Metastasis: The Cellular View

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In order to disseminate throughout the body, the cells of a solid tumour must be able to accomplish the following tasks. They must detach from neighbouring cells, break through supporting membranes, burrow through other tissues until they reach a lymphatic or blood vessel, and then migrate through the lining of that vessel. Next, individual cells or clumps of cells must enter the circulatory system for transport throughout the body. If they survive the journey through lymphatic vessels, veins, and arteries, they will eventually lodge in a capillary of another organ, where they may begin to multiply and form a secondary tumour.

Laboratory researchers have intensively studied this process in the hope that insight into the mechanisms of metastasis will provide ways to devise effective therapies. Each step has been individualized and studied, and mechanisms have been elucidated at the cellular and even the molecular level.

Angiogenesis

As is mentioned above in Tumour progression: the clinical view, the formation of capillaries (a process known as angiogenesis) is an important step that a tumour undergoes in its transition from a small harmless mass of cells to a life-threatening malignant tumour. When they first arise in healthy tissue, tumour cells are not able to stimulate capillary development. At some point in their development, however, they call on proteins that stimulate angiogenesis, and they also develop the ability themselves to synthesize proteins with this capacity. One of these proteins is known as vascular endothelial growth factor (VEGF). VEGF induces endothelial cells (the building blocks of capillaries) to penetrate a tumour nodule and begin the process of capillary development. As the endothelial cells divide, they in turn secrete growth factors that stimulate the growth or motility of tumour cells. Thus, endothelial cells and tumour cells mutually stimulate each other.

Cancer cells also produce another type of protein that inhibits the growth of blood vessels. It seems, therefore, that a balance between angiogenesis inhibitors and angiogenesis stimulators determines whether the tumour begins capillary development. Evidence suggests that angiogenesis begins when cells decrease their production of the inhibiting proteins. Angiogenesis inhibitors are seen as promising therapeutic agents.

Microinvasion

The process of invasion begins when one cancer cell detaches itself from the mass of tumour cells. Normally, cells are cohesive and stick to one another by a series of specialized molecules. An important early step in cancer invasion appears to be the loss of this property, known as cellular adhesion. In many epithelial tumours it has been shown that cell-adhesion molecules such as E-cadherin, which helps to keep cells in place, are in short supply.

Another type of adhesion that keeps cells in place is their attachment to the extracellular matrix, the network of substances secreted by cells and found between them that helps to provide structure in tissues. Normally, if a cell is unable to attach to the extracellular matrix, it dies through induction of the cell suicide program known as apoptosis. Cancer cells, however, develop a means to avoid death in this situation.

In order to gain access to a blood or lymphatic channel, cancer cells must move through the extracellular matrix and penetrate the basement membrane of the vessel. To do this, they must be able to forge a path through tissues, a task they perform with the aid of enzymes that digest the extracellular matrix.

The cell either synthesizes these proteins or stimulates cells in the matrix to do so. The breakdown of the extracellular matrix not only creates a path of least resistance through which cancer cells can migrate but also gives rise to many biologically active molecules — some that promote angiogenesis and others that attract additional cells to the site.