Understanding Cancer Causes: Ancient Times to Present

Early theories about cancer causes

From the earliest times, physicians have puzzled over the causes of cancer. Ancient Egyptians blamed cancers on the gods.

Humoral theory

Hippocrates believed that the body had 4 humors (body fluids): blood, phlegm, yellow bile, and black bile. When the humors were balanced, a person was healthy. The belief was that too much or too little of any of the humors caused disease. An excess of black bile in various body sites was thought to cause cancer. This theory of cancer was passed on by the Romans and was embraced by the influential doctor Galen’s medical teaching, which remained the unchallenged standard through the Middle Ages for over 1,300 years. During this period, the study of the body, including autopsies, was prohibited for religious reasons, which limited progress of medical knowledge.

Lymph theory

Among theories that replaced the humoral theory of cancer was the formation of cancer by another body fluid, lymph. Life was believed to consist of continuous and appropriate movement of the fluid parts of the body through the solid parts. Of all the fluids, the most important were blood and lymph. Stahl and Hoffman theorized that cancer was composed of fermenting and degenerating lymph, varying in density, acidity, and alkalinity. The lymph theory gained rapid support. John Hunter, the Scottish surgeon from the 1700s, agreed that tumors grow from lymph constantly thrown out by the blood.

Blastema theory

In 1838, German pathologist Johannes Muller demonstrated that cancer is made up of cells and not lymph, but he believed that cancer cells did not come from normal cells. Muller proposed that cancer cells developed from budding elements (blastema) between normal tissues. His student, Rudolph Virchow (1821-1902), the famous German pathologist, determined that all cells, including cancer cells, are derived from other cells.

Chronic irritation theory

Virchow proposed that chronic irritation was the cause of cancer, but he believed incorrectly that cancers “spread like a liquid.” In the 1860s, German surgeon, Karl Thiersch, showed that cancers metastasize through the spread of malignant cells and not through some unidentified fluid.

Trauma theory

Despite advances in the understanding of cancer, from the late 1800s until the 1920s, trauma was thought by some to cause cancer. This belief was maintained despite the failure of injury to cause cancer in experimental animals.

Infectious disease theory

Zacutus Lusitani (1575-1642) and Nicholas Tulp (1593-1674), 2 doctors in Holland, concluded at almost the same time that cancer was contagious. They made this conclusion based on their experiences with breast cancer in members of the same household. Lusitani and Tulp publicized the contagion theory in 1649 and 1652, respectively. They proposed that cancer patients should be isolated, preferably outside of cities and towns, in order to prevent the spread of cancer.

Throughout the 17th and 18th centuries, some believed that cancer was contagious. In fact, the first cancer hospital in France was forced to move from the city in 1779 because people feared cancer would spread throughout the city. Although human cancer, itself, is not contagious, we now know that certain viruses, bacteria, and parasites can increase a person’s risk of developing cancer.

Development of modern knowledge about cancer causes

Viral and chemical carcinogens

In 1915, Katsusaburo Yamagiwa and Koichi Ichikawa at Tokyo University, induced cancer in lab animals for the first time by applying coal tar to rabbit skin. More than 150 years had passed since clinician John Hill of London recognized tobacco as a carcinogen (a substance known or believed to cause cancer in humans). Many more years passed before tobacco was “rediscovered” as the most destructive source of chemical carcinogens known to man.

Today we recognize and avoid many specific substances that cause cancer: coal tars and their derivatives (like benzene), some hydrocarbons, aniline (a substance used to make dyes), asbestos, and many others. Ionizing radiation from a variety of sources, including the sun, is also known to cause cancer. To ensure the public’s safety, the government has set safety standards for many substances, including benzene, asbestos, hydrocarbons in the air, arsenic in drinking water, and radiation.

In 1911, Peyton Rous, at the Rockefeller Institute in New York, described a type of cancer (sarcoma) in chickens caused by what later became known as the Rous sarcoma virus. He was awarded the Nobel Prize for that work in 1968. Several viruses are now linked to cancer in humans, for example:

• Long-standing infection with the hepatitis B or C viruses can lead to cancer of the liver.
• One of the herpes viruses, the Epstein-Barr virus, causes infectious mononucleosis and has been linked to non-Hodgkin lymphomas and nasopharyngeal cancer.
• People with human immunodeficiency virus (HIV) have greater increased risk of developing several cancers, especially Kaposi sarcoma and non-Hodgkin lymphoma.
• Human papilloma viruses (HPVs) have been linked to many cancers, especially those of the cervix, vulva, vagina, anus, and penis. Some head and neck cancers (mostly the tongue and tonsils) are linked to the high-risk types of HPV, too. Today there are vaccines to help prevent HPV infection.

