Tag Archives: cervical cancer

Douglas Lowy, John Schiller, and the Vaccine Against Cervical Cancer: Postscript

Our October 12, 2017 post, Douglas Lowy, John Schiller, and the Vaccine Against Cervical Cancer, has reached a gratifying number of people. Since some readers might welcome a bit more background vis-à-vis the remarkable human papillomavirus (HPV) life cycle, or details concerning the use of virus-like particles (VLPs) in the experimental stages of the vaccine’s development, or how the vaccine might actually work, here are a few additional points.

The post noted that the replication cycle of HPV is regulated by the differentiation states of the cells making up the layers of an intact, stratified epithelium or mucosae. “Since the outer layer of the skin is comprised of dead cells, cutaneous HPV infection requires a break or puncture of the skin for the virus to access cells of the underlying germinal stratum of the epithelium. In the actively dividing basal cells, the viral genome replicates more frequently than the cellular genome, thus amplifying the viral genome copy number. However, because the viral genes that encode the capsid proteins are not expressed in these cells, progeny virus particles, which might induce an immune response, are not yet produced. As the basal cells differentiate and move up in the epithelium, the viral genomes replicate only once per cell cycle, on average, to maintain the viral genome copy number. Then, as the infected cells go through their final stages of differentiation in the outer layers of the epithelium, the virus life cycle switches to its productive phase. Capsid proteins are produced, and thousands of virus particles are generated from the each of the infected, terminally differentiated cells.” [How cellular differentiation regulates HPV gene expression and replication is detailed in the textbook, Virology: Molecular Biology and Pathogenesis.]

The post noted that by coupling its replication cycle to the differentiated state of the host cell within the stratified epithelium, HPV can produce progeny virus particles only in the terminally differentiated cells that comprise the outermost live cells of the epithelium. In this way, HPV productive infection does not activate an antiviral immune response. [The host’s immune response eventually does clear many HPV infections. Also, the incidence of HPV-associated lesions is higher in immunosuppressed patients.]

Here then is an additional key point. After the amplification stage, the viral genomes replicate in the basal cells, but only in conjunction with cellular DNA replication. In that way, the viral genome copy number is maintained in the basal cells. Moreover, and importantly, when the basal cells divide, one daughter cell remains behind as a basal cell, while the other daughter cell migrates up into the epithelium. Thus, one daughter cell will differentiate and thereby enable the virus to complete its replication cycle—at a level in the epithelium or mucosae beyond the reach of immune attack—while the other daughter cell remains behind in the basal layer, where it sustains the persistent infection.

Another consequence of this remarkable replication cycle is as follows. Since there are no blood or lymphatic vessels in the stratum of the epithelium or mucosae where the productive replication is occurring, the infection tends to remain localized, thereby giving rise to warts or tumors.

Since HPVs are difficult to study and propagate, one might ask how Lowy and Schiller were able to assess the antibody titers that were induced by inoculation with the HPV VLPs. The answer is that they used a pseudovirion-based immune assay. Pseudovirions are essentially VLPs that contain a plasmid that carries a reporter gene.

One last point. I believe it is generally the case that vaccines due not prevent virus infections per se. Rather, they enable the host to bring an infection under control more quickly, before symptoms might arise. Considering that cervical carcinomas may develop after years of virus persistence, despite a continuing immune response against the virus the whole time, how then might the vaccine protect against the cancer? Here is a thought. Bearing in mind that the human immune response naturally clears many HPV infections over time, perhaps the vaccine protects the host by enhancing immune surveillance to clear the infection before the emergence, or malignant progression of HPV-induced lesions. Or, perhaps the vaccine actually prevents infection.





Frederick Li, p53, and the Li-Fraumeni syndrome

Frederick Li passed away on June 12 of this year. In 1969, Li and Joseph Fraumeni, working together at the U.S. National Cancer Institute, discovered a familial (inherited) cancer syndrome, known as the Li-Fraumeni syndrome. Members of Li-Fraumeni syndrome families have a greatly increased risk of developing several types of cancer; particularly breast cancer, but also brain tumors, leukemias, and other cancers as well (1).

