Cancer metastasis and angiogeneis (DONE) Flashcards
Difference between tumour and cancer
Tumour: mass of cells from uncontrolled cell proliferation
Cancer: tumour with invasive (malignant) features or the propensity to develop them
Benign tumour characteristics
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
Malignant tumour characteristics
Not self contained or localised
Presence of invading cells at tumour periphery
Propensity to spread
Have capacity for rapid growth
Malignant tumours: clinical consequences
Spread of tumour cells to other organs
Colonization
Impairment of function
Hard to treat
Metastasis is an important prognostic factor
Spread of a tumour to a secondary (distant) site
Most cancer patients (95%) die because of metastases
Metastatic tumours
Hard to treat surgically
Impair organ function
Tend to be chemo-resistant
How do cancers metastasize?
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
Some tumours favour particular organs for metastasis
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
Anatomic hypothesis
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
Seed and soil hypothesis
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
Metastasis stages
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
Cell-cell adhesion
E-cadherin plays a critical role in tumour metastasis
Reduced expression of E-cadherin increases the invasiveness of tumour cells
Loss of E cadherin leads to metastatic tumours
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
Tumour cell invasion
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
Cancer cell-basement membrane interactions mediated by integrins
Activation of integrin signalling promotes invasive characteristics: cell survival, growth, membrane changes, migratory capacity, MMP production
Certain integrins associated with cancer progression
Proteases facilitate tissue invasion
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
Invasion into surrounding tissue
Malignant tumour cells secrete proteases that target the basement membrane/extracellular matrix
Facilitates local tissue penetration and entry into circulatory system
Angiogenesis
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
Tumour angiogenesis
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
Cancer treatment
Traditional, non-pharmacological: surgery, radiotherapy
Traditional, pharmacological: chemotherapy
Alkylating agents- nitrogen mustards, platinum, triazenes
Antimetabolites- methotrexate, 5FU
Microtubule disrupting agents- taxanes
Targeted therapies
Exploiting features of the cancer itself
Endocrine treatments for ER+ breast cancer
Inhibitors of angiogenesis
Inhibitors of internal signalling cascades that promote metastasis
Angiogenesis inhibition
Avastin (bevacizumab)
Binds to VEGF
Prevents activation of endothelial EGFR
Src: a multifunction mediator of metastatic behaviour
Survival Proliferation Angiogenesis Adhesion Invasion/migration
