Cancer remains a major global health challenge, imposing a significant burden on individuals, families, and healthcare systems
The link between viruses and cancer was first proposed in the early 20th century when Ellermann and Bang demonstrated that cell-free tumor extracts could transmit avian leukemias, followed by Rous’s identification of a viral origin for sarcomas in 1911
Among oncogenic viruses, human papillomaviruses (HPVs) are one of the most well-established contributors to cancer. HPVs belong to the Papillomaviridae family and are non-enveloped viruses with a double-stranded DNA genome of approximately 8,000 base pairs. Based on their oncogenic potential, HPVs are classified into low-risk and high-risk types
Despite the widespread prevalence of HPV infections, most individuals with high-risk HPV do not develop cancer. However, persistent infection, combined with genetic susceptibility and other environmental factors, increases the risk of malignant transformation. Vaccination against high-risk HPV strains has been shown to significantly reduce the incidence of HPV-associated cancers, making prevention an effective strategy in combating this viral-induced oncogenesis.
This manuscript explores the complex relationship between HPV and cancer, with a particular focus on the molecular mechanisms of oncogenesis driven by HPV infection. We will examine the role of E6 and E7 oncoproteins in tumor progression, the epidemiology of HPV-related cancers, and emerging strategies for diagnosis, prevention, and treatment.
Human papillomavirus (HPV) is a widespread virus known for its ability to infect epithelial cells of the skin and mucosa, leading to both benign and malignant lesions. It is primarily transmitted through direct skin-to-skin contact, including sexual contact, making it one of the most common sexually transmitted infections worldwide.
We begin with an exploration of HPV virology. HPV is a member of the Papillomaviridae family, one of the oldest known viral families
Next, we delve into the mechanisms of carcinogenesis. The HPV genome is organized into three distinct regions: (1) the early (E) region, which includes the E1, E2, E4, E5, E6, and E7 genes involved in viral replication; (2) the late (L) region, responsible for encoding the primary (L1) and secondary (L2) capsid proteins; and (3) a non-coding region (NCR), also referred to as the long control region (LCR), positioned between the L1 and E6 open reading frames (ORFs) (
Following this, we review the epidemiology of HPV-related cancers. Approximately 280 types of papillomaviruses have been identified in vertebrates
Among the various HPV types, HR-HPVs 16, 18, 31, 33, and 45, along with LR-HPVs 6 and 11, are the most prevalent strains
Finally, we cover the diagnostic, preventive, and therapeutic strategies for HPV-related cancers. This includes current HPV screening methods, particularly for cervical cancer, the global impact of HPV vaccination programs, and the evolving treatment landscape for HPV-induced cancers. The section concludes with a discussion of the ongoing challenges in the fight against these cancers, as well as potential future directions for research and clinical applications.
For HPV to penetrate and initiate an infectious process, there must be continuity in the epithelial tissues so that the virus can come into contact with the permissive basal cells. Once the virus infects these target cells, viral replication begins in the spinous layer. The assembly of virions occurs in the upper strata of the epithelium, specifically in the differentiated granular cells, as this maturity event is essential for successful viral assembly. Finally, in the squamous cells, virions are expelled and may initiate a new infection cycle
As mentioned earlier, the HPV viral genome is divided into three main regions: the early (E) region, the late (L) region, and the non-coding region (NCR), also known as the long control region (LCR). The early region encodes proteins involved in viral replication (E1, E2) and transformation (E6, E7), while the late region encodes the major capsid proteins L1 and L2 that form the viral structure. The non-coding region contains regulatory elements essential for viral DNA replication and transcription. HPV types are categorized into low-risk (LR) and high-risk (HR) groups based on their association with benign or malignant lesions. High-risk HPV types, such as HPV-16 and HPV-18, are closely linked to cancer development, particularly cervical cancer, due to their ability to disrupt normal cell cycle control through the activity of E6 and E7 oncoproteins, which target tumor suppressor proteins like p53 and retinoblastoma protein (pRB)
The process of high-risk HPV infection initiates when the virus infiltrates host cells via micro-trauma to the genital epithelium during sexual intercourse. This facilitates the active proliferation of diverse HPV types, enabling the viral capsid protein L1 to attach to receptors on basal cells, leading to internalization of the virus through endocytosis, with HPV types 16 and 18 employing Clathrin-mediated endocytosis, while HPV 31 utilizes Caveolin-mediated endocytosis
This mechanism clearly shows that HPV-induced carcinogenesis begins with the expression of E6 and E7 oncoproteins that block p53 and RB and that immortalize the compromised cell, and thereby, the functionality of their DNA, also, certain experiments have shown that the baseline E6 and E7 expression in HPVs is very low since the E2 protein, through the URR regulatory region remains virtually silenced. Given this, it is evident that only a virus infection with high viral concentrations could generate enough E6 units and E7 to initiate this mechanism. In fact, there is a greater chance of neoplastic transformation in infections with a high viral load, where the immune system is unable to eradicate the infection. We may know the mechanism of immortalization with such a low viral load, though, because it has been shown that some persistent infections with low viral loads produce an effective tumor phenotype. This question was addressed by the finding that the viral DNA was broken up and incorporated into the cellular genome in the majority of carcinomas. Most of the time, some virus pieces in the E2 area losing its ability to act on URR and give the command to maintain the expression of E6 and E7 repressed, thus, a small amount of virus will be deregulated and produce copious amounts of E6 and E7 protein, which begins the process of blocking of p53 and RB so effectively
Transmission of HPV virus occur by direct contact between the skin and mucous membranes, with sexual relationships is the main form of contact, although there are others such as those which occur between mother and child at the time of childbirth. Rubbing and moisture promote transmission. It appears that transmission through objects such as surgical materials, clothing, and fomites in general occurs. However, the entire virus not just DNA fragments must be spread for infection to occur.
