Characteristics, Events, and Stages in Tumorigenesis
Franklyn De Silva, Jane Alcorn in The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
In carcinogenesis, the immune system can play a dual role, either initiating wound healing-related pathway signaling to assist in fostering an environment favorable to cancer or eliminating cells that have undergone malignant transformation due to early cancer-initiating events (e.g., immunoediting) [959–961]. Cancers associated with immunosuppression might be a consequence of tumor viruses [929, 946, 954, 962]. Aging and loss of immune surveillance for epitopes of specific viral cytotoxic T-cells can result in the viral promotion of cancers [946, 963, 964]. Common to tumors of persistent latent or pseudo-latent infections is the discontinuation of tumor virus replication that form infectious virus particles (i.e., lytic replication), which is an important strategy for immune evasion [946]. Viruses which typically exist as naked nucleic acids in a plasmid or episome inside the cell rely on the machinery of the host cell to replicate upon cell division [946, 965]. Host cell death is triggered as a consequence of the productive replication of viruses (i.e., cytopathic effect); consequently, virus latency may seem to best explain the link with virus-mediated tumorigenesis [946, 965]. Yet, this effect is harnessed to target and eliminate cancer cells through cell death, which underlies the general premise behind viral oncolytic therapies used in immunotherapy (i.e., oncolytic virotherapy) [946, 965–968]. Here, oncolytic viruses (OV) are used to preferentially remove neoplastic cells, sparing healthy cells (e.g., HSV-1 based OV) [968–971].
Role of High-Risk Human Papillomaviruses in Breast Carcinogenesis
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
The HPV genome is about 7.9 kb in size and encodes early (E) and late (L) proteins and noncoding region (NCR) (Figure 8.1). Early are designated as E1, E2, E4, E5, E6, and E7, and late proteins as L1 and L2. In a host cell, the viral DNA is transcribed as a polycistronic mRNA that is cleaved to yield the different viral proteins. The E1 and E2 genes are expressed first upon viral entry into the host cell, and they encode viral DNA replication proteins (Motoyama et al. 2004). The E5 protein along with E1, E2, and E4 are replication proteins that allow the viral DNA (Figure 8.1) to be replicated as an episome in low copy number (Longworth and Laimins 2004a; Doorbar 2005). During the process of differentiation of epithelial cells, the p670 promoter on viral DNA causes increased expression of E1, E2, E4, and E5 proteins, resulting in increased viral DNA amplification. Therefore, E5 is a viral replication protein that helps in replicating the viral episomal DNA (Moody and Laimins 2009).
Human Papillomavirus (HPV)
Meera Chand, John Holton in Case Studies in Infection Control, 2018
HPV is a double-stranded DNA virus, which characteristically integrates into the host cell genome. HPV preferentially infects squamous epithelial cells, including skin and anogenital and respiratory mucosa. Most HPV infections are cleared rapidly; the median duration of a new infection is estimated to be around eight months, with 70% of infections cleared within one year and 90% within two years. Latent infections are not well defined, but an estimated 10% are transforming type infections—probably where the viral episome is maintained in the basal epithelial layer. The process of transformation is driven, at least in part, by two viral oncogenes, E6 and E7. These genes encode products that subvert the host cellular machinery to the advantage of the virus and its replication strategy, preventing apoptosis (programmed cell death) and promoting cell-cycle progression. Cell-cycle deregulation is thought to involve many other steps, and in some cases may be associated with the integration position of the viral episome (viral genetic material) in the host genome, which can affect transcription of host and viral gene products.
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
An ideal gene therapy would be a life-long treatment, and, despite the long half-life of AAV episomes, they may not be able to provide decades of transgene persistence. As such, methods are being developed to deliver genome-editing components together with therapeutic constructs that may provide a more lasting response. This would combine the integrative benefit of LV with the tropism control exhibited by AAV (and certain serotypes). The principle is to encourage the integration of therapeutic DNA into known and ‘benign’ loci. For example, the AAVS1 locus is a natural integration site for wild-type AAV [84]. While recombinant AAV predominantly reside episomally, it is possible to use double-strand break-mediated homologous recombination to insert the desired therapeutic construct into the AAVS1 locus [84]. Alternatively, methods to achieve hepatocyte-specific editing of the albumin locus have been developed [85]. These integrations utilize the natural albumin promoter to attain high levels of liver-specific expression of a desired protein with reduced potential for genotoxicity due to heterologous transgenic promoters. The latter method is under clinical investigation for the treatment of MPS I and MPS II in phase I trials (NCT02702115 and NCT03041324). An analogous method is also under investigation for the treatment of Fabry disease [86,87].
Promise of gene therapy to treat sickle cell disease
Published in Expert Opinion on Biological Therapy, 2018
Zulema Romero, Mark DeWitt, Mark C. Walters
Adeno-associated virus (AAV): are non-enveloped viruses with a linear, single-stranded DNA of 4.7kb encoding the replication (rep) and capsid (cap) genes between 145-bp inverted terminal repeats (ITRs). Both the sense and antisense strands of the AAV DNA are packaged into AAV capsids with equal frequency [92]. Recombinant AAV (rAAV) has a long track record in gene therapy [93,94]. In the absence of Rep proteins, the rAAV becomes an effective vehicle to deliver DNA to the nucleus. The ITR-flanked transgenes or DNA templates are maintained as episomes that are not integrated [94]. AAV serotype 6 (AAV6) has been found to be the most efficient at transducing human HSPC. To date, the highest rates of HDR in HSPC under in vitro culture conditions were observed with AAV6 as a HDR donor, although there appears to be considerable inter-individual variability in transduction efficiency [95].
Evolving role of human papillomavirus as a clinically significant biomarker in head and neck squamous cell carcinoma
Published in Expert Review of Molecular Diagnostics, 2019
Caitlin McMullen, Christine H. Chung, Juan C. Hernandez-Prera
Most HPV infections are cleared by immune response without causing cancer; however, HR viral subtypes may not clear as rapidly, and its persistence induced malignant transformation [21]. After transmission, the virus binds to different cell surface receptors and enters the cells located in the reticulated epithelium within in the tonsillar crypts of the host [22]. The viral DNA migrates to the nucleus and establishes itself as an episome at a low copy number or integrates to the host cell genome. After integration, the host cellular machinery coordinates viral replication, amplification, and transcription, which lead to the expression of oncoproteins [16]. HR viral subtypes produce oncoproteins that inactivate tumor suppressor genes and initiate the malignant transformation of the host cell. More specifically, the viral E6 oncoprotein promotes degradation of the p53 protein by ubiquitination, which disrupts the p53-mediated cellular response to DNA damage [23,24]. The E7 oncoprotein ubiquitinates the retinoblastoma protein (pRb), and its degradation causes in the release of E2F which then initiates the transcription of S phase genes [25,26]. In an attempt to inhibit the E7-mediated cell cycle progression to the S phase, feedback loops are activated and result in increased expression of host protein, p16INK4A [27].
Related Knowledge Centers
- Cpg Site
- DNA
- Gene Expression
- Gene Therapy
- Plasmid
- Metaphase
- Adeno-Associated Virus
- Epstein–Barr Virus
- Scaffold/Matrix Attachment Region