Invasion, intravasation, hematogenous spread, extravasation, colonisation

Question 1

Intravasation

Answer 1

Perivascular TAMs secrete EGF to attract motile tumour cells (via binding EGFR) towards vessels

Cancer cells can move singly or in clusters

Endothelial cells lining capillaries are induced
by
* TAM derived TNF
* Cancer cell derived TGFß and MMP1.

Induction causes vascular-endothelial (VE) adherens junction disassociation and EC retract allowing cancer cells to transmigrate in between/around cells (Paracellular).

Other signals induce contraction of
actomyosin actin-myosin cytoskeleton filaments in EC

Creates pores IN the endothelial cells to
allow transcellular migration of cancer cells into the blood vessel.

Question 2

Transport in the blood (hematogenous spread)

Answer 2

Cancer cells in the blood are called circulating tumour cells (CTC)
These CTCs survive in the circulation through formation of platelet emboli

Platelets link between macrophages and tumour cells, a structure that protects from shear force (fluid flow)

Induces further EMT by platelet secretion of TGFß and
cytokines

Platelets lay down fibrin in presence of tumour cell secreted protease thrombin (cleaved from fibrinogen) to protect cancer cells from surveilling natural killer cells.

Rapid tumour growth causes secretion of cell clusters of invasive mesenchymal CTCs (Fibronectin and N-Cadherin+)

Regression of tumour growth, after successful therapy, is associated by presence of single, epithelial CTCs in the blood (EpCAM, cytokeratin, E-cadherin+)

Recurrence of a tumour, shows an increase in number again in mesenchymal- like CTC clusters

Question 3

Extravasation

Answer 3

Cancer cell releases IL-8 to activate neutrophils which bridge between EC and cancer cell/platelet emboli

Expression of ICAM-1 (on EC and Cancer cell) and P-selectin (on EC and platelets) allows adhesion via neutrophil LFA1 integrin and sialyl-Lewis-X proteins

Cancer cell releases chemokines to recruit and activate monocytes that release VEGF

VEGF dismantles adherens junctions, EC retraction allowing transmigration into
organ tissues

Question 4

Colonisation

Answer 4

During the process of colonisation, circulating cancer cells (CTC) die en mass

• Passing through endothelial cells (cell injury)
• lack of survival signals (growth factors)
• lack of supportive structure (anoikis)
• tumour cell killing by neutrophils (immunity)

Surviving cells pass into tissues as Disseminated Tumour Cells (DTC). <1% DTC form metastatic tumours. The process of metastasis selects for cells that can survive all steps.