Metastasis Flashcards
What is the sequence of events which occurs in metastasis?
detachment of tumour cells form their neighbours
invasion of surrounding connective tissue
intravasation into lumen of vessels
evasion of host defence mechanisms
adherence to endothelium at remote location
extravasation of cells from vessel lumen into surrounding tissue
survival and growth in new environment
E-cadherin is expressed in many carcinomas. T/F?
True
What proteinases are often over expressed in cancer cells?
Matrix metalloproteinases
E-cadherin is calcium dependent and sometimes in cancer cells there is a mutation so that the calcium binding domain of E-Cadherin is missing. What effect does this have?
Unfunctional E-cadherin allowing aggressive tumour invasion
What are integrins?
Cell-surface molecules that bind to extracellular matrix molecules
Specific integrins seem to promote invasion and metastasis. Describe possible mechanisms by which this occurs
Decreased adhesion to the basement membrane surrounding the epithelium
increased migration through stroma
increased adhesion to basement membrane or endothelial cells of blood vessels
Describe the mechanism by which HGF can induce epithelial cells to dissociate and scatter in culture.
HGF binds to c-met (a receptor tyrosine kinase) causing increased tyrosine phosphorylation of B-catenin which disrupts E-cadherin mediated adhesion
What type of collagen do matrix metalloproteinases degrade and why is this relevant to metastasis?
Type four collagen - which makes up the basement membrane thus allowing tumour to break through the bm
Describe the role of VEGF in metastasis
VEGF is expressed by hypoxic cancer cells
VEGF binds to its receptors on nearby endothelial cells causes these cells to migrate towards the tumour and start to form new blood vessels
the newly formed vessels are weak and leaky which allows fibrinogen to leak out and a clot to form
the clot provides a good surface for the endothelium to grow onto
Tumour cells can exploit the abilities of lymphocytes to intravasate and extravasate. T/F?
True
What are the ten major characteristics of cancer cells?
Unlimited multiplication Escape from growth suppressors Promotion of invasion and metastasis Resistance of apoptosis Stimulation of angiogenesis Maintenance of proliferative signalling Elimination of cell energy limitations Evasion of immune destruction Genome instability and mutation Tumour enhanced inflammation
Metastasis is the leading cause of cancer related death. How does metastasis cause death?
Physical obstructions
Compromised organ function
Competing with healthy tissue for nutrients and oxygen
How do mesenchymal cells differ from epithelial cells?
Loose or no interactions between cells No cell-cell junctions No clear apical/basolateral membranes No apicobasal polarised distribution of organelles and cytoskeleton Mobile and sometimes invasive
E-cadherin binding is homotypic. What does this mean?
E-cadherin on one cell binds to e-cadherin on another cell
What molecules facilitate the binding of E-cadherin to the actin cytoskeleton?
alpha and beta catenin
E-cadherin expression can be disrupted in cancer by silencing of the CDH1 promoter. How does this occur?
Methylation mutations in proteins which interact with e-cadherin such as beta catenin
What transcription factors normally suppress E-cadherin and can be over-expressed in cancer cells?
Slug
Snail
Twist
Integrins exhibit bidirectional signalling. T/F?
True
How many possible heterodimers can be formed from integrins?
24
Where are integrins found?
basal epithelial cells
focal adhesions of migrating cells
In what ways is altered intern expression useful for cancer cells?
Supports oncogenic growth factor receptor signalling
Allows cell migration and invasion
Allows extravasation from blood vessels
Causes colonisation of metastatic sites
Allows survival of circulating tumour cells
In metastasis, why cells secrete HGF?
Stromal cells
What protein is activated by urokinase plasminogen activator?
Plasminogen is activated to plasmin
What is the function of cathepsin K collagenolytic activity?
Matrix degradation
What type of cancers commonly spread through the lymphatic system?
Carcinomas e.g. breast, colon and lung
What type of cancers commonly spread through the blood?
Sarcomas
Some carcinomas such as kidney, colorectal and prostate
What type of cancers commonly spread through transcoelomic spread?
