The effect of Human papillomavirus on head-and-neck cancers

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Introduction

Environ 20% des cancers ont une origine virale. The main oncogenic virus are Epstein Barr virus, hepatitis B virus and hepatitis C virus, human T-lymphotropic virus, human herpesvirus 8 and human papillomavirus (HPV), which is the best known by scientists. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1500926/).

In 2008, among the 12.7 million new cancers worldwide, 4.8% were because of HPV. (2)

HPV cause donc de nombreux cancer qui se trouvent sur différents organes like the cervical cancer. Plus récemment, scientists ont découvert qu’il avait un lien avec some head and neck cancers: HPV causes head and neck squamous cell carcinoma (HNSCC). We found these squamous cell carcinoma (SCC) in oral cavity, in larynx, in oropharynx, in paranasal sinus and in nostril. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208923/)

HNSCC can also be caused by a high consummation of tobacco and of alcohol. (Fakhry, C, 2008) The ones which are caused by HPV are called HPV-positive HNSCC.

HPV has been the subject of many studies. Their aim was to find with which mechanisms HPV involves the development of HNSCC.

1. Human papillomavirus

1.1 General description

Following the classification of the International Committee on Taxonomy of Viruses (ICTV), the family of HPV is Papillomaviridae. Up to now, scientists have discovered 29 genera of papillomaviruses. Among them, only five are found in humans. This means that there are fives HPV that are: Alphapapillomavirus, Betapapillomavirus, Gammapapillomavirus, Mupapillomavirus and Nupapillomavirus. (http://www.sciencedirect.com/science/article/pii/S0042682210001005)

Alphapapillomavirus are responsible for mucosal and cutaneous lesions. Betapapillomavirus, Gammapapillomavirus, Mupapillomavirus and Nupapillomavirus are responsible for cutaneous lesions in humans. (http://www.sciencedirect.com/science/article/pii/S004268220400220X)

Inside a genus, HPV has been separated in types. One type represents one strain. Scientists have identified nearly 200 types of HPV. It is important to know that all these strains are not dangerous, just about 40 of them can infect humans. The others are harmless and do not cause any symptoms. (Kreimer, A.R., Clifford, G.M.)

Among those causing symptoms, there are HPV with a low oncogenic potential (6, 11) and with a high oncogenic potential (16, 18, 31, 33, 35, 45, 51, 52, 55, 58, 59, 68, 73, 82, 83). (http://www.ncbi.nlm.nih.gov/pubmed/14530303)

All these strains do not have an effect on head and neck. Types 16, 18, 31 and 33 account for 99% of HPV-positive HNSCC.

HPVs do not affect all parts of the head and neck with the same frequency. The distribution of the different HPV in HNSCC depends of the head and neck sites. (Kreimer, A.R., Clifford, G.M.) This is the case of HPV type 16 (HPV16) and HPV18 which are the two most common ‘high risk’ HPV found in HNSCC. HPV16 is the most present. It represents about 87% of cancers of the oropharynx, 68% of cancers of the oral cavity and 69% of cancers of larynx. HPV18 represent about 1% of cancers of the oropharynx, 8% of cancers of the oral cavity and 4% of cancers of larynx. (Human_Papillomavirus_Detection_in_Head_and_Neck.2.pdf)

HPV types 3, 6, 11, 16, 33, 45, 51, 52, 56, 58, 59 and 68 can also be involved in a coinfection. (Human_Papillomavirus_Detection_in_Head_and_Neck.2.pdf)

1.2 Virus structure

HPV is a virus which has a double-stranded DNA. This virus therefore belong to the Group I of the Baltimore classification. It is a circular DNA of about 7.9 kb. It has a capsid which is about 55 nm in diameter. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815356/) This capsid is composed of 72 capsomeres. (Szentirmay, Z., pólus, K.)