Frederick Li and Joseph Fraumeni  in 1991

In 1990, Li and Fraumeni, in collaboration with Stephen Friend and coworkers at the Massachusetts General Hospital Cancer Center, discovered that all Li-Fraumeni syndrome families harbor germ line mutations in TP53; the gene which encodes the cellular p53 protein (2). This report was the first to document that a mutation in TP53 can be inherited. What’s more, the 1990 paper proved to a previously skeptical medical community that heredity can play a major role in some cancers. [Fraumeni says that environmental factors such as air pollution, occupational exposures, diet, and even viruses were, at the time, considered far more likely causes of cancer than genetic mutation (3).]

Although Li’s research focus concerned genetic mutations that might cause cancer, rather than virology, his story is relevant to the blog because p53 is a key factor in the life cycles of the DNA tumor viruses (i.e., the polyomaviruses, papillomaviruses, and adenoviruses). Moreover, p53 was discovered by virologists. So, we begin with a brief review of the discovery of p53 and its mode of action.

In 1979, the p53 protein was discovered independently by several research groups. The discovery happened when David Lane and Lionel Crawford at the Imperial Cancer Research Fund, and Daniel Linzer and Arnold Levine at Princeton University, unexpectedly discovered a non-viral protein of molecular mass around 53 in association with immunoprecipitates of the SV40 LT protein in SV40-transformed cells.

Importantly, the SV40 LT protein was already known to be a key factor in the ability of that virus to induce neoplastic transformation. What’s more, the papillomavirus E6 gene product likewise interacts with p53, as do the adenovirus E1B proteins. Furthermore, each of these viral proteins promotes transformation, and each does so by either inactivating p53 or by facilitating its degradation. Taken together, these facts strongly implied a role for p53 in transformation. See Aside 1.

[Aside 1: Our last posting featured Harald zur Hausen and his discovery that cervical cancer is caused by papillomaviruses (4). Recall that papillomavirus genomes are integrated into the cellular DNA of cervical cancer cells. Harald zur Hausen and coworkers found that while these integrated viral genomes often contain deletions, two papillomavirus genes, E6 and E7, are present and transcribed in all cervical cancer cells; a finding which implied that these viral genes act to initiate and maintain the neoplastic state. And especially germane to the current tale, Peter Howley and coworkers demonstrated that the interaction of the papillomavirus E6 gene product with p53 results in the degradation of p53.]

At the time TP53 was discovered, it was thought to act like the oncogenes carried by the retroviral RNA tumor viruses. Retrovirus oncogenes are actually captured cellular genes, which promote cancer when they are inappropriately expressed under control of viral promoter elements. However, clues eventually emerged which pointed to a very different understanding of p53’s function. The p53 protein is actually a tumor suppressor. Evidence in that regard included the mid 1980s findings of David Wolf and Varda Rotter at the Weizmann Institute, and others as well, who showed that cell lines derived from a number of sporadic (nonfamilial) cancers have TP53 genes that are dysfunctional by mutation. Importantly, it is the loss of p53 function, rather than its expression, which may lead to cancer. [Retroviral oncogenes act dominantly when introduced into non-malignant cells, whereas mutations in tumor suppressor genes are recessive to their wild-type alleles.]

Why, we ask, do the polyomaviruses, papillomaviruses, and adenoviruses inactivate p53? The answer reveals a key tumor suppressor function of p53. Basically, it is because these DNA viruses require the cellular DNA replication enzymes and substrates to support their own DNA replication. Since these cellular enzymes and substrates are available only in dividing cells, these viruses induce cells to bypass the complex circuits that regulate exit from the G0 or “resting” phase of the cell cycle. They do this by freeing the cellular E2F transcription factor from the blocking activities of the pRb family of tumor suppressor proteins, in that way enabling cells to enter into S phase. [The multifunctional SV40 LT protein, the papillomavirus E7 gene product, and the adenovirus E1A protein carry out this function for their respective viruses.] However, p53 remains as a crucial component of a cellular surveillance mechanism that prevents cells from undergoing unscheduled and potentially disastrous cell divisions. If the cell should enter an inappropriate S phase, p53 triggers apoptosis; a cell death program that can be activated by a variety of signals from within and outside the cell. [From the point of view of the host, cell suicide by p53-mediated apoptosis is preferable to the generation of rampant daughter cells that might produce full-blown tumors.] Consequently, the clever DNA tumor viruses (which comprise three unrelated virus families) undermine the normal regulatory functions of p53, as well as those of pRb. See reference 5 for details on these mechanisms.

