100 years infection and cancer

There are many reasons to get excited in anticipation of this year’s Lindau Nobel meeting that is now less than two weeks away. One aspect of the meeting I personally enjoy is the appreciation for the historical perspective of science. One recurring theme of many Nobel laureates in Medicine or Physiology during the last 50 years is the fascinating relationship between infections and cancer, and in fact this year marks the 100th anniversary of one of first important discoveries in the field.

Peyton Rous (Nobel Prize for Physiology or Medicine in 1966) in 1910 described a malignant chicken sarcoma which could be propagated by transplanting its cells, forming new tumors in other chicken. He also showed that these tumors were caused by a virus (the Rous Sarcoma Virus), but it took 15 years of discussions before the scientific community unanimously accepted this connection. In the 1930s Rous discovered that the giant warts (benign tumors of the skin that can progress to cancer) of rabbits in the Southwestern US were caused by papilloma viruses.

It took another 30 years until viruses were found to also cause tumors in man. By the late 1960s the first oncogenes were discovered: part of the genetic material of viruses and able to induce tumors in human cells. David Baltimore, Renato Dulbecco and Howard M. Temin (Nobel Prize for Physiology or Medicine in 1975) studied the mechanisms of how viruses transform normal cells into tumor cells, including the enzyme reverse transcriptase that transcribes the genetic information of RNA viruses into DNA.

Michael Bishop and Harold Varmus (Nobel Prize for Physiology or Medicine in 1989) discovered that most oncogenes are in fact of cellular and not viral origin, acquired by viruses during replication in the host cell. 

BaruchBlumberg (Nobel Prize for Physiology or Medicine in 1976) began working on serum protein polymorphisms and inherited susceptibility to disease in the late 1950s. This work led him to the discovery of the Australia Antigen (now called Hbs Antigen) in 1963 and by 1967 the Hepatitis B virus was isolated. By 1969, blood donors were tested for Hepatitis B virus and rates of post-transfusion hepatitis soon soon decline.

After testing for Hepatitis B virus became available, it became obvious that there is a strong the geographical correlation between chronic Hepatitis B infection and liver cancer. A first vaccine against Hepatitis B virus was approved in 1982, and a decrease in liver cancer was first detected in 1990. Since 2003, vaccination for Hepatitis B is in use worldwide.

Harald zur Hausen (Nobel Prize for Physiology or Medicine in 2008) in the late 1960s started to study the role of the newly discovered Epstein-Barr virus in causing Burkitt’s lymphoma. He showed that Epstein-Barr virus DNA was integrated into the genome of these tumors, rather than causing a chronic infection.

In the mid 1970s he switched to searching for an infectious agent causing cervical cancer. Cervical cancer was long thought to be related to an infection, starting with the observation in 1842 by Rigoni-Stern that this cancer is more common in married women, widows and prostitues than in virgins and nuns. After initially trying to detect herpes simplex virus in cervical cancer tissue, zur Hausen switched to studying human papilloma viruses. In 1983 he and his coworkers successfully isolated HPV-16, and later detected DNA from this virus in half of all cervical cancer biopsies. HPV-18 was isolated in 1984 and in the following years his laboratory studied the mechanisms by which human papilloma viruses induce cervical cancer. A causal relationship between human papilloma viruses and a subset of oral cancers was discovered in 2000. The first vaccine against human papilloma virus infection was approved in 2006 with the expectation to decrease the rate of cervical cancer in the coming decades.

Françoise Barré-Sinoussi and Luc Montagnier received the Nobel Prize for Physiology or Medicine in 2008 for their work on the human immunodeficiency virus that is causing the aquired immundeficency syndrome (AIDS). Patients with AIDS have a dramatically increased risk to develop lymphomas associated with Epstein-Barr virus infection. The rare tumor Kaposi sarcoma is also much more common in AIDS patients, but it soon became clear that it is not HIV itself that is causing the tumor – no HIV proviral DNA was detected in Kaposi sarcoma samples, and the risk for Kaposi sarcoma was not the same for every HIV-infected person. This led to the search for another infectious agent, and in 1994 Kaposi-sarcoma associated herpesvirus was discovered by Yuan Chang, Patrick Moore and colleagues. This virus is required for Kaposi sarcoma to develop, and is also responsible for two other rare cancers.

The pathologist Robin Warren was studying gastritis-causing bacteria in the late 1970s, and in 1981 was joined by the gastroenterologist Barry Marshall (shared Nobel Prize for Physiology or Medicine in 2005). Their work not only showed that the bacterium Helicobacter pylori is involved in most cases of gastritis and peptic ulcer, but also that chronic H. pylori infection increases the risk of gastric cancer and lymphoma of the stomach. This makes H. pylori one of the few infectious agents that are not viruses to be implicated in causing tumors in man. 

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