As of 2014, the World Health Organization’s International Agency for Research on Cancer (IARC) has identified more than 100 chemical, physical, and biological carcinogens. Many of these associations were recognized long before scientists understood much about how cancer develops. Today, research is discovering new carcinogens, explaining how they cause cancer, and providing insight into ways to prevent cancer.

By the middle of the 20th century, scientists had the instruments they needed to work on some of the complex problems of chemistry and biology that remained unsolved. James Watson and Francis Crick, who received a Nobel Prize in 1962 for their work, had discovered the exact chemical structure of DNA, the basic material in genes.

DNA was found to be the basis of the genetic code that gives orders to all cells. After learning how to translate this code, scientists were able to understand how genes worked and how they could be damaged by mutations (changes or mistakes in genes). These modern techniques of chemistry and biology answered many complex questions about cancer.

Scientists already knew that cancer could be caused by chemicals, radiation, and viruses, and that sometimes cancer seemed to run in families. But as the understanding of DNA and genes increased, they learned that it was the damage to DNA by chemicals and radiation, or the introduction of new DNA sequences by viruses that often led to the development of cancer. It became possible to pinpoint the exact site of the damage on a specific gene.

Scientists discovered that sometimes defective genes are inherited, and sometimes these inherited genes are defective at the points where certain chemicals also tend to cause damage. In other words, most of the things that caused cancer (carcinogens) caused genetic damage (mutations) that looked a lot like the mutations that could be inherited and could result in the same types of cancer if more mutations were introduced.

No matter which way the first mutation started (inborn or spontaneous), the cells that grew from the mutated cells led to groups of abnormal cells (called clones, or duplicates of the abnormal cell). The mutant clones evolved to even more malignant clones over time, and the cancer progressed by more and more genetic damage and mutations. The big difference between normal tissues and cancer is that normal cells with damaged DNA die, while cancer cells with damaged DNA do not. The discovery of this critical difference answered many questions that had troubled scientists for many years.

Oncogenes and tumor suppressor genes

During the 1970s, scientists discovered 2 particularly important families of genes related to cancer: oncogenes and tumor suppressor genes.

Oncogenes: These genes cause cells to grow out of control and become cancer cells. They are formed by changes or mutations of certain normal genes of the cell called proto-oncogenes. Proto-oncogenes are the genes that normally control how often a cell divides and the degree to which it differentiates (or specializes in a specific function in the body).

Tumor suppressor genes: These are normal genes that slow down cell division, repair DNA errors, and tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer.

It may be helpful to think of a cell as a car. For it to work properly, there need to be ways to control how fast it goes. A proto-oncogene normally functions in a way that is similar to a gas pedal – it helps the cell grow and divide. An oncogene could be compared to a gas pedal that is stuck down, which causes the cell to divide out of control. A tumor suppressor gene is like the brake pedal on a car. It normally keeps the cell from dividing too quickly just as a brake keeps a car from going too fast. When something goes wrong with the gene, for example if a mutation causes it to stop working, cell division can get out of control.

Slowly, medical scientists are identifying the oncogenes and tumor suppressor genes that are damaged by chemicals or radiation and those that, when inherited, can lead to cancer. For example, the 1990s discovery of 2 genes that cause some breast cancers, BRCA1 and BRCA2, is a step forward because these genes can be used to identify people who have a higher risk of developing breast cancer.

Other genes have been discovered that are linked to cancers that run in families, such as cancers of the colon, rectum, kidney, ovary, thyroid, pancreas, and skin melanoma. Familial cancer is not nearly as common as spontaneous cancer (cancer that is caused by DNA damage that starts during a person’s lifetime). Cancer linked to heredity is less than 15% of all cancers. Still, it’s important to understand these cancers because with continued research in genetics we may be able to identify more people at very high risk.

Once researchers recognized the importance of specific genetic changes in cancer, they soon began working to develop targeted therapies (drugs or substances that interfere with specific molecules) to overcome the effects of these changes in tumor suppressor genes and oncogenes.