The first cancer linked to HPV was CC. With about 604,000 new cases in 2020, it ranks fourth among the most common cancers in women. 90% of CC deaths in 2020 happened in low- and middle-income countries. HIV-positive women are more likely to acquire CC, accounting for about 5% of all cases.
It was found in 2020 by GLOBOCAN that there were 324,635 yearly instances of melanoma skin cancer
In accounting for 70% cases of esophageal cancer, it was found that this cancer predominantly affects men. It classifies as the sixth leading cause of cancer-related death globally, with approximately 604,000 new cases and 544,000 deaths reported each year. This cancer is primarily divided into two subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC represents over 85% of all cases and is most prevalent in regions such as East and South-Central Asia, Eastern and Southern Africa, and Northern Europe. In contrast, EAC is more common in Western countries and its incidence has been rising steadily. Studies show that HPV infection is present in 20% of males and 18.4% of females with ESCC. The most frequently identified HPV genotypes in ESCC include HPV16 (11.4%), followed by HPV18 (2.9%), HPV6 (2.1%), HPV11 (2.0%), HPV52 (1.1%), HPV33 (0.8%), and HPV31 (0.6%)
With 2,206,771 occurrences in both males and females combined, LC was the second most common type of cancer in 2020. Although tobacco use is the main risk factor for 80–90% of LC cases, there are other possible causes as well. It ranks as the seventh leading cause of cancer-related death and the eleventh most common kind of cancer. LC can also happen to those who don't smoke. According to research, HPV infection may be a major risk factor for LC in nonsmokers and ought to be taken into account while assessing patients
The cervix, anogenital region, head and neck, and skin are among the body areas where HPV has a known association with a number of cancers. However, HPV's direct involvement in malignancies like glioblastoma, colorectal, lung, and breast cancers is still debatable, even though it might contribute to early changes throughout time. Plasmids harboring HPV 16 and 18 immortalized mammary epithelial cells, as demonstrated by Band et al.
The most common form of anal cancer, anal squamous cell carcinoma SCC, is associated with anal HPV infections. About 90% of anal SCC is caused by HPV
After ovarian, uterine, and CC cancers, vulvar cancer is the fourth most frequent type of gynecological cancer, accounting for 3–5% of all gynecological malignancies. Every year, about 27,000 women worldwide receive a vulvar cancer diagnosis. Asia has recorded the lowest incidence of vulvar cancer, whereas Europe, North and South America, and Oceania had the highest rates
The Food and Drug Administration (FDA) currently approved three preventive HPV vaccines; (i) Gardasil (tetravalent vaccine that works against HPVs 18, 16, 11 and 6), (ii) Cervarix (bivalent vaccine that works against high risk HPVs 18 and 16) and (iii) Gardasil-9 (nonavalent vaccine that works against HPVs 58, 52, 45, 33, 31, 18, 16, 11 and 6). Also, there are currently three other HPV vaccinations on the market: Cervavac, Walwax, and Cecolin
Walvax and Cecolin, on the other hand, are prescribed in two doses to girls aged 9 to 14. Over 90% of main high-risk HPVs are protected against by these vaccines. These vaccines have been created with recombinant DNA technology, in which vaccines employ virus-like particles, or VLPs, which have been demonstrated to be extremely immunogenic, completely safe, and have been shown to produce high antibody titers and herd immunity when given to teenage girls between the ages of 9 and 19
CRISPR/Cas9 is a novel genetic research technique that has replaced zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN). For every new target site, ZNFs and TALENs require recoding of proteins using large DNA segments (500–1,500 bp). In contrast, CRISPER-Cas9 can be easily modified to target any genomic sequence by changing the 20 bp protospacer of the guide RNA
HPV causes tumor spread and transforming normal cells into malignant ones by using its oncoproteins to boost viral load and maintain viral replication. Additionally, the E6 and E7 oncoproteins inactivate the p53 and pRB genes, which are essential for carcinogenesis, and deactivate the apoptotic pathway. This happen by initiation of unwinds HPV's supercoiled circular DNA by the E1 and E2 complex
Before receiving therapy, both animal and human studies have been conducted to determine the benefits and drawbacks of utilizing viral delivery mechanisms, such as adenoviruses and lentiviruses, compared with non-viral delivery mechanisms, including electroporation, microinjection and lipid-based nano particles, for this therapy. It has been found that the CRISPR-Cas9 technique can effectively modify the E7 and E6 genes, resulting in reactivation of the pRB and p53 genes, respectively
Short/small interfering RNAs (siRNAs) are double-stranded RNAs with two base pair 3' overhangs and a length of almost 21 nucleotides. Through the mRNA degradation of particular target genes in the cytoplasm, they reduce gene expression