CARCINOGENESIS – HOW CANCER STARTS
Cancer results when the changes, required for the hallmarks of cancer, have occurred. To understand how cancer develops, we now need to turn to how external factors bring about cancer – a process known as carcinogenesis. Fundamentally, cancer results from damage to DNA. All agents that damage DNA, therefore, are potential carcinogens – agents that cause cancer. The reverse is not true, however; not all agents that help cause cancer themselves directly damage DNA, though this always lies at the end of the process. Examples of cancer-causing substances that do not directly damage DNA include alcohol and the sex hormones involved in causing breast and prostate cancer. There are many sorts of carcinogens and many are well known – cigarette smoke and ionizing radiation, for example. Taking cigarette smoking, we know that typically it is necessary to smoke many cigarettes for many years for cancer to develop. This suggests that the process of carcinogenesis is slow and potentially has more than one step. From the discussion above, it would be predicted that mutations would be necessary for different sets of genes to cause the hallmark changes described by Hanahan and Weinberg. Such a chain of events was also postulated in the early 1990s and is now often referred to as the ‘Vogelstein cascade’, with each step in the chain representing a new mutation.
Dr Vogelstein’s group studied inherited bowel cancer, a condition in which there are a number of recognized pre-cancerous (also called pre-malignant) steps that could be identified in patients. They collected tissues from patients and set about identifying which genes were abnormal in the various steps along the pathway from normal bowel lining to a clinically obvious cancer. It turned out to be possible to identify candidate genes that need to be damaged for each step of the cascade to occur. Subsequent work has demonstrated that similar cascades of events apply to all tumour types, though the individual genes involved and the sequence of damage varies.
One fruitful way to identify genes has been to study families with so-called ‘inherited’ cancers. The term is a bit of a misnomer as the cancer is not inherited in the same way as, say, a diamond necklace, that is, as an intact, fully formed object. What is inherited is a greatly increased risk of developing a disease early, often in a very florid, aggressive form. One such disease is called adenomatous polyposis coli (APC). Patients with the disease develop multiple benign adenomas from an early age. In time, some of this progress to cancer, and without treatment death typically occurs in the early 40s from bowel cancer. Studies of patients with the disease showed that they had abnormalities in a particular gene, which was named APC. The identification of the APC gene in these patients led to further study of the function of the gene, which turns out to function as an ‘off-switch’. If it is knocked out, an important check on cell growth is removed and adenomas form. As is often the way with inherited cancers, the much commoner, non-inherited cancers turned out to share similar abnormalities. Studies of non-inherited bowel cancer confirm that the APC gene is malfunctioning in around 80% of these sporadic cases, so the gene clearly has a key function in regulating the normal growth of the bowel lining.