HPV genome is divided into a non-coding DNA strand and a coding DNA strand. This one is composed of 8 open reading frames (ORF). (http://www.ijmm.org/article.asp?issn=0255-0857;year=2007;volume=25;issue=1;spage=10;epage=17;aulast=Gnanamony) The individual frames of the ORF are classified in two categories. On the one hand we have the genes of early (E) expression and on the other hand we have the genes of late (L) expression. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208923/)

1.2.1 Genes of early expression

The genes of early expression encode for the proteins E1, E2, E3, E4, E5, E6, E7 and E8. They are expressed just after the infection, and before the DNA replication. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815356/)

E1 protein is involved in the DNA replication (4). E2 protein is involved in the DNA replication too, but also in RNA transcription. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180061/) E5, E6 and E7 are oncoproteins. E5 protein is involved in the cell transformation and also in the DNA replication. It can makes the immune system to not recognise the infected cell. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248866/) E6, E7 are involved in the cell transformation. (Vac1.pdf) These are the proteins that are the most carcinogenic. All their activities have for aim to support the continued proliferation of cells, which have been contaminated. Thus, because of these oncoproteins, cancer cells will grow. (5) E6 degrades the tumour suppressor protein p53. This is done thanks to ubiquitin and then thanks to proteasomes. In addition, in order to increase the survival of the infected cells, E6 increases the expression of apoptosis inhibitory such as cIAP2 (cellular Inhibitor of Apoptosis Protein). Finally, E6 actives the hTERT (human Telomerase Reverse Transcriptase), which is the one coding for the catalytic subunit of the telomerase complex. Thanks to that, the infected cells become immortal. E7 degrades the tumour suppressor proteins pRb (Retinoblastoma protein), p107 and p130. (5)

1.2.2 Genes of late expression

The genes of late expression encode for the proteins L1 and L2. These proteins are the structural proteins of viral capsid. The late genes are expressed at the end of the viral cycle. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815356/)

1.3 Virus infection

1.3.1 Transmission

Le HPV est un virus très commun. Pour qu’autant de personnes soient en possession de ce virus, sa transmission se fait de plusieurs façons. Tout d’abord, une personne peut être infectée dès sa naissance. Cela est réalisé à cause de la vertical transmission. Dans ce cas là, la mère transmet le HPV à son enfant.(http://www.hindawi.com/journals/idog/2010/326369/abs/)

Une autre façon de devenir infecté est lors d’un rapport sexuel. Dans ce cas-là, il est connu que les organes génitaux sont vulnérables. C’est d’ailleurs la principale cause de cervical cancers. (10) Mais il est important de savoir que les organes de la tête et du cou sont aussi vulnérables. La contamination de ces organes se fait par oral sex. Oral sex veut dire rapport entre un sex d’une personne et la cavité bucale d’une autre. Ainsi, plus une personne do oral sex, plus elle a de risques d’avoir un HNSCC augmente. (http://jama.jamanetwork.com/article.aspx?articleid=1104983)

Une étude intéressante indique que les hommes ont trois fois plus de chances d’être contaminés par un oral HPV que les femmes. Dans le cas du HPV16, les hommes ont cinq fois plus de chances d’être contaminés. Cette fréquence plus importante pour les hommes peut s’expliquer par le fait que les hommes ont plus de partenaires sexuels que les femmes au cours de leur vie. (http://jama.jamanetwork.com/article.aspx?articleid=1104983) Une autre explication est le fait que le taux de transmission est plus important à partir des femmes vers les hommes qu’à partir des hommes vers les femmes. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600292/).

Une troisième façon d’avoir des HPV-positive HNSCC est lorsque deux partenaires s’embrassent. Cependant, la contamination se fait dans le cas de open-mouthed kissing. Plus une personne à de open-mouthed kissing partners, plus elle a de chance de devenir contaminée par le virus du HPV. Ce moyen de contamination peut vite devenir un problème. En effet, il est très fréquent que deux partenaires se donnent des open-mouthed kisses. Ainsi, des personnes peuvent devenir HPV-positive alors qu’elles ne sont pas exposées à un risque de contamination «classique». (11)

Finally, HPV can enter in an organism if this one has micro injuries of its epidermidis or of its mucous membrane. It is also possible if there is a skin abrasion. (Morshed)

All these factors make the virus able to penetrate into the stem cells which are in the epithelium.

