Virus Causes Cancer: Papillomavirus and Cervical Cancer

Did you know some viruses induce cancer unintentionally? Have you heard of the Gardasil vaccine that prevents cervical cancer? In the 1980s, some parts of the papillomavirus genome were discovered in patients with cervical cancer. It had been hypothesized that the integration of papillomavirus DNA causes cervical cancer. However, any testing on humans would be deemed unethical. Therefore, this hypothesis was never proven, but the proof was indirectly supported by the study with the Gardasil vaccine.

Papilloma virus infects the basal epithelial cells (the bottom of the epithelium). Its replication cycle is tailored to the stratified structure, in which it starts by establishing itself in the basal layer, and then replicates effectively when it gets closer to the top to disseminate its progeny. The major barrier for the papillomavirus is that the top layer is made of terminally differentiated cells (meaning that they can no longer divide). This poses a threat to the replication cycle, because only dividing cells can provide the machinery for the virus to make copies of its genome. Without the machinery, the virus is at a dead end. Papillomavirus only codes for 8 proteins. 2 of them are responsible to overcome this barrier (i.e. release E2F, degrades p53). They both reactivate signaling molecules to reinitiate the cell cycle.

In the figure, G0 refers to the growth arrested phrase which the terminally differentiated cells are in. The reactivation of signaling molecules leads to the re-entry into the G1 phrase. And after G1 phase, cells can then divide, giving papillomavirus the required machinery to replicate.

It is rare that the viral DNA gets integrated into the human genome. However, when the integration happens, the proteins that are responsible for reinitiating cell cycle are made. As a result, cells with integrated genomes divide uncontrollably. And that is why papillomavirus causes cancer. So why did I say “virus causes cancer unintentionally”? The goal of viruses is to replicate and disseminate. The integration leads to the end of the replication cycle, thus cancer is not intended to happen.

Back to home page

References:

Tatyana V. Golovkina  – Associate Professor in the Department of Microbiology at the University of Chicago

5: zur Hausen H, Meinhof W, Scheiber W, Bornkamm GW. Attempts to detect virus-secific DNA in human
tumors. I. Nucleic acid hybridizations with complementary RNA of human wart virus. Int J Cancer.
1974;13(5):650-6.
6: H Zur Hausen, H Schulte-Holthausen, H Wolf, K Dörries, H Egger. Attempts to detect virus-specific DNA in
human tumors. II. Nucleic acid hybridizations with complementary RNA of human herpes group viruses. Int J
Cancer. 1974, 13 (5): 657-664
7: zur Hausen H, Gissmann L, Steiner W, Dippold W, Dreger I. Human papilloma viruses and cancer. Bibl
Haematol. 1975 ;(43):569-71.

31: Dürst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its
prevalence in cancer biopsy samples from different geographic regions. PNAS. 1983;80(12):3812-5
32: Ikenberg H, Gissmann L, Gross G, Grussendorf-Conen EI, zur Hausen H. Human papillomavirus type-16-
related DNA in genital Bowen’s disease and in Bowenoid papulosis. Int J Cancer. 1983;32(5):563-5.
33: Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen H. A new type of
papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer.
EMBO J. 1984;3(5):1151-7.