cellular basis of malignancy

Question 1

adherens junctions proteins and effect with carcinogens

Answer 1

• consist of E-cadherin (extracellular protein found in space between cells), alpha and beta catenin
• carcinogens show loss of E-cadherin-mediated adhesion and adherens junction function during EMT

Question 2

Epithelial-to-mesenchymal transition (EMT)

Answer 2

occurs during both embryonic development and carcinoma progression
mesenchymal cells are like fibroblasts

Question 3

in diffuse type cancers, EMT occurs irreversibly following…

Answer 3

• mutational inactivation of E-cadherin gene (occurs early in cancer development)
• loss of express of E-cadherin following methylation of its promoter
• mutation of the alpha catenin gene

Question 4

when does reversible EMT occur

Answer 4

in response to growth factors e.g. hepatocellular growth factor (HGF)

Question 5

Hepatocyte growth factor receptor

Answer 5

transmembrane tyrosine kinase that:
-activates RAS oncoproteins that activates snail and repress the E-cadherin gene
(GF –> HGFR –> RAS –> Snail –> repressed E-cadherin)
-phosphorylate E-cadherin causing degredation
-phosphorylate B-catenin causing dissociation from adherens junction

Question 6

what are the various ways in which tumour cells increase their sensitivity to HGF receptor

Answer 6

• over-expression
• gene-amplification (increased copy no.)
• missense point mutation
• co-expression with HGF in the same cells, establishing autocrine loops

Question 7

autocrine

Answer 7

a growth factor that a cell produces activates a receptor the same cell produced

Question 8

what is the defining characteristic of cancer

Answer 8

invasion - hydrolytic enzymes give cancers the ability to break out of tissue compartments

Question 9

two proteolytic systems

Answer 9

uPA

MMP

Question 10

proteolytic enzymes

Answer 10

enzymes with a capacity to destroy local ECM

Question 11

uPA

Answer 11

activates plasminogen to form plasmin

Question 12

MMP

Answer 12

• have zinc in their active form

- with plasma they destroy ECM at edge of tumours

Question 13

the complex which contributes towards tumour cell invasion

Answer 13

• receptors for growth factors (GFR)
• receptors for proteolytic enzymes (uPA receptors)
• receptors for ECM (integrins)

GFR and integrins, signal into the cell to promote EMT

uPAR signal into ECM so that tumour cells can invade and destroy tissue

Question 14

functions performed by MMP proteolytic activity during tumour invasion

Answer 14

ECM - carves pathway for cell migration, released ECM-bound growth factor

laminin 5 - release fragments that promote migration

E-cadherin - supresses epithelial cell adhesion (leads to EMT)

latent growth factors - degrades binding proteins to release growth factors

Question 15

types of hypoxic cells

Answer 15

• viable and necrotic

Question 16

viable hypoxic cells

Answer 16

• resistant to radiotherapy as radiation need oxygen to cause cell death
• tend to stop proliferating therefore resistant to forms of chemotherapy
• select for agressive cells (p53 cells can survive in hypoxic cells) = genotype
• activates hypoxia-inducaible factor HIF1a turning on gene expression e.g. vascular endothelial growth factor (VEGF) resulting in angiogenesis = phenotype
• turns on HGFR leading to EMT

Question 17

angiogenesis and the key mediator

Answer 17

development of a new blood vessels growing in from surrounding preexisting blood vessels (neighbouring)
- key mediator VEGF (vascular endothelial growth factor)

Question 18

vasculogenesis

Answer 18

progenitor cells, stem cells, come in and produce new blood vessels from scratch

Question 19

what induces angiogenesis

Answer 19

• metabolic stress e.g. hypoxia or hypoglycemia
• inflammation
• activation of oncogenes = mutations of RAS (turn it on) or mutation of p53 (which normally knock it out)

Question 20

what does VEGF do

Answer 20

talks to vascular endothelial cells cause their proliferation, survival and their migration. causes formation of networks of BVs (commonly leaky BVs)

Question 21

forms of angiogenesis

Answer 21

• sprouting
• co-option of coexisting BVs
• intussusception
• recruitment of progenitors (e.g. angioblasts)
• mimicry