Invasion and Metastasis Flashcards
How are tumours grouped into different types?
By their tissue of origin
What is the name for benign and malignant tumours arising from the epithelium?
Adenoma/Papilloma and Carcinoma
What is the name for benign and malignant tumours arising from connective tissue?
Lipoma/Fibroma/Haemangioma and Sarcoma
What is the name for benign and malignant tumours arising from lymphoid tissue?
Lymphoid hyperplasia and Lymphoma
What is the name for benign and malignant tumours arising from haemopoietic tissue?
Myeloid proliferations and Leukaemia
What is the name for benign and malignant tumours arising from germ cells?
Terratoma and Germinoma
How is benign large colon adenoma seen macroscopically?
Polyps
What is a prerequisite to the metastatic cascade?
Accumulation of genetic mutations
Which hallmarks of cancer are important for metastatic disease?
- Inducing angiogenesis
- Activating invasion and metastasis
What happens in growth and invasion?
Primary tumour forms and invades tissues locally.
What happens in transport to distant sites?
Intravasation, transport through the circulation and arrest in microvessels of various organs
What happens for metastasis to thrive at a new site?
Extravasation into new tissue, formation of micrometastasis, and colonisation of a macrometastasis
What does metatstasis require?
Environmental changes
What is detected in stroma surrounding many human cancers?
Tumour associated macrophages
What does a lack of ability to express tumour associated macrophages correlate with?
Decreased risk of developing metastsis.
How do tumour cells and macrophages support each other in cell migration of mammary tumours?
Macrohoages express EGF which acts on the EGF receptor of tumour cells. Tumour cells then express CSF-1 which works on the CSF-1 receptor in the macrophage.
What needs to be disrupted in order for cell migration to occur?
Cell-cell adhesions
What is epithelial-mesenchymal transition?
EMT = when structure of cells goes from strong cell-cell adhesions and interactions to more like mesenchyme cells in phenotype
What cell-cell interactions are disrupted?
- Tight junctions
- Adherens junction
- Desmosomes
What is an adherens junction?
Junction formed by 2 cadherin molecules which span the extracellular membrane of both cells.
What is the adherens junction regulated by?
Ca2+
What happens on the intracellular side of the cadherin?
Many proteins can bind to it to help regulate its function and confer more structure and stability to keep the cell rigid
What change in E-cadherin expression is associated with aggressive bladder cancer?
Aberrant or (-) - advanced tumour stage, tumour de-differentiation, lymph node metastasis and increased risk of death.
What is EMT activated by?
Different signalling pathways, producing Twist, Snail and SIP1.
What do the EMT pathways result in?
Inhibition of E-cadherin expression, and induction of mesenchymal marker expression
How many migration strategies are there?
4
Name the migration strategies
- Ameoboid
- Mesenchymal (single cells/chains)
- Cluster/cohorts
- Multicllular strands/sheets
Which tumour types migrate via the ameoboid strategy?
- Lymphoma
- Leukaemia
- SCLC
Which tumour types migrate via the mesenchymal strategy?
- Fibrocarcinoma
- Glioblastoma
- Anaplastic tumours
Which tumour types migrate via the cluster/cohort strategy?
- Epithelial cancer
- Melanoma
Which tumour types migrate via the multicellular strand/sheet strategy?
- Epithelial cancer
- Vascular tumours
What are the 4 steps in mesenchymal migration?
- Protrusion
- Adhesion
- Translocation
- Retraction
What happens in protrusion?
Polymerised actin pushes the membrane at the leading edge in the direction of movement driven by key Rho family GTPases
What happens in adhesion?
Cell forms new contacts close to the leading edge using a Rho family GTPase
What happens in translocation?
Acto-myosin contraction promotes translocation of the cell body using a Rho family GTPase
What happens in retraction?
Loss of adhesions in tail end of cell and tail retraction
What underpins mesenchymal migration?
Integrin signalling
What are integrins?
Transmembrane receptors that attach the cell cytoskeleton to the ECM - made of an alpha and beta subunit. 24 heterodimers (18a and 8b)- and mediate focal adhesions
Which direction do integrins signal in?
Both into and out of the cell
Why do invading cancer cells have to have a proteolytic function?
So they can move through and degrade the ECM
Name some ECM Degrading Proteases
- Matrix metalloproteinases (MMPs)
- Serine proteases
- Adamalysin-Related Membrane proteases
- Bone-morphogenic protein -1 type metalloproteases
- Heparanases
- Cysteine proteases
What is angiogenesis?
New blood vessel formation
What induced angiogenesis in tumours?
Hypoxia
What is the mechanism fro hypoxia-induced tumour angiogenesis?
Tumour larger than 2mm requires more blood vessels. Endothelial cells release paracrine growth factors. Tumour cells secrete VEGF.
What is sometimes seen within a tumour?
High levels of necrosis in the centre of large tumours
What can transport cancer cells to distant sites?
- Blood vessels
- Lymphatics
- Body cavities via direct invasion
Why can cancer cells move via lymphatics?
No basement membrane
Give some examples of transport to distant sites via body cavities
- Colon cancer to peritoneum
- Lung cancer to pleurae
- Brain cancer to ventricles
What are the steps that take a CTC to extravasation?
Capture -> Rolling -> Arrest -> Exravasation between endothelial cells
May go from capture straight to arrest
What cell surface receptors mediate rolling?
- E-selectin and P-selectin receptors on endothelium
- CD44, CEA and PODXL on tumour cell
What cell surface receptors mediate arrest?
- ICAM1 and VCAM1 receptors on endothelium
- Integrins on tumour cell
How might a CTC begin to grow within a blood vessel?
Adherence of platelets onto CTC. Another CTC with platelets binds to a nucleated cell by platelet mediated capture and then subsequent growth occurs
