tumour angiogenesis, invasion and metastasis

Question 1

what is a malignant tumour

Answer 1

unlimited growth of a tumour

migration of tumour cells to surrounding stroma where they are free to disseminate to distance

Question 2

describe 4 steps in cancer progression

Answer 2

1. transformation = extensive mutagenic and epigenetic change and clonal selection
2. angiogenesis = new blood vessel formation
3. motility and invasion = epithelial to mesenchymal formation
4. metastasis = colonisation of target organs

Question 3

define vasculogenesis

Answer 3

formation of new blood vessels from progenitors

Question 4

what are the 3 types of angiogenesis

Answer 4

vasculogenesis = organ growth

normal angiogenesis = wound repair placenta during pregnancy

pathological angiogenesis = tumour angiogenesis, ocular and inflammatory disorder

Question 5

describe the process of tumour angiogenesis

Answer 5

1. small tumour enlarges to point where oxygen/nutrients not enough
2. tumour turns on expression of angiogenesis genes for new blood vessel growth
3. new blood vessels grow in and around tumour = increased oxygen delivery = increased growth and route for cells to shed off and spread

Question 6

what is tumour hypoxia

Answer 6

hypoxia = strong stimulus for tumour angiogenesis

increases with distance from capillaries = transcription of genes involved in angiogenesis , tumour cell migration and metastasis

Question 7

describe angiogenic factors

Answer 7

stimulate directional growth of endothelial cells
vascular endothelial growth factor
fibroblast growth factor 2
placental growth factor
angiopiotietin 2
- secreted by tumour cells and stored bound to components of extracellular matrix and released by enzymes aka matrix metalloproteases

Question 8

VEGF signalling

Answer 8

1. VEGF binds to VEGF-R2 on endothelial cells
2. this activates 3 major signal transduction pathways
3. VEGF activates all survival, vascular permeability, gene expression and cell proliferation
4. all these pathways essential for angiogenesis

Question 9

mechansims of tumour cell motility and invasion

Answer 9

increased mechanical pressure by rapid cellular proliferation
increased motility of malignant cells
increased production of degradative enzymes by tumour cells and stromal cells

Question 10

describe epithelial mesenchymal transition

Answer 10

loss of:
epithelial shape and cell polarity
cytokeratin intermediate filament expression
epithelial adherens junction protein

acquisiton of:
fibroblast-like shape and motility 
invasiveness 
vimentinin intermediate filament expression 
mesenchymal gene expression 
protease secretion

Question 11

cell adhesion molecules and invasion

Answer 11

E-cadherins

• homotypic adhesion molecule
• calcium dependence
• inhibits invasiveness
• binds b-catenin

Question 12

what does loss of E-cadherins cause

Answer 12

disrupted cell-cell adhesion
loss of contact inhibition = cell growth on top of eachother
mutation/loss of E-cadherin

Question 13

stromal cell. contribution to tumour progression

Answer 13

factors released by stromal cell include angiogenic, growth factors and cytokines/proteases
plasmin = activates matrix metalloproteases = allows invasion by degrading extracellular matrix and releasing matrix bound angiogenic factors

Question 14

sites of tumour metastasis

Answer 14

breast
colorectal 
gastric 
lung 
pancreatic 
prostate

Question 15

describe treatment for tumour angiogenesis

Answer 15

success within targeted therapy to angiogenetic factors

cell motility = no success in cell-cell adhesion molecules

invasion = clinical trials with matrix metalloproteases unsuccesful in decreased tumour burden

Question 16

describe avastin = monoclonal antibody

Answer 16

1st specific antiangiogenesis drug
approved for colorectal, lung, kidney and ovarian cancers and eye disease
binds to VEGF
prevents VEGF binding to VEGF receptors on endothelial cells