Investigating the Link Between Papilloma Virus and Cervical Cancer

Introduction
What Is Human Papillomavirus?
Viral  Replication Transformation and Immunology
Mechanisms of Human Papillomavirus-Induced Oncogenesis
References


The human papillomavirus infection is known to cause cervical cancer. The majority of human papillomavirus infections are harmless and typically clear spontaneously. However, persistent infection with high-risk human papillomavirus has been observed to cause cervical cancer, alongside cancer of the anus, vulva, vagina, penis,  and oropharynx.

Human papillomaviruses are known to infect the epithelial cells to produce viral particles exclusively; this occurs only in fully mature epithelial cells. The human papillomavirus causes the normal cell cycle control to be thrown Into disarray, resulting in uncontrolled cell division and the accumulation of genomic damage. Testing for the presence of human papillomaviruses has great clinical significance in preventing low-grade cytology and enabling monitoring after treatment for cervical (and other anogenital and oropharyngeal) cancer.

The causal link between the human papillomavirus infection of the cervix and cervical cancer is a hallmark discovery of the past three decades. This discovery arose from observing human papillomavirus 16 in cervical cancer tissue by Harald zur Hausen and his research team. This was followed by a worldwide effort that employed molecular biologists, clinicians, vaccinologists, and epidemiologists to develop a prophylactic (preventative) vaccine for human papillomaviruses with a 70-80% efficacy in preventing cervical cancer. Collectively, this resulted in zur Hausen being awarded the Nobel Prize in Physiology or medicine in 2008.

papillomavirus

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What Is Human Papillomavirus?

Human papillomavirus belongs to the papilloma family of hosts – including those in the animal kingdom. The taxonomy of the family is based on the homology of genome sequences, biological function, and pathological effects produced. More than 100 types of human papilloma have been discovered; these include 13 high-risk types directly responsible for human neoplasia (uncontrolled, abnormal growth of cells or tissues)  in the anogenital and oropharyngeal area.

The prevalence of human papillomavirus occurs because of both incident and persistent infections that have failed to clear and subsequently accumulated over time. Prospective studies have supported this. >90% of new human papillomavirus infections regress (return to a previous and less advanced or worse state) in 6–18 months at any age.

Persistent infection is a prerequisite for progression to cervical intraepithelial neoplasia (CIN). The duration of infection informs the probability of the clearance of human papillomavirus, with longer persistence correlated with a reduced probability of clearance. Human papillomavirus that occurs in women > 30 years persists longer relative to younger women as there is an increased likelihood of persistent infections over a longer period.

CIN1, in particular, is an insensitive histopathological sign of the infection; CIN2 shows the potential to result in cancer, and CIN3 is the most clinically relevant neoplasia, representing the best endpoint for cervical cancer in both vaccination and screening trials.

Risk factors for the persistence and progression of human papillomavirus include immunodeficiency and the type of human papillomavirus. Other factors include the use of oral contraceptives, chlamydia infection, as well as sexual and reproductive factors. Type 16 human papillomavirus is the most likely variant to persist and cause CIN3 subsequent cervical cancer. Therefore, genotyping the virus could improve risk stratification among women with human papillomavirus.

In a recent study that investigated the cytopathological and histopathological cervical cancer diagnosis, 36374 cervical cancers across 432 studies were subject to PCR-based human papillomavirus DNA testing. Types 16, 18, and 45 accounted for more than or equal infections in several cancer cases compared to women with normal cytology.

Type 16 comprises the largest proportion in western Central Asia but the smallest in Africa. Both Types 16 and 18 are the most common in high-grade pre-cancerous growths. Due to the high proportion of cervical cancers attributed to types 16 and 18, current vaccines can prevent approximately 70% of cancers worldwide, of which half are high-grade, pre-cancerous growths.

Viral Replication Transformation and Immunology

The human papillomavirus infects the cervical epithelium, which rests on the basement membrane supported by the dermis. The virus gains access to the basal cells through small abrasions in the cervical epithelium. After infection, early human papillomavirus genes are expressed, enabling viral DNA replication (E1-5, E6, and E7).

