Guest Author - Nina Shavel

Cancer cells are abnormal in that they proliferate out of control, creating a tumour. To become cancerous or malignant, a cell must undergo a series of genetic changes (mutations) in a variety of vital genes to achieve certain characteristics. Hanahan and Weinberg’s paper in the Cell (2000) named these characteristics ‘the hallmarks of cancer’, steps along the path to malignancy that all cancer cells must achieve.

The hallmarks include:
• Too much proliferation due to excess signalling
• Insensitivity to signals that inhibit proliferation
• Insensitivity to death signals (apoptosis)
• Immortalisation – unlimited number of divisions
• Growth of blood supply (angiogenesis) for the tumour
• Metastasis – spread of cancer cells from one site within the body to another
Cancer cells must also avoid being recognised and eliminated by the immune system.

Normally cells in the human body only divide when a signal molecule called a growth factor binds to its receptor on the cell surface, promoting a sequence of events within the cell which tell it to divide. Cancer cells get around this by having mutations that cause overactivity of the growth factor signalling pathway. For example, in some breast cancers there are too many growth factor receptors (HER2) on the cell surface, promoting excessive proliferation. This type of cancers can be treated with herceptin, an antibody which binds to the HER2 receptors and blocks division signals from them.

The division of cells in the body is also controlled by inhibitory signals. These molecules also bind to the receptors on cell surface, but these receptors are different from growth promoting ones and cause a sequence of events that inhibits proliferation. Cancer cells avoid inhibition by having mutations that make certain steps of the signalling pathways inactive.

Normally when cells have mutations, mechanisms within them tell them that they have been damaged. As mutations are dangerous, often a suicide mechanism called apoptosis kicks in within the damaged cells and destroys them. However, some mutated cells survive and go on to become cancerous because they have mutations which prevent activation of the death pathway, allowing them to live on and proliferate, creating more mutated cells.

Cancer cells need to go on dividing indefinitely (so called immortality) while normal cells are restricted to only a certain number of divisions, after which they must stop. It is likely that normal cells have the limit on cell divisions because their telomeres (ends of chromosomes) get shorter with each division. When telomeres get too short, a mechanism within the cell will stop it from further proliferation. Cancer cells get around the limit by activating an enzyme which helps telomeres grow so they do not get shorter.

Tumours need to grow their own blood supply so that the cancer cells can be supplied with adequate oxygen and nutrients to continue dividing. Without angiogenesis (growth of new blood vessels), it is likely that the tumour would be unable to expand beyond around 2 mm. Thus, cancer cells secrete molecules that act on vessel cells to promote blood vessel formation.

Metastasis is the most dangerous aspect of cancer and causes 90% of all cancer deaths. When cancer cells have spread throughout the body, surgery to remove the tumour will not cure the cancer. Recurrence of cancer after treatment is often caused by growth of pockets of cells at a different site in the body that managed to survive the original chemotherapy and radiotherapy. It is thought that cancer cells are able to metastasise because of mutations that encourage cell movement but we do not know as much as we like about this process. Much research is going on at the moment to try to identify the culprit mutations so treatments can be targeted against them.