Cancer

Question 1

Role of beta catenins in Wnt

Answer 1

Central transducer of canonical Wnt singles => enter the nucleus => relief of TCF/LEF mediated transcriptional repression

Question 2

Beta catenin is found in 3 complexes

Answer 2

Cadherin
TCF/LEF
APC, axin, GSK3, CK1

Question 3

Beta catenin is located at which junction

Answer 3

Cell-cell adherens junctions

Question 4

Beta catenin is located at which junction?

Answer 4

Cell-cell adherens junctions

Question 5

Beta catenin is regulated by ________________ in adherens junctions.

Answer 5

Tyrosine kinases

Question 6

Beta catenin is regulated by ___________________ such as ______ in cytoplasm

Answer 6

Serine kinases
GSK3

Question 7

What three pathways do Wnt target genes activate? And what do all pathways begin with?

Answer 7

[1] Wnt/Beta-catenin
[2] Wnt/CA2+
[3] Planar cell

Binding of Wnt to Frizzld and recruitment of dishevelled family proteins

Question 8

Repression of _________ expression has a key role in pathological EMT

Answer 8

E-cadherin

Question 9

Downregulation mechanisms of E-Cadherin [6]

Answer 9

Transcriptional regulators
Genetic mutations of gene CDH1
Proteolytic degradation
Receptor tyrosine kinases -> phosphatase
Oncogenes -> Fos
TCF/Beta-catenin complex

Question 10

Outcomes of down regulating E-Cadherin [4]

Answer 10

Reduction of strength of cellular adhesion
Increase cell motility
Cancer cells to cross basement membrane and metastasise
Interaction in Wnt/Beta-catenin pathway

Question 11

Loss of E-cadherin has two effects on cancer

Answer 11

Alters signalling of beta-catenin/wnt
Modulates cell-cell adhesion

=> development of epithelial derived tumour types
Tumour progression - invasion or metastasis

Question 12

loss of cadherin from adherens junctions results in….

Answer 12

Release of its partner beta-catenin, into cytosol which activates Wnt pathway

Question 13

Oncogenes

Answer 13

Mutated proto-oncogene becomes oncogene => loss of growth control

Question 14

Tumour suppressor genes

Answer 14

Copies of the TSG on both homologues are mutated => loss of growth control

Question 15

Factors influencing invasion by cancer cells [3]

Answer 15

Abnormal or increased cell motility
Secretion of proteolytic enzymes
Decreased cellular adhesion

Question 16

Two types invasion

Answer 16

Single cell invasion
- mesenchymal
- amoeboid

Collective cell migration
- coordinated
- cohort

Question 17

Increased cellular motility indicates abnormalities in the regulatory mechanism enabled by:

Answer 17

Autocrine growth stimulation
Reduced apoptosis
Telomerase activity

Question 18

What are the three families of matrix metalloproteases?

Answer 18

[1] interstitial collagenases
- degrade collagen type I, II and III

[2] gelatinases
- degrade type IV collagen and gelatin

[3] stromelysins
- degrade type IV collagen and proteoglycans

Question 19

VEGF angiogenesis

Answer 19

Tumour cannot grow beyond 1-2mm in diameter due to hypoxia
Secretion of VEGF
Formation of new vascular system that provides nutrients and oxygen
Tumour growth and proliferation
Potential escape to metastasise

Question 20

Podosomes and invadopodia ECM degradation through:

Answer 20

Zinc-related MMPs
Cathepsin
Cystein protease
Serine protease

Question 21

Podosomes

Answer 21

Found in epithelial cells, smooth and cardiac muscle and macrophages
Actin centre and integrins
Form bridges with cytoskeleton and ECM

Question 22

Invadopodia

Answer 22

Found in carcinoma cells, fibroblasts
Larger actin centre
Lead invasion via degradation of ECM

Question 23

6 steps in cancer progression

Answer 23

Local invasion
Intravasation
Dissemination
Extravasation
Micrometastasis
Macroscopic metastasis

Question 24

Paget’s seed and soil hypothesis

Answer 24

1889

Question 25

What is the cancer metastasis target?