Li, Fraumeni, and collaborator, Stephen Friend knew that they could not identify the genetic mutation underlying the Li-Fraumeni syndrome by conventional linkage analysis. That was so because Li-Fraumeni syndrome families are quite rare and, moreover, the cancer death rate among affected family members is high (nearly all individuals who carry the mutation develop cancer). So, their strategy was to investigate plausible candidate genes. They chose TP53 because, in their words: “Inactivating mutations of p53 have been associated with sporadic osteosarcomas, soft tissue sarcomas, brain tumors, leukemias, and carcinomas of the lung and breast. Together, these tumors also account for more than half of the cancers in selected series of LFS families (2).” Furthermore, evidence was emerging that TP53 actually encodes a tumor suppressor protein.

The finding by Li, Fraumeni, Friend, and their coworkers, that the TP53 mutation is present in the normal cells of Li-Fraumeni syndrome individuals, as well as in their tumor cells, proved that the mutation is passed down through the germ line. Yet these findings raise the following interesting question. If the TP53 mutation is present in all cells of an affected individual, why does that individual have “only” one or a few tumors? The reason, at least in part, is that progression to full blown cancer requires additional genetic changes. [Apropos that, Li helped discover that people with the Li-Fraumeni syndrome are particularly prone to developing additional tumors when given radiation therapy to treat their cancers.]

Li and his collaborators closed their 1990 paper as follows: “In conclusion, we have shown that alterations of the p53 gene occur not only as somatic mutations in human cancers, but also as germ line mutations in some cancer-prone families (3).” With that paper, the three researchers, and their collaborators, became the first to demonstrate a genetic condition in which a predisposition to cancer is passed from one generation to the next.

Li was born in Canton, China, in 1940. His father was a general in the Chinese Army (Kuomintang), who fought against the Japanese domination of China during the Second World War. The Li family immigrated to the United States in 1947, and opened a Chinese restaurant in White Plains, N.Y.

At 16 years of age, Li matriculated at NYU, where he majored in physics. He earned his MD from the University of Rochester.

Li joined the NCI in 1967, but spent the last 30 years of his career at the Dana-Farber Cancer Institute in Boston, where he also held appointments as a professor at Harvard Medical School and at Harvard’s School of Public Health. In 1991, he was appointed head of Dana-Farber’s Division of Cancer Epidemiology and Control. David G. Nathan, a former president of Dana-Farber, said that Li had been recruited to Dana-Farber to bring more scientific rigor to cancer research there (3). In 1996, Li was appointed to the NCI’s National Cancer Advisory Board by President Bill Clinton.

Li founded a clinic for immigrants in Boston’s Chinatown, where he frequently treated patients at night for free. He retired from his medical activities in 2008 because of dementia resulting from Alzheimer’s disease.

In July 2012, Joseph Fraumeni celebrated his 50th anniversary as a scientist at the NCI. He observed the occasion by stepping down as the NCI’s Director of the Division of Cancer Epidemiology & Genetics. He continues to serve as a senior investigator and adviser at the NCI and NIH, where his major research contributions concerned the environmental and genetic determinants of cancer. Fraumeni is an elected member of the US National Academy of Sciences.

Stephen Friend was on the Harvard Medical School faculty from 1987 until 1995, when he joined the Fred Hutchinson Cancer Research Center as chairman of Pharmacology. His research focused on genomic analysis of large patterns of gene expression. In 1997, Friend and Leroy Hood co-founded the company, Rosetta Inpharmatics, which specialized in genomic approaches to drug discovery. When Rosetta was acquired by Merck in 2001, Friend served as a Merck Senior Vice President and led the parent company’s Oncology Early Discovery and Development Divisions. Friend left Merck in 2009 to advocate for and promote open access biomedical research. Earlier, in 1986, Friend cloned the gene encoding pRB; the first tumor suppressor gene to be isolated.


1. Li, F.P., and Fraumeni J.F. Jr. 1969. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Annals of Internal Mededicine. 71:747-752.

