Cancer

The term cancer derives from the observation by Hippocrates in 400 B.C. that the veins radiating from a breast cancer resembled the legs of a crab, hence karkinoma in Greek and cancer in Latin. Cancer is not a single disease, but is many different diseases that all share common biological and pathological characteristics. In most western societies, cancer is a leading cause of death. The disease may develop in any body tissue or organ and over one hundred different types of cancer can occur in adults. Cancer also occurs in children and may even be present at birth.

The first clues to the cause of cancer came over two hundred years ago from an observation by Percivall Pott, a London doctor, who in 1775 found a high incidence of scrotal cancer in men who had worked as chimney sweeps. Later, radiation was found to cause skin cancer and tragically Marie Curie (1867–1934) the discoverer of x rays, died of a cancer caused by prolonged exposure to radiation. During the second half of the twentieth century, epidemiologists (those who study disease in populations) linked exposure to certain environmental toxins and particular types of cancer. Most notably, cigarette smoking and lung cancer, sunlight and skin cancer, and certain industrial chemicals to the cause of bladder and liver cancer. Finally several viruses were also been implicated in causing cancer, such as the hepatitis B virus and cancer of the liver, the Epstein Barr virus and lymphoma, and the human papilloma virus and cancer of the cervix. These important observations all suggested that specific external environmental agents could cause specific cancers.

How then could a diverse range of external agents such as chemicals, radiation and viruses, all lead to the development of cancer? The answer to this question has come over the last 25 years from two different lines of investigation; studies on cancer causing viruses and research into the genetics of some rare cancers in children.

In 1910, Frances Peyton Rous (1879–1970) isolated a virus from a cancer in chickens (a sarcoma) that caused new sarcomas to develop when infected into healthy chickens. Rous's work languished for over 50 years until he was awarded a Nobel Prize in 1966. By this time, methods for the study of viruses and cancer had improved considerably and many new animal derived viruses were found to cause cancer in a range of species. These viruses could also induce cancer-like changes when introduced into normal cells grown in the laboratory. A genetic study of these cancer causing viruses identified a small number of genes termed viral oncogenes (v-oncogenes) which, when introduced into cells, could transform the normal cells into malignant cells.

The presence of viral oncogenes led to the search for endogenous cellular oncogenes, which might cause cancer. In a crucial experiment in the late 1970s, DNA from mouse cells which had been transformed by a chemical carcinogen, was transfected into normal mouse cells. The normal mouse cells became malignant suggesting that a gene within the cancer (a proto-oncogene) had been mutated by exposure to the chemical and was able to induce cancer. Surprisingly, when these endogenous cellular oncogenes were eventually isolated they were found to be homologous to virally derived oncogenes.

In the early 1970s the American pediatrician and scientist, Alfred Knudson at the Fox Chase Cancer Center studied retinoblastoma, a rare childhood eye cancer that is sometimes inherited but is most often sporadic. He observed that children who had inherited retinoblastoma often had the cancer at birth, and were at high risk of developing multiple cancers in both eyes. Children with later onset retinoblastoma usually had no family history and developed isolated tumors. Knudson reasoned that children with inherited retinoblastoma had a germline mutation in one allele of a recessive cancer gene. The germline mutation was the first of two hits in knocking out a recessive cancer gene. This is known as Knudson's two hit hypothesis. Later genetic studies found the first hit in children with inherited retinoblastoma to be a partial deletion of the long arm of chromosome 13 causing loss of the tumor suppressor gene, RB1.

These two directions of study independently identified two different classes of cancer gene, the oncogene and tumor suppressor gene, that when mutated in a given cell can set in train the sequence of events leading to the development of a cancer.