Answer 25

Generation of permissive micro environment in target organ - VEGFR1 expressing progenitor cells go to pre-metastatic site Deposition of fibronectin indicate potential cancer cells incoming

Question 26

Stroma cells

Answer 26

Provide CT framework of the tumour Important in health and pathology Genetic mutations in epithelial cells result in activated stroma Tumour and trona evolve together

Question 27

Mutations in _____________________ that specifically regulate paracrine growth factor expression initiate epithelial cancers

Answer 27

Stromal cells

Question 28

Mutations in _____________ that specifically regulate paracrine growth factor depression initiate epithelial cancers

Answer 28

Stromal cells

Question 29

Stroma cells secrete (2)

Answer 29

Signal proteins that stimulate cancer cell growth and division Proteases for further remodelling of ECM

Question 30

Origin of carcinoma associated fibroblasts

Answer 30

Trasndifferentiation of cancerous epithelium through EMT Mesothelium, pericytes Endothelial cell via endoMT Activation of local fibroblasts Bone marrow MSC recruitment CAF stem cell? Self-renewal

Question 31

CAFs function

Answer 31

Interaction with cancer cells Tumour immunology - CAFs are capable of sampling, processing, and presenting tumor antigens via major histocompatibility complex 1 (MHC-I). Angiogenesis ECM remodelling

Question 32

Track generation in cancer

Answer 32

Tracks are made in ECM by fibroblasts Squamous cell carcinoma cells use these tracks to invade ECM

Question 33

Anoikis

Answer 33

Normal response in cells that lose contact with surrounding ECM an neighbouring cells

Question 34

Avoiding Anoikis

Answer 34

Survival signals derived from their junctional signalling networks Normal matrix attachment

Question 35

Anoikis pathway

Answer 35

Integrin signalling initiates BH3-only pro-apoptotic genes Inhibition of anti-apoptotic proteins - BH123 protein aggregation - opening pores in outer mitochondrial membrane Activates caspase cascade especially from cytochrome C Cell death

Question 36

Anoikis pathway autocrine mechanisms

Answer 36

Production of TrkB protein Activates Akt/PkB pathway

Question 37

Paracrine mechanisms of Anoikis

Answer 37

Involves interactions with external components e.g. immune cells

Question 38

4x pathways of Anoikis avoidance

Answer 38

EGFR Glucose transporters IGF1R FAK

Question 39

Give the EGFR resistance pathway

Answer 39

EGFR -> SRC -> P13K -> mTOR

Question 40

Give the glucose transporter resistance to Anoikis pathway

Answer 40

Glucose transporters -> NADPH -> AMPk -> ATP production and survival

Question 41

IGF1R resistance pathway to Anoikis

Answer 41

IGF1R -> P13k -> mTOR

Question 42

FAK structure

Answer 42

125 kDa protein N-terminal FERM domain Central kinase domain C-terminal FA targeting domain

Question 43

FAK function

Answer 43

Mediates integrin and RTK signalling

Question 44

Explain nuclear and FAK promotion of cell proliferation and survival

Answer 44

Autophosphorylation and Src recruitment => activation of FAK Triggers P13K pathway Phospholipid production Akt kinase activation Inhibition of cell death machinery

Question 45

FAK interaction with P53

Answer 45

Loss of cell adhesion -> increased FAK FERM domain of FAK can interact with p53 suppressing its transcriptional activity FAK promotes ubiquitin proteasome mediated p53 degradation by mdm2

Question 46

FAK interaction with RIP death domain

Answer 46

FAK can directly inhibit Anoikis by sequestering and inhibiting death domain of RIP protein This protein can either induce apoptosis or lead to pro-survival signalling FAK binding shifts towards pro-surviving signalling