1.3.2 Virus development

Human papillomavirus can only grow in the nucleus of target cells. This is done thanks to the replication machinery. Therefore HPV infects cells in contact with the external environment which are the epithelial cells. HPV infects more particularly the basal and parabasal cells. Thus, the virus infects stem cells. (Szentirmaz Z 2005) If this is the epidermis that is infected, virus will infect keratinized stratified squamous epithelia. Indeed, the epidermis is mainly composed of cells called ‘keratinocytes’. (7) Anyway, DNA replication can only be done in squamous epithelial cells. (Morshed, K., Polz-Gruszka, D 2014)

Once cells have been infected, HPV does not alter them. Cells do not undergo any change. At some point, virus replication starts. (Szentirmaz Z 2005) Proteins that have a role in cell replication operate. This is the case of the early gene proteins like E1 and E2 proteins. E6 bind to p53 protein and E7 bind to pRb protein. These proteins are regulators of keratinocytes. Thus, the effects of E6 and E7 proteins stop the cell division because p53 and pRb are not able to help in the mitosis process.(7)

The infected host cell will start to produce many copies of HPV. The virus is then free to propagate out of the infected host cells. HPV is able to reach all organs of head and neck. Once an organ is infected, it is currently impossible to predict what this infection will become. It can either stay as an invisible state for the cells. This state is called ‘latent’. The virus can also persist or disappear by itself. The infected cells can also be transformed into cancer cells.

(Szentirmaz Z 2005)

1.4 Symptoms

HPV is primarily a quiet infection which does not present a lot of symptoms. When a patient has a pain in his head or in his neck, this is probably because he already has a cancer.

Among these symptoms, there are a sore that does not heal and a difficulty to swallow. There are also a sore throat that does not go away and a change or a hoarseness in the voice. However, it is very hard to describe all the symptoms that can occur because they depend on the part of the head or of the neck which is cancerous.

In addition, if the oral exfoliated cells of a patient contain oncogenic HPV, there is a significantly increase in the risk of having a head and neck cancer. (Smith, E.M., Ritchie, J.M.)

3 The effect of Human papillomavirus on head-and-neck cancers

Before 1983, scientists were convinced that head and neck cancers were only associated with a high alcohol and tobacco consumption. But there was a significant increase in the number of people with a head and neck cancer who didn’t consume any of these substances. That’s why scientists found that there was a link between the virus and these cancers. (Fakhry, C, 2008). But only some HPV which are the oncogenic HPV are responsible for HPV-positive HNSCC. (van Houten, 2001)

Once HPV infect an organ, in order to have cancer cells it is necessary that there is an integration of the HPV DNA. This will make the malignant transformation possible. The integration disrupts or delete the E1 and E2 ORF. This cause the upregulation of the E6 and E7 oncoproteins. (Szentirmay, Z 2005)

E6 and E7 oncoproteins will express themselves continuously. This will cause a genomic instability. (zzz3) Indeed, E6 and E7 have effects on p53, pRb, p107 and p130 tumour suppressors, on the cIAP2 apoptosis inhibitor and on the hTERT gene which is coding for the catalytic subunit of the telomerase complex. (5) This genomic instability can transform the infected cells into tumorigenic cells. These cells are cells which tend to form tumours. (zz3)

In addition to these modifications, there is an increase in the mitotic rate are there are alterations of the infected cells’ chromosomes which cause aneuploidy. There is also more and more mutations in the infected cells’ genome. ((Szentirmay, Z 2005)

The oncogenic HPV therefore have an important effect in the transformation of healthy cells into cancer cells.

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