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A novel mechanism of cancer development

Epstein-Barr virus (EBV) infections occur in almost all adults worldwide and are a high risk factor for some types of cancer. Researchers from Heidelberg have now come up with a novel mechanism that promotes carcinogenesis involving an EBV protein rather than the genome of the virus. The EBV protein BNRF1 induces the excessive amplification of the centrosomes of the spindle apparatus, and leads to chromosomal instability and inaccurate distribution of chromosomes to daughter cells during mitosis.

Epstein-Barr viruses: electron microscope image. © DKFZ

The Epstein-Barr virus (EBV) was discovered in 1964 in the B lymphocytes of a lymphatic system cancer called Burkitt’s lymphoma. Burkitt’s lymphoma is a common type of cancer in tropical Africa. EBV was the first human virus to be associated with cancer. However, the Nobel Prize for discovering that viruses cause cancer was not awarded for research into EBV. It was not until 44 years after the virus’s first description by the British pathologist Michael Epstein and his assistant Yvonne Barr, that Harald zur Hausen from the German Cancer Research Center (DKFZ) was awarded the Nobel Prize for his research on human papillomaviruses. It has consistently proved quite difficult to identify infectious agents such as viruses as causes of human cancer, especially so when it comes to the potentially oncogenic effect of EBV in human cells.

A virus that is implicated in a broad range of different diseases

Prof. Dr. Dr. Henri-Jacques Delecluse, director of the German-French research unit “Unité Inserm 1074” at the DKFZ. © DKFZ

There are two major reasons for this. First, it turned out that 95 percent of all adults worldwide are infected with EBV, usually without displaying any symptoms. Second, it was demonstrated that a number of very different diseases are associated with EBV infection, including non-Hodgkin’s lymphoma (including Burkitt’s lymphoma) and Hodgkin’s lymphoma, as well as other completely unrelated tumours such as nasopharyngeal carcinoma that is very common in East Asia. EBV infections are also associated with around 10 percent of all gastric cancer cases as well as Pfeiffer’s disease, an unpleasant but usually harmless disease common in teenagers and young adults. Pfeiffer’s disease is better known as the kissing disease, mononucleosis or glandular fever.

Prof. Dr. Dr. Henri-Jacques Delecluse, a pathologist from the DKFZ, has been studying the connections between EBV infections and cancer for almost twenty years. Since 2012, Delecluse has been director of a research unit (Unité Inserm 1074), which was established at the DKFZ by the French Institut National de la Santé et de la Recherche Médicale (INSERM). Delecluse is also the director of the DKFZ Division of Pathogenesis of Virus-Associated Tumours (see also “New Franco-German unit on cancer and infections in Heidelberg”).

A few years ago, Delecluse and his team showed that the different EBV-associated pathologies are due to genetically different EBV strains that also have different levels of malignity. However, it proved difficult to pinpoint how the virus manages to reprogramme somatic cells into cancer cells. “We were aware only from a limited number of cases how somatic cells transformed into cancer cells. Until recently, we still did not know how the majority of tumours developed,” said Delecluse presenting the researchers’ latest results, which have been published in the journal “Nature Communications”. The paper describes the unexpected finding that carcinogenesis is not due to the genetic material of the virus, but instead is promoted by a viral protein. This study also involved researchers from the DKFZ Division of Cell-Cycle Control and Carcinogenesis led by Prof. Dr. Ingrid Hoffmann.

Protein-induced chromosomal instability

Schematic showing an Epstein-Barr virus with the tegument that contains the BNFR1 protein. © DKFZ

In humans, EBV primarily infects B lymphocytes of the immune system and the mucous membranes of the mouth and throat, where the virus can persist for a long time without causing disease. EBV belongs to the family of herpes viruses that have a protein-containing layer called a tegument between the nucleocapsid, which contains the viral DNA, and the viral shell. The researchers have now shown that the tegument protein BNRF1 induces the amplification of centrosomes in EBV-infected host cells. Centrosomes are the organelles that form a mitotic spindle, enabling cell division to take place. The infectious particle BNRF1 leads to the formation of an excessive number of centrosomes, and hence to more than two spindle poles. As a result, normal cell division is prevented as the chromosomes are no longer divided equally and accurately between the two daughter cells. Chromosomal instability and aneuploidy are an acknowledged cancer risk factor. However, the mechanism described by the researchers causes cancer in a completely different way from that of human tumour viruses studied so far. The researchers found that the virus can induce chromosomal instability without establishing a chronic infection. Tumours that do not necessarily carry the viral genome can therefore develop. EBV particles that are deficient in BNRF1 do not interfere with the distribution of the chromosomes to the daughter cells during mitosis. However, EBV particles in which BNRF1 is reincorporated regain the ability to produce excessive centrosomes. The researchers detected BNRF1 in the centrosome compartment of cells infected with EBV.

Cell division during tripolar mitosis caused by the excessive amplification of centrosomes in an EBV-infected B lymphocyte. © DKFZ

“For the first time ever we have discovered that a component of the viral particle is a cancer driver,” explained Delecluse. “All human tumour viruses studied so far cause cancer in a completely different way. Usually, the genetic material of the viruses needs to be permanently present in the cell, thus enabling the transcription and activation of viral genes that promote the development of cancer.” In his acceptance speech for the Nobel Prize in 2008, Harald zur Hausen suggested that over 10 percent of all cancers caused by infections are associated with Epstein-Barr viruses. This corresponds to about two percent (approximately 300,000 cases) of all new cancers diagnosed worldwide every year. Based on their new findings on the mode of action of the BNRF1 protein, Delecluse and his colleagues suspect that EBV could even cause the development of additional tumours that might not previously have been linked to the virus because they do not carry viral genetic material. The number of EBV-associated cancers might therefore be even higher than originally assumed. 

According to the findings of the researchers from Heidelberg, every EBV infection – including the initial infection – represents a risk factor for cancer development because all EBV infections increase the risk of chromosomal instability and aneuploidy. This risk increases in proportion to the frequency of contact with viral particles. Patients with compromised immune systems, for example, in whom the viruses can multiply excessively are therefore more vulnerable. Delecluse therefore emphasises the need to push forward with the development of a vaccine against EBV in order to prevent people from getting infected with this virus in the first place. An EBV vaccine prototype already exists. A few years ago, Delecluse and his colleagues developed EBV mutants that have no genetic material in their protein shell, and are therefore not capable of causing any disease. However, these virus-like particles (VLP) look like intact viruses and are thus recognised by the human immune system. This makes them an ideal basic material for a preventive vaccine against EBV-associated cancers.

Original publication:

Shumilov A, Tsai M-H, Schlosser YT, Kratz A-S, Bernhardt K, Fink S, Mizani T, Lin X, Jauch A, Mautner J, Kopp-Schneider A, Feederle R, Hoffmann I, Delecluse H-J: Epstein-Barr virus particles induce centrosome amplification and chromosomal instability. Nature Communications 2017, DOI: 10.1038/ncomms 14257

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