metastasis and angiogenesis

Question 1

outline general tissue architecture

Answer 1

epithelium is separated from mesenchyme (nerves, collagen fibres, fibroblasts) by the basement membrane. the ECM contains a number of cell types

Question 2

what are the major components of the basement membrane?

Answer 2

• type IV collagen
• laminin
• heparan sulfate proteogylcans
• entactin

Question 3

what are the minor components of the basement membrane?

Answer 3

collagen XVIII
collagen XV
SPARC
fibulins

Question 4

how is the epithelium organised in normal tissues?

Answer 4

only cells bound to the basement membrane can divide

Question 5

how is the epithelium organised in carcinoma in situ?

Answer 5

cells are still bound to basement membrane, but contact inhibition is lost

Question 6

how is the epithelium organised in a malignant carcinoma?

Answer 6

cells gain the ability to breach the basement membrane

Question 7

through which routes can metastasis occur?

Answer 7

• blood vessels
• lymphatics
• body cavities

Question 8

what are the stages of the metastatic cascade?/

Answer 8

1- clonal expansion, growth 
2- metastatic subclone
3- adhesion to and invasion of the basement membrane 
4-- passage through the ECM 
5- intravasation 
6- interaction with host lymphoid cells 
7- tumour cell embolus 
8- adhesion to basement membrane 
9-- extravasation 
10- metastatic deposit 
11- angiogenesis

Question 9

what are the key molecular events in metastasis?

Answer 9

• changes in cell adhesion
• production of proteolytic enzymes
• changes in balance of positive and negative regulators of angiogenesis

Question 10

what types of changes in cell adhesion occur in metastasis?

Answer 10

• homophilic cell-cell interactions: E-cadherin
• cell substrate interactions: integrins
• heterophilic cell-cell interactions: immunoglobulin superfamily

Question 11

what types of proteolytic enzymes are produced in metastasis?

Answer 11

matrix metalloproteinases

uPA/uPAR system

Question 12

what is meant by ‘epithelial-mesenchymal transition’?

Answer 12

switch in phenotype from polarised epithelium to motile, fibroblastoid or mesenchymal phenotype

Question 13

what are the characteristics of EMT?

Answer 13

• dissolution of epithelial tight junctions
• actin cytoskeleton reorganisation
• loss of apical/basal polarity
• induction of mesenchymal gene expression program
• migration through basement membranes

Question 14

which oncogenic pathways contribute to EMT?

Answer 14

oncogenic Ras co-operates with endogenous TGF beta signalling

Question 15

which proteins mediate cell-cell adhesion?

Answer 15

cadherins

Question 16

which types of protein mediate cell-matrix adhesion?

Answer 16

integrins

Question 17

what do E-cadherins do?

Answer 17

participate in homotypic cell-cell interaction - form a link between adjacent cells and actin cytoskeleton

form a zipper-like structure - dependent on Ca2+

Question 18

what is the evidence between a loss of E-cadherin, invasion and metastasis?/

Answer 18

• immunohistochemical studies: reduced E-cadherin expression in malignant disease
• invasiveness of cancer cell lines

Question 19

outline how mouse models identified a link between E–cadherin loss and metastasis

Answer 19

mouse crossed with transgenic mice expression a dominant interfering E-cadherin mutation showed early invasion and metastasis