Cancers which originate in the peritoneal cavity such as ovarian and colorectal
What steps are involved in intravasation?
Attachment
degradation of basement membrane
diapedesis
new leaky blood vessel formation
What steps are involved in extravasation?
Attachment
degradation of basement membrane
diapedesis
new structural sound blood vessel formation
Most cancer cells do not survive transport in the blood. Why is this?
shear stress of blood flow
immune detection
anoikis
What is anoikis?
Form of programmed cell death which occurs in anchorage-dependent cells when they detach from the ECM
Cancer cells in the blood start to slow down and marginalise then roll along the endothelium. What molecules mediate this?
Selectins
The arrest of cancer cells on the endothelium during extravasation is mediated by which molecules?
Integrins
Which molecules mediated diapedesis in extravasation of cancer cells?
Junctional adhesion molecules
Spread and crawling of cancer cells. along the endothelium in extravasation is mediated by which molecule?
Cell adhesion molecules
What are selectins?
Carbohydrate binding transmembrane molecules
What is the main physiological function of selectins?
mediate leukocyte recruitment to sites of inflammation or to lymphoid tissues
Enhances expression of selection ligands by cancer cells is correlated with metastasis and a poorer prognosis. T/F?
True
Define angiogenesis
The formation of new vessels from existing vasculature
When cancer cells become hypoxic, which transcription factor mediates VEGF production?
Hypoxia inducible factor (HIF)
What molecules usually inhibit angiogenesis?
Thrombospondin
Endostatin
Tumstatin
Angiostatin
Angiostatin is a fragment of….?
Plasminogen
Endostatin is a fragment of….?
Collagen type XVIII
Tumstatin is a fragment of….?
Collagen type IV
What are the two models which determine where metastasis occur?
Seed and soil hypothesis
Mechanical model
Describe the mechanical theory of metastasis?
Blood flow patterns determine which organ the cancer cells travel to first and the relative size of cancer cells and capillaries leads to the efficient arrest of most circulating cancer cells in the first capillary bed that they encounter
The tumour microenvironment contains cancer associated fibroblasts. What do these secrete?
MMPs
Cytokines
IL-8
VEGF
The tumour microenvironment contains cancer associated pericytes. What is the role of pericytes in cancer?
Low pericyte coverage results in leaky vessel structure which facilitates tumour cell invasion and extravasation
How do M1 and M2 macrophages differ in their response to tumour?
M1 macrophages are tumorocidal
M2 macrophages promote tumour growth
A large abundance of tumour associated macrophages is associated with poor clinical outcomes. T/F?
True
The tumour microenvironment contains tumour associated macrophages. What do these secrete?
MMPS and growth factors
Sustaining proliferative signalling is a hallmark of cancer. What type of drugs can be used to combat this?
EGFR inhibitors
Evading growth suppressors is a hallmark of cancer. What type of drugs can be used to combat this?
Cyclin dependent kinase inhibitors
Avoiding immune detection is a hallmark of cancer. What type of drugs can be used to combat this?
Immune activating anti-CTLA4 monoclonal antibodies
Enabling replicative immortality is a hallmark of cancer. What type of drugs can be used to combat this?
Telomerase inhibitors
Tumour promoting inflammation is a hallmark of cancer. What type of drugs can be used to combat this?
Selective anti-inflammatory drugs
Activating invasion and metastasis is a hallmark of cancer. What type of drugs can be used to combat this?
inhibitors of HGF / c-met
Inducing angiogenesis is a hallmark of cancer. What type of drugs can be used to combat this?
inhibitors of VEGF signalling
Genome instability and mutation is a hallmark of cancer. What type of drugs can be used to combat this?
PARP inhibitors
Resisting cell death is a hallmark of cancer. What type of drugs can be used to combat this?
Proapoptopic BH3 mimetics
Dysregulating cell energetics is a hallmark of cancer. What type of drugs can be used to combat this?
Aerobic glycosides inhibitors
