Cancer metastasis and angiogeneis (DONE)

Question 1

Difference between tumour and cancer

Answer 1

Tumour: mass of cells from uncontrolled cell proliferation
Cancer: tumour with invasive (malignant) features or the propensity to develop them

Question 2

Benign tumour characteristics

Answer 2

Generally self contained
Localised to one area
Well-defined periphery
Slow growing- expand outwards from central mass
Compression of surrounding tissues e.g. brain, abdomen, blood vessels

Question 3

Malignant tumour characteristics

Answer 3

Not self contained or localised
Presence of invading cells at tumour periphery
Propensity to spread
Have capacity for rapid growth

Question 4

Malignant tumours: clinical consequences

Answer 4

Spread of tumour cells to other organs
Colonization
Impairment of function
Hard to treat

Question 5

Metastasis is an important prognostic factor

Answer 5

Spread of a tumour to a secondary (distant) site

Most cancer patients (95%) die because of metastases

Question 6

Metastatic tumours

Answer 6

Hard to treat surgically
Impair organ function
Tend to be chemo-resistant

Question 7

How do cancers metastasize?

Answer 7

Routes of spread:
Lymphatic system- common pathway for the initial spread of solid tumours, pattern of lymph node involvement follows natural route of drainage
Circulatory system (hematogenous spread)- capillaries common site
Tumour cells can often be emboli within vessels
Through the body wall into the abdominal and chest cavities (transcoelomic)- peritoneal cavity

Question 8

Some tumours favour particular organs for metastasis

Answer 8

Prostate favours bone marrow, also brain, lungs and liver
Pancreas favours liver, also lungs
Breast favours bone marrow, also liver and brain
Colon favours liver, also bone marrow and lungs

Question 9

Anatomic hypothesis

Answer 9

Determined by pattern of blood/lymphatic flow
Secondary tumours occur in the organs which are first encountered by the disseminating cancer cells
Capillary bed of the first organ encountered may promote mechanical arrest and attachment

Question 10

Seed and soil hypothesis

Answer 10

The provision of a fertile environment (soil) in which compatible tumour cells (seed) can grow
Appropriate growth factors or extracellular matrix in target environment
Selective chemotaxis at target organ
Compatible adhesion sites on the endothelial lumen
Alluded to the importance of the tumour microenvironment in supporting metastasis

Question 11

Metastasis stages

Answer 11

Loss of cell-cell adhesion within primary tumour
Invasion into surrounding tissue and entry into circulation
Survival and extravasation
Colonisation of metastatic sites and re-growth of tumour

Question 12

Cell-cell adhesion

Answer 12

E-cadherin plays a critical role in tumour metastasis

Reduced expression of E-cadherin increases the invasiveness of tumour cells

Question 13

Loss of E cadherin leads to metastatic tumours

Answer 13

E cadherin loss enables disaggregation of cancer cells from one another
Over 75% of metastatic cancers exhibit CDH1 abnormalities
CDH1 mutations involved with several cancers: breast, liver, prostate, stomach, endometrium, ovary and lung
Loss of E cadherin expression/function correlates with poor prognosis

Question 14

Tumour cell invasion

Answer 14

First barrier to tumour cells is the basement membrane
Form of ECM that regulates cell and tissue architecture
Physically separates epithelia from stroma
Stores growth factor molecules
Loss of BM barrier allows direct invasion into stroma

Question 15

Cancer cell-basement membrane interactions mediated by integrins

Answer 15

Activation of integrin signalling promotes invasive characteristics: cell survival, growth, membrane changes, migratory capacity, MMP production
Certain integrins associated with cancer progression

Question 16

Proteases facilitate tissue invasion

Answer 16

Proteases provide a controlled degradation of components of the extracellular matrix
Metalloproteinases:
Collagenase, gelatinase and stromelysins which can be soluble and or secreted
Membrane type (MT_MMP) group are anchored in the plasma membrane

Question 17

Invasion into surrounding tissue

Answer 17

Malignant tumour cells secrete proteases that target the basement membrane/extracellular matrix
Facilitates local tissue penetration and entry into circulatory system

Question 18

Angiogenesis

Answer 18

The formation of new blood vessels from pre-existing ones
Blood supply needed for tumour growth >2mm
Facilitates tumour metastasis: primary tumour growth, entry into/exit out of circulation, re-growth of secondary deposits

Question 19

Tumour angiogenesis

Answer 19

Release of angiogenic factors and proteases by tumour cells
Degradation of BM and proliferation of endothelial cells
Migration of endothelial cells in direction of tumour
Formation of tubular structures which anastomose with the existing vasculature

Question 20

Cancer treatment

Answer 20

Traditional, non-pharmacological: surgery, radiotherapy
Traditional, pharmacological: chemotherapy
Alkylating agents- nitrogen mustards, platinum, triazenes
Antimetabolites- methotrexate, 5FU
Microtubule disrupting agents- taxanes

Question 21

Targeted therapies

Answer 21

Exploiting features of the cancer itself
Endocrine treatments for ER+ breast cancer
Inhibitors of angiogenesis
Inhibitors of internal signalling cascades that promote metastasis

Question 22

Angiogenesis inhibition

Answer 22

Avastin (bevacizumab)
Binds to VEGF
Prevents activation of endothelial EGFR

Question 23

Src: a multifunction mediator of metastatic behaviour

Answer 23

Survival
Proliferation
Angiogenesis
Adhesion
Invasion/migration