2. Malkin, D., F.P. Li, L.C. Strong, J.F. Fraumeni Jr, C.E. Nelson, D.H. Kim, J. Kassel, M.A. Gryka, F.Z. Bischoff, M.A. Tainsky, and S.H. Friend. 1990. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233-1238.

3. Grady, D., Frederick P. Li, Who Proved a Genetic Cancer Link, Dies at 75, N.Y. Times, June 21, 2015.

4. Harald zur Hausen, Papillomaviruses, and Cervical Cancer, Posted on the blog June 19, 2015.

5. Norkin, L.C. 2010. Virology: Molecular Biology and Pathogenesis, ASM Press.

Harald zur Hausen, Papillomaviruses, and Cervical Cancer

Harald zur Hausen (1936- ) was awarded a share of the 2008 Nobel Prize in Physiology or Medicine for discovering that papillomaviruses cause cervical cancer. He received the award jointly with Luc Montagnier and Françoise Barré-Sinoussi, who were given their portion for discovering HIV (1). Before getting on with zur Hausen’s story per se, we begin with bit of earlier history.

zur hausen Harald zur Hausen in 2008

Genital warts are benign epithelial tumors that have been known and associated with sexual promiscuity since the time of the ancient Greeks. In 1907 these lesions were unequivocally proven to be an infectious disease by Italian researcher, G. Ciuffo, who showed that they can be transmitted by filtered extracts of wart tissue; a finding which also implied that the etiologic agent is a virus. Ciuffo inoculated himself to advance his case.

Ciuffo’s finding is relevant to our story since members of the papillomavirus family of DNA viruses are the cause of warts. What’s more, and importantly, some papillomaviruses  also cause malignant cervical carcinomas.

In 1933 Richard Shope, at the Rockefeller Institute, became the first researcher to isolate a papillomavirus, the cottontail rabbit papillomavirus. Shope went on to show that this virus is the cause of skin papillomas in its rabbit host. This finding by Shope was the first to demonstrate that a DNA virus can be tumorigenic.

Years earlier, in 1911, Peyton Rous discovered that an RNA virus—the Rous sarcoma virus (the prototype retrovirus)—causes solid tumors in chickens. Peyton Rous was Richard Shope’s friend and colleague at the Rockefeller Institute. In 1934 Shope asked Rous to characterize the warts that the rabbit papillomavirus induces in jackrabbits. Rous found those warts to be benign tumors that could progress to malignant carcinomas.

Despite the earlier findings of Ciuffo, Shope, and others, the notion that genital warts in humans is a sexually transmitted malady was slow to gain acceptance. Oddly, perhaps, recognition of that truth was prompted by a 1954 report that American servicemen, who had been serving in Korea, were transmitting genital warts to their wives upon returning to the U.S (T. J. Barrett, et al., J. Am. Med. Assoc. 154:333, 1954). [Sexually transmitted diseases were a long-standing problem in the military. Servicemen were most often infected by sex workers who frequented the vicinity of military quarters.]

The key discoveries of this tale are Harald zur Hausen’s 1983 and 1984 findings that two human papillomavirus subtypes, HPV-16 and HPV-18, together account for about 70% of all cervical cancers. Considering that more than 120 distinct HPV subtypes have been identified, the high degree of association of cervical carcinoma with only two of these subtypes provided compelling evidence for the viral etiology of this malignancy. Later studies showed that HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58 are responsible for another 20% of cervical cancers. Indeed, an HPV infection is present in virtually all cervical carcinomas. See Aside 1.

[Aside 1: Cervical cancer was once the leading cause of cancer-related deaths in women in the United States. However, the number of cervical cancer deaths in the industrialized world decreased dramatically over the last 40 years, largely because of the Pap test, which can detect pre-cancer cervical lesions in their early stages. The CDC website reports 12,109 cervical cancer cases and 4,092 deaths from cervical cancer in the U.S. in 2011 (the most recent year for which data are available). Worldwide, cervical cancer was responsible for 275,000 deaths in 2008. About 88% of these deaths were in developing countries (J. Ferlay et al., Int. J. Cancer, 127:2893, 2010).]

