Cancer: Mechanisms of Invasion and Metastasis

For tumours to become malignant, they need to metastasise – but out of the millions of cells released into the blood/lymph stream – only a few metastases are formed – therefore metastasis is an inefficient process.

Why? Because only certain subclones possess the right characteristics to complete all the steps to achieve metastasis.

The tumour cells need to:
1) detach themselves from surround tumour cells,
2) breach basement membrane,
3) traverse extracellular matrix,
4) breach basement membrane of endothelial cells.

They need to do this at the site of metastasis as well.

Invasion of extracellular matrix

The tumour cells become increasingly motile. Normal cells are adhered to each other. Adhesion molecules mediate this adhesion (e.g.: cadherin family of transmembrane glycoproteins is one such example). In tumours, there is down regulation in expression of these molecules, so cells have decreased adherence and increase motility. They now need to attach to the basement membrane, and this is mediated by receptors such as laminin and fibronectin. Once attached, they need to actively degrade membrane and gain access to the extracellular matrix. Penetration is also assisted by passive growth pressure. Tumour cells secrete proteolytic enzymes, or induce host cells to do so. There is a regulation of protease activity, but antiproteases – but obviously this regulation is lost here.

Now, the tumour cells need to be propelled into the extracellular matrix, this is done by two things
1) motility factors made by tumour cells,
2) cleavage products of matrix components (i.e.: collagen, laminin etc).

Note that the proteolytic enzymes not only cleave pathway through basement membrane, but also through ECM. That is, “roads” are set up so tumour cells can traverse the ECM.

Vascular Dissemination and Homing of tumour cells

They enter the vascular system via the same mechanism described above – the most important being the proteolytic enzymes produced by the tumour cells, and host cells. Once reaching the vascular system, the tumour cells are highly vulnerable to attack from natural killer cells. So, tumour cells clump to other tumour cells (i.e.: homotypic adhesion) or tumour cells clump to blood cells (i.e.: heterotypic adhesion). This enhances tumour cell survival. Then, they adhere to the endothelium (e.g.: adhesion molecules ==> integrins, laminin receptors) and proteolytically cleave the basement membrane to reach the site of implantation. Vascular dissemination does not always correlate to drainage patterns.

Category: Pathology Notes