In the mid and superficial zones, which are the upper layers of the epithelium, the viral genome is further replicated, with subsequent expression of genes. The late genes L1 and L2 encapsulate the viral genome to form progeny in the nucleus. Once they sell lyses and viral particles are shed, a new infection is initiated.

Intraepithelial lesions of low grade increase the likelihood of productive viral replication. The number of high-risk human papillomavirus that progress to high-grade cervical intraepithelial cancers is unknown.

The integration of the human papillomavirus genome into the host chromosome is associated with the progression of untreated lesions to invasive cancer – this is also associated with the loss or disruption of E2, E6, and E7 oncogene expression upregulation.

Cervical Cancer

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Mechanisms of Human Papillomavirus-Induced Oncogenesis

E6 and E7 form interactions that are well characterized with the end products of the tumor suppressor gene; E6 interacts with TP53, and E7 interacts with retinoblastoma proteins. TP53 protects genomic integrity as it forces apoptosis or causes cell cycle arrest until DNA replication errors are repaired. TP53 is targeted for degradation by E6 via the ubiquitin pathway. This subsequently prevents apoptosis and enables these potentially transformed cells (as a consequence of accumulated mutation) to replicate.

E7 contributes to oncogenesis through its interaction with, and subsequent targeting for degradation of, the retinoblastoma family members RB1, RBL1, and RBL2. These are known as pocket proteins. As a consequence of degradation, the transcription factors of the E2F family are released and activated.

These transcription factors drive the expression of the genes involved in the next phase of the cell cycle (S-phase); these include cycling's A and E, which results in entry into the cell cycle and the promotion of DNA synthesis (characteristics of the S-phase).

The human papillomavirus also perpetuates oncogenesis via immune evasion. High-risk papillomaviruses have evolved several mechanisms that minimize immune detection:

  • E6 decreases the expression of CDH1 on the cell surface, reducing the identity as human papillomavirus antigens
  • Toll-like receptors activate antigen-presenting cells; E6 and E7 inhibit the expression of toll-like receptor 9. Moreover, E7 reduces the expression of a constituent of the peptide processing and presentation pathway, TAP1, which prevents the activation of cytotoxic T cells.
  • E6 and 7 inhibition of interferon synthesis through specific interactions with proteins such as IRF-1 and IRF-3, as well as downregulation of proinflammatory cytokines.

There is a well-established link between the human papillomavirus and cervical cancer. The virus is sexually transmitted on has increased in prevalence worldwide over the most recent decades. Through the comprehensive roll-out of cervical screening programs, an epidemic of cervical cancer has been avoided. This roll-out has not been equivocal; however, developing countries, at present, are disparate in their cervical cancer burden, owing to limitations in human papillomavirus vaccination and cervical screening implementations.

Read Next: Hybrid Capture-Based Human Papillomavirus Detection Versus PCR

References:

  • Münger K, Baldwin A, Edwards KM, et al. (2004) Mechanisms of human papillomavirus-induced oncogenesis. J Virol. doi:10.1128/JVI.78.21.11451-11460.2004.
  • Burd EM. (2003) Human papillomavirus and cervical cancer. Clin Microbiol Rev. doi:10.1128/CMR.16.1.1-17.2003.
  • World Health Organization. Human papillomavirus (HPV) and cervical cancer. Available at: https://www.who.int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer. Last accessed December 2021.
  • Crosbie EJ,Einstein MH, Franceschi S, et al. (2013). Lancet.  doi:10.1016/S0140-6736(13)60022-7.

Further Reading

Last Updated: Jan 31, 2023

Hidaya Aliouche

Written by

Hidaya Aliouche

Hidaya is a science communications enthusiast who has recently graduated and is embarking on a career in the science and medical copywriting. She has a B.Sc. in Biochemistry from The University of Manchester. She is passionate about writing and is particularly interested in microbiology, immunology, and biochemistry.

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