Harald zur Hausen was a child in Germany during the Second World War, growing up in Gelsenkirchen-Buer, which was then a center for German coal production and oil refining and, consequently, a major target for allied bombing. [The city also contained a women’s sub-camp of the Buchenwald concentration camp. The Nazis used its prisoners for slave labor.] All members of zur Hausen’s family survived the war. However, zur Hausen’s primary education contained significant gaps because schools were closed during the allied bombing (2).

Despite the gaps in zur Hausen’s early education, he was keenly interested in biology and dreamed of becoming a scientist. Yet at the University of Bonn he opted to study medicine, rather than biology. After zur Hausen received his medical degree, he worked as a medical microbiologist at the University of Düsseldorf, where he enjoyed the opportunity that the University gave him to carry out research on virus-induced chromosomal aberrations.

Although zur Hausen was fascinated by his research, he was soon aware of the deficiencies in his scientific background. So, in 1966 he looked to enhance his proficiency as a scientist by securing a postdoctoral position in the laboratories of Gertrude and Werner Henle at the Children’s Hospital of Philadelphia.

The Henles were a German-born husband and wife research team, known for their work on flu vaccines. More apropos to our story, they are also known for demonstrating the link between the recently discovered Epstein-Barr virus (EBV; a herpesvirus) and infectious mononucleosis, as well as for showing that EBV is the etiologic agent of Burkitt’s lymphoma; a cancer found in parts of Africa. EBV was, in fact, the first virus associated with a cancer in humans. [Gertrude Henle’s mother was murdered by the Nazis in 1943.]

Although zur Hausen took part in the Henles’ experiments involving EBV, he did so grudgingly because he was intimidated by his inexperience in molecular biology. In his own words: “I urged Werner Henle to permit me to work with a different agent, namely adenovirus type 12, hoping that this relatively well established system would permit me to become acquainted with molecular methods. He reluctantly agreed. I started to work eagerly on the induction of specific chromosomal aberrations in adenovirus type 12-infected human cells…and, to please my mentor, I demonstrated electron microscopically the presence of EBV particles directly in… Burkitt’s lymphoma cells (2).”

In 1969 zur Hausen returned to Germany to take an appointment as an independent scientist at the University of Wurzburg. His research was now focused entirely on EBV. Specifically, he wanted to challenge the prevailing view that Burkitt’s lymphoma tumors are persistently infected with EBV (i.e., that the tumors continuously produce low levels of the virus).

I presume that zur Hausen was interested in this issue because it was reasonable to believe that EBV gene expression is necessary to maintain the neoplastic state of the Burkitt’s tumor cells. Persistent infection would be one means by which viral genes could be carried by the cells. But zur Hausen believed that EBV DNA might be maintained in Burkitt’s lymphoma cells, even if they did not produce EBV particles.

Werner Henle in Philadelphia (and also George Klein in Stockholm) sent zur Hausen a large number of Burkitt’s lymphoma cell lines and tumor biopsies to aid in his study. One of those cell lines, the Raji line of Burkitt’s lymphoma cells, did not produce EBV particles. Nevertheless, zur Hausen isolated sufficient EBV DNA from the Raji cells to prove that multiple copies of EBV DNA were maintained in them. This was the first time that tumor virus DNA was shown to be present in malignant human cells that were not producing virus. See Aside 2.

[Aside 2: In 1968 Renato Dulbecco and co-workers were the first to discover viral DNA integrated by covalent bonds into cellular DNA (J. Sambrook et al., Proc. Natl. Acad. Sci. U S A. 60:1288, 1968). They were studying cells transformed by the polyomavirus, SV40. Integration explained how SV40 genes could be stably maintained and expressed in transformed cells, in the absence of productive infection. Integration is now recognized as a key event in cell transformation by members of several virus families, including the polyomaviruses, papillomaviruses, and the oncogenic retroviruses.

The situation in the case of EBV, a herpesvirus, is different, as herpesviruses are able to enter into a latent state in host cells. In the latent state the viral genome is maintained as an episome, and only a subset of the viral genes (i.e., those concerned with latency) are expressed. The episomal viral genome is replicated by the cellular DNA replication machinery during the cell cycle S phase, and a viral gene product, EBNA-1, ensures that viral genomes are equally partitioned between the daughter cells. In 1978 George Klein and co-workers were the first to demonstrate episomal EBV DNA in a cell line derived from a Burkitt’s lymphoma biopsy (S. Koliais et al., J. Natl. Cancer. Inst. 60:991, 1978).]

