A key feature that distinguishes cancer cells from all other cells is the capability to spread throughout the body by two related mechanisms: invasion and metastasis.
Invasion refers to the direct extension and penetration by cancer cells into neighbouring tissues. The proliferation of transformed cells and the progressive increase in tumour size eventually leads to a breach in the barriers between tissues, leading to tumour extension into adjacent tissue. Local invasion is also the first stage in the process that leads to the development of secondary tumours or metastases.4, 7, 10
Metastasis, from the Greek methistanai, meaning to move to another place, describes the ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through these systems and invade normal tissues elsewhere in the body. This process proceeds in an orderly and predictable manner, sometimes termed the 'metastatic cascade'.4, 7, 10
The ability of cancer cells to migrate from a primary site of disease is attributed to the mutation of genes that regulate the production of proteins that normally tether cells to their surrounding tissues. Decreased synthesis by cancer cells of a number of substances that bind them to neighbouring cells, together with the abnormal synthesis of enzymes capable of degrading the bonds between cells and tissues, allow cancer cells to escape the primary tumour site.4, 7, 10
Angiogenesis has a role in tumour growth, invasiveness and metastasis.32, 33 Tumour angiogenesis refers to the growth of new vessels which develop following stimulation of endothelial cells within existing vascular networks near the tumour, providing a blood supply for that tumour.33 A balance of stimulators and inhibitors tightly control angiogenesis under normal circumstances.2, 26 One specific and potent promoter of angiogenesis is vascular endothelial growth factor (VEGF).26
Vascular endothelial growth factor (VEGF)
VEGF is a cytokine which exerts its effects on vascular endothelial cells promoting the formation of new blood vessels and is critical to both normal and tumour angiogenesis:26, 34 VEGF is over-expressed in a variety of solid tumours and certain hematologic malignancies. VEGF action involves:26
- binding to and activating two structurally related membrane receptor tyrosine kinases (TKs)
- switching on of multiple signaling pathways
- stimulating the growth, survival, and proliferation of vascular endothelial cells
- promoting tumour growth and contributing to tumour invasion and metastasis.
Tyrosine kinases (TK)
Tumour growth and progression is further reliant on the activity of specific cell membrane receptors which control signaling pathways within the cell. Cell signaling or 'signal transduction' involves the communication process where messages or signals from outside the cell are transferred to the nucleus inside the cell.26 Tyrosine kinases (TK) are a subgroup of growth receptors involved in the signal transduction process.26 Because TKs are regulators of the signal transduction process, they play a role in cellular processes such as proliferation, migration, metabolism, differentiation and survival.26 Several important growth factors and other TKs have been identified:26
- EGFR family
- platelet derived growth factor receptor (PDGF)
- vascular endothelial growth factor (VEGF)
- transforming growth factor (TGF)
- fibroblast growth factor (FGF).
Access a current text and map the stages of the metastatic cascade, explaining the events in the development of metastases.
Distinguish between the different members of the EGFRs family.
Apart from EGFR components of the TKs involved in signal transduction, list two other TK receptors and the specific cancer they are expressed in.
Distinguish between the different members of the VEGF receptors, including the receptor which leads to the development of anti-angiogenic agents in cancer therapy.