch1 binds to Smo protein
• transcription factor Gli is proteolytically processed to generate truncated Gli
• When the Hh ligand binds to Ptch1, Smo separates from Ptch1 which enables Smo to activate Gli
• activated Gli enter the nucleus to induce transcription of a variety of target genes

Question 10

What is the function of the hedgehog signalling pathway?

Answer 10

• vital for diverse developmental processes such as regulation of cell fate and stem cell maintenance
• mis-regulation of the Hh pathway causes birth defects and cancers (eg basal-cell carcinoma)
• cancer causing mutations cause extra high levels of Hh which leads to elevated Gli

Question 11

How can tumour growth be suppressed using Hh?

Answer 11

• Hh ligands are produced by tumours an affect in both paracrine and autocrine manner
• tumour growth can be suppressed by Hh inhibitors which is anti-cancer therapy

Question 12

What does the Wnt signal pathway use?

Answer 12

• frizzled receptor protein contains an extracellular ligand binding site and an intracellular effector site extending into the cytoskeleton
• secreted Wnt protein ligand

Question 13

What is the mechanism of the Wnt signal pathway

Answer 13

• in absence of ligand, b-catenin is destroyed by a multi protein degradation complex
• the complex phosphorylates b-catenin so it can be destroyed in proteasomes
• when bound to Wnt ligand it activates Frizzled which activates Dishevelled.
• this inhibits the degradation complex and b-catenin destruction, resulting in its accumulation
• b-catenin enter nucleus and binds and activates TCF transcription factors which induces the expression of oncogenes (eg MYC)

Question 14

What is the function of the Wnt signal pathway?

Answer 14

• Wnt-controlled gene expression plays many roles in embryonic development
• activating mutations n the b-catenin gene is found in colon cancer and melanomas
• mutations in the degradation complex was to the instability of b-catenin, resulting in expression of oncogenes (eg MYC)

Question 15

What does the notch signal pathway use?

Answer 15

• differs from other signalling pathways as it requires direct cell to cell contact
• notch receptor glycoproteins (notch 1-4)
• delta 1/3/4 ligands

Question 16

What is the function of the notch signal pathway?

Answer 16

• regulates the development of many vital organs (brain, heart etc)
• one cell tells an adjacent cell which path of differentiation to take
• mis-regulation is implicated in T and B cell malignancies, breast cancer, skin cancer

Question 17

What does the FGF signal pathway use?

Answer 17

• fibroblast growth factor receptor (FGFR 1-4)
• secreted FGF ligands (23 isoforms)

Question 18

What is the mechanism of the FGF signal pathway?

Answer 18

• binding of the ligand to 2 adjacent receptors forms an active homodimer
• this activated dimer is a tyrosine kinase that induces auto-phosphorylation whilst converting recruited proteins into an active state
• many of these proteins are also tyrosine kinases that initiate a cascade of downstream signalling events