In 1972, while zur Hausen’s attention was focused on EBV and Burkitt’s lymphoma, his research direction took a providential turn that would lead to his most important discoveries. It happened as follows.

Recent seroepidemiological evidence was suggesting a link between herpes simplex virus type 2 (HSV-2), a well known genital infection, and cervical cancer. Since HSV-2, like EBV, is a herpesvirus, and since zur Hausen had already demonstrated that EBV DNA is present in Burkitt’s lymphoma tumor cells, zur Hausen believed he was well positioned to search for HSV-2 DNA in cervical cancer biopsies. However, in this instance, all his repeated attempts failed.

Harald zur Hausen then came across anecdotal reports of genital warts converting to squamous cell carcinomas. Importantly, those genital warts were known to contain typical papillomavirus particles. Taking these two points into account, zur Hausen considered the possibility that papillomaviruses, rather than herpesviruses, might be the cause of cervical carcinomas. Indeed, his initial thought was that the genital wart papillomavirus might also be the etiologic agent for cervical carcinomas.

Thus, Harald zur Hausen began his foray into papillomavirus research. His first experiments found papillomavirus particles in benign plantar (cutaneous) warts. His next experiments demonstrated that there are multiple papillomavirus subtypes. [In brief, zur Hausen used in vitro-transcribed plantar papillomavirus RNA as a hybridization probe against the DNA from various plantar and genital warts. Only some of the plantar wart DNAs, and none of the genital wart DNAs, reacted with his planter wart RNA probe. Restriction endonuclease patterns of a variety of human papillomavirus isolates confirmed that the HPVs comprise a heterogeneous virus family.]

Harald zur Hausen’s next experiments sought to detect papillomavirus DNA in cervical carcinoma biopsies. However, his initial trials in this crucial undertaking were unsuccessful.  He was using DNA from HPV-6 (isolated from a genital wart) as a hybridization probe in those failed attempts. But zur Hausen and co-workers had at hand a number of additional HPV subtypes, from which they prepared other DNA probes. DNA from HPV-11 (from a laryngeal papilloma) indeed detected papillomavirus DNA in cervical carcinomas.

In 1983, two of Zur Hausen’s former students, Mathias Dürst and Michael Boshart, using HPV-11 DNA as a probe, isolated a new HPV subtype, designated HPV-16, from a cervical carcinoma biopsy. In the following year, they isolated HPV-18 from another cervical carcinoma sample. Harald zur Hausen’s group soon determined that HPV-16 is present in about 50% of cervical cancer biopsies, while HPV-18 is present in slightly more than 20%. [The famous HeLa line of cervical cancer cells contains HPV-18 DNA.]

Additional key discoveries took place during the next several years, including the finding that papillomavirus DNA is integrated into the cellular DNA of cervical carcinoma cells. This finding clarified how papillomavirus genes persist in the cancers, and also revealed that the cancers are clonal (see Aside 2, above). Moreover, while the integrated viral genomes often contain deletions, zur Hausen’s group found that two viral genes, E6 and E7, are present and transcribed in all cervical cancer cells. This finding implied that E6 and E7 play a role in initiating and maintaining the oncogenic state. [In 1990 Peter Howley and co-workers demonstrated that the interaction of the E6 gene product with the cellular tumor suppressor protein p53 results in the degradation of p53. In 1992 Ed Harlow and coworkers showed that the E7 gene product blocks the activity of the cellular tumor suppressor protein pRb. Reference 3 details the mechanisms of papillomavirus carcinogenesis.]

The above findings led to widespread acceptance that cervical carcinoma is caused by papillomaviruses. Yet acceptance was not immediate. The prevailing belief, that herpesviruses cause cervical carcinoma, was well-entrenched and slow to fade away. It was based on the observation that many women afflicted with cervical carcinoma also had a history of genital herpes. But, individuals infected with one sexually transmitted pathogen are often infected with others as well. Apropos that, genital warts were long thought to be associated with syphilis, and later with gonorrhea. In any case, in 1995 the World Health Organization officially accepted that HPV-16 and HPV-18 are oncogenic in humans.

