R4.5f: Invasion and Metastasis

Invasion

The major causes of death from cancer are local invasion and metastasis. Invasion occurs first, and requires many small steps to proceed:

  • Cancer cells must reduce their adhesion to each other to be able to mobilise. This is accomplished by downregulation of extracellular cadherin molecules which normally glue the cells to each other.
  • The extracellular matrix, including the basement membrane, must be degraded so space exists for tumour cells to invade. This is achieved by production of proteases which cleave the collagen and other proteins. Alternatively, ambeoid invasion involves tumour cells ‘climbing’ along the collagen fibres to invade, without requiring destruction of the ECM.
  • Tumour cells must be able to adhere to the ECM to pull themselves along. This may be accomplished by the expression of cell surface receptors. The degredation of the ECM may lead to expression of new proteins that encourage tumour cells to adhere.
  • Tumours must develop locomotion, a complex interaction of binding to ECM proteins in the direction of travel, releasing the binding of the ECM behind, and contracting the cytoskeleton to shift the cell forward.

The extracellular matrix is an interactive environment which both inhibits and encourages the progression of the tumour cells.

Metastasis

Metastasis also requires several steps:

  • Tumour cells must enter the blood stream (intravasate). This may be a passive (cells are shed into the bloodstream constantly) effect or active (some cells may seek out the vessel directly). A complex interplay of cytokines is responsible in the active case.
  • Tumour cells must survive in the blood stream. This is difficult due to the shearing forces as well as the presence of numerous lymphocytes. Tumour cells are found to clump together with platelets, preventing destruction from shearing forces.
  • Tumours must extravasate from the blood vessel. The site of extravasation is dependent on the tumour, and some tissues may express cytokines that attract tumour cells to them. Once established, tumours must express cytokines that promote angiogenesis and survival. Of the millions of tumour cells shed each day from even small tumours, only some may be able to develop into a metastasis.

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Bibliography
1. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.
2. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144(5), 646–674. doi:10.1016/j.cell.2011.02.013