Graeme Finlay 1

Question 1

What is the difference between benign and malignant tumours?

Answer 1

Benign tumours are slow growing, well differentiated and often surrounded by a capsule of fibrous tissue they are non-invasive and rarely fatal
Malignant tumours are invasive, faster growing and have an increased fraction of S-Phase cells, they lose differentiated features of the parental cells and contain areas of necrosis

Question 2

What are germ cell tumours?

Answer 2

Rare tumours derived from germ cells which can be benign or malignant including teratomas which arise from pluripotent stem cells and can have tissues from all three germ layers

Question 3

What are blastomas?

Answer 3

Rare cancers from progenitor cells which are embryonal tumours composed of undifferentiated tissues occurring in children and including hepatoblastoma, nephroblastoma, medulloblastoma and retinoblastoma

Question 4

What are sarcomas?

Answer 4

Tumours which arise from connective tissue

Question 5

Why are gliomas and lymphomas always considered malignant?

Answer 5

Because from the onset of tissue growth there is no barrier to prevent spread

Question 6

What are carcinomas?

Answer 6

Tumours derived from epithelial tissues which make up the majority of tumours

Question 7

What is the difference between squamous cell carcinomas and adenocarcinomas?

Answer 7

Squamous cell carcinomas are carcinomas derived from squamous epithelium while adenocarcinomas are derived from glandular tissue

Question 8

What is the normal function of the hippo pathway?

Answer 8

It is a pathway that negatively controls the growth of organs, operating in both flies and mammals and including sensors for cell density, protein kinase signalling molecules and nuclear targets

Question 9

How does the hippo pathway proceed normally?

Answer 9

Merlin is an upstream regulator interacting with surface receptors to induce a kinase cascade consisting of hippo and warts in drosophila or mammalian Ste20-like kinase 1/2 and large tumour suppressor homolog
These kinases target the transcriptional co-activator proteins Yorkie in drosophila or Yes-associated protein and transcriptional co-activator with PDZ-binding motif in humans Phosphorylation by large tumour suppressor homolog causes these proteins to be exported supressing gene activation

Question 10

What do the transcriptional co-activator proteins Yorkie in drosophila or Yes-associated protein and transcriptional co-activator with PDZ-binding motif in humans normally activate?

Answer 10

these activate a genetic program associated with cell growth, proliferation, survival and stem call maintenance

Question 11

What activates hippo signalling?

Answer 11

Planar cell polarity, apicobasal cell polarity, cell-cell adhesion, contact inhibition, mechanotransduction

Question 12

What is planar cell polarity and how does it activate hippo signalling?

Answer 12

Planar cell polarity is an ordered array of cells in a specific orientation across a cellular field which regulates the hippo pathway via FAT proteins

Question 13

What is apicobasal cell polarity and how does it activate hippo signalling?

Answer 13

The presence of functionally distinct membrane domains (apical and basolateral) in epithelial cells leads to YAP/TAZ repression. Abnormal expression of proteins determining this polarity in cancer may cause YAP/TAZ derepression

Question 14

What is cell-cell adhesion and how does it activate hippo signalling?

Answer 14

This is mediated by both adherens and tight junctions. These junction proteins such as E and alpha cadherin physically bind to and inhibit the function of YAP and TAZ. Junction proteins are often abnormal in cancers and this could lead to YAP/TAZ activation

Question 15

What is contact inhibition and how does it activate hippo signalling?

Answer 15

Cell proliferation is density dependent as normally cells stop dividing if the physically contact their neighbours. In cancer cells this regulation is lost

Question 16

What is mechanotransduction and how does it activate hippo signalling?

Answer 16

Cells growing under tension inactivate hippo and activate YAP/TAZ

Question 17

What is YAP/TAZ?

Answer 17

YAP is Yes-associated protein and TAZ is transcriptional co-activator with PDZ-binding motif these proteins work to drive cell proliferation

Question 18

What are the normal functions of the hippo pathway?

Answer 18

During development the hippo pathway functions in blastocyst formation where activation of hippo on the inside cells allows them to adopt the inner cell mass fate and a lack of hippo activation in the outside cells leads to YAP accumulation in the nucleus and activation of the trophectoderm
The hippo pathway also functions during repair of an injury where it is inactivated to activate YAP/TAZ supporting regeneration

Question 19

How does the hippo pathway function during cancer development?

Answer 19

Loss of hippo signalling leads to overgrowth and tumour development

Question 20

What are some examples of the hippo pathway functioning in cancer development?

Answer 20

Mutational inactivation of merlin leads to the tumour syndrome neurofibromastosis type 2
Gene silencing by promoter hypermethylation has been described in a variety of cancers for the MST 1 and 2 genes and LATS 1 and 2 genes
YAP is overexpressed in some cancers

Question 21

What is mechanotransduction?

Answer 21

Tension is maintained across epithelial layers by binding of cellular integrins to the extracellular matrix at focal adhesions
If the extracellular matrix is rigid then cells can stretch activating mechanotransduction processes

Question 22

What molecules are activated by mechanotransduction?

Answer 22

The Rho GTPase and ROCK myosin-activating kinase

These act on contractile cables of actinomyosin which inhibits the hippo pathway and activates YAP/TAZ

Question 23

How does mechanical stress lead to the activation of YAP/TAZ?

Answer 23

Mechanical stress may cause the unveiling of a binding site for an unknown inhibitor
Contractile F-Actinomyosin may directly sequester or inhibit LATS 1/2

Question 24

What does YAP/TAZ activation due to mechanical stress lead to?

Answer 24

Mesenchymal stem cell differentiation into osteoblasts rather than adipocytes or neurons
Endothelial proliferation rather than death
Mammary epithelial proliferation, migration, and invasion in a rigid ECM as opposed to acini differentiation. Deposition of rigid collagen may activate YAP/TAZ forming an aggressive breast lump which will lead to a cancer