Harald zur Hausen was awarded one half of the 2008 Nobel Prize for Medicine or Physiology for proving that cervical cancer is caused by human papillomaviruses. By the time of his award, his findings had led to key insights into the mechanism of HPV-mediated carcinogenesis and, importantly, to the development of a vaccine to prevent cervical cancer. See Aside 3.

[Aside 3: The first generation of Gardasil, made by Merck & Co., helped to prevent cervical cancer by immunizing against HPV types 16 and 18, which are responsible for an estimated 70% of cervical cancers. Moreover it also immunized against HPV types 6 and 11, which are responsible for an estimated 90% of genital warts cases. Apropos genital warts, there are 500,000 to one million new cases of genital warts (also known as condylomata acuminate) diagnosed each year in the United States alone.

The original vaccine was approved by the USFDA on June 8, 2006. An updated version of Gardasil, Gardasil 9, protects against the HPV strains covered by the first generation of the vaccine, as well as five additional HPV strains (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58), which are responsible for another 20% of cervical cancers. Gardasil 9 was approved by the USFDA in December 2014.]

Harald zur Hausen reviewed the overall contribution of viruses to human cancer in his 2008 Nobel lecture (4). Some of his key points are as follows. HPVs were discussed above with respect to cervical carcinoma. HPVs also are associated with squamous cell carcinomas of the vagina, anus, vulva, and oropharynx. What’s more, 40% of the 26,300 cases of penile cancer reported worldwide in 2002 could be attributed to HPV infection.

Epstein-Barr virus too was discussed above. This member of the herpesvirus virus family causes nasopharyngeal carcinoma, as well as Burkitt’s lymphoma. Another herpesvirus, human herpesvirus 8, causes Kaposi’s sarcoma; the most frequent cancer affecting AIDS patients. Hepatitis B virus (HBV, a hepadnavirus), as well as hepatitis C virus (HCV, a flavivirus), causes hepatocellular carcinoma. The human T-lymphotropic virus 1 (HTLV-1), a retrovirus, induces adult T-cell leukemia. And the recently discovered Merkel cell polyomavirus (MCPyV) is responsible for Merkel cell carcinoma.

Harald zur Hausen estimated that viruses directly cause about 20% of all human cancers, and a similar percentage of all deaths due to cancer! And while 20% might seem to be a remarkably high figure for the extent of viral involvement in human cancer, zur Hausen suggests that it is actually a minimal estimate. That is so because it is difficult to determine that a particular virus is actually the cause of a cancer. Consequently, it is likely that other examples of viral involvement in human cancer will be discovered.

Harald zur Hausen gave two principal reasons for why it is difficult to establish that an infectious agent is the cause of a cancer in humans. First: “… no human cancer arises as the acute consequence of infection. The latency periods between primary infection and cancer development are frequently in the range of 15 to 40 years…” Second: “Most of the infections linked to human cancers are common in human populations; they are ubiquitous… Yet only a small proportion of infected individuals develops the respective cancer type.”

Viruses also contribute to the human cancer burden in an indirect way. For instance, HIV types 1 and 2 play an indirect role in cancer via their immunosuppressive effect, which is the reason for the extraordinarily high prevalence and aggressiveness of Kaposi’s sarcoma in AIDS patients.

Bacterial infections also contribute to the cancer burden. For example, Helicobacter pylori infections may lead to stomach cancer. What’s more, the parasites Schistosoma, Opisthorchis, and Clonorchis have been linked to rectum and bladder cancers in parts of Northern Africa and Southeast Asia, where they are prevalent.

Obviously, but important enough to state anyway, knowing that a particular cancer is caused by a particular infectious agent opens the possibility of developing a rational strategy to prevent that cancer. Gardasil is an exmple. A vaccine against HBV is also available, and one against HCV is under development.


1. Who discovered HIV, Posted on the blog January 23, 2014.

2. MLA style: “Harald zur Hausen – Biographical”. Nobelprize.org. Nobel Media AB 2014. Web. 27 May 2015. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2008/hausen-bio.html&gt;

3. Norkin, Leonard C. (2010) Virology: Molecular Biology and Pathogenesis. ASM Press, Washington, D.C. See Chapters 15 and 16.

4. Zur Hausen, Harold, The search for infectious causes of human cancers: where and why. Nobel Lecture, December 7, 2008.