<i>In vitro</i> Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

Gray, Eve; Pett, Mark R.; Ward, Dawn; Winder, David M.; Stanley, Margaret; Roberts, Ian; Scarpini, Cinzia G.; Coleman, Nicholas

doi:10.1158/0008-5472.can-09-3335

Cited by 74 publications

(111 citation statements)

References 43 publications

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“…1 However, a subset of HPV16-positive invasive cervical carcinomas maintains viral DNA only as episomes 21 and besides the integrated monomeric forms, head-to-tail concatemers of fulllength HPV genomes flanked by truncated copies also exist. 22 Finally, the E5 protein was identified by mass spectrometry in CaSki cells giving the definitive proof that HPV-16 E5 does exist and it may contribute to the malignant phenotype of some cervical cancers, even in cells exclusively containing an integrated HPV genome.…”

Section: Discussionmentioning

confidence: 99%

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Paolini¹,

Curzio²,

Cordeiro

et al. 2016

Human Vaccines & Immunotherapeutics

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HPV16 persistent infection is a well-known condition that precedes human cancer development. High risk HPV E5 proteins cooperate with E6/E7 oncogenes to promote hyper-proliferation of infected cells leading to possible cancer progression. Thus, presence of E5 viral transcripts could be a key marker of active infection and, in turn, a target of immunotherapy. Purpose of the study is to detect E5 transcripts in clinical samples and to explore the activity of novel anti-HPV16 E5 DNA vaccines. HPV transcripts were detected by PCR with specific primers encompassing the splice-donor sites of E5 transcript. For E5-based immunotherapies, 2 E5-based versions of DNA vaccines carrying whole E5 gene or a synthetic multiepitope gene were improved by fusion to sequence of PVX coat protein. These vaccines were challenged with a new luminescent animal model based on C3-Luc cell line. E5 transcripts were detected in clinical samples of women with HPV positive low-grade SIL, demonstrating the validity of our test. In C3 pre-clinical mouse model, vaccine candidates were able to induce a strong cellular immunity as indicated by ELISPOT assays. In addition, E5-CP vaccines elicited strong anti-tumor effects as showed by decreased tumor growth monitored by animal imaging. The tumor growth inhibition was comparable to those obtained with anti-E7 DNA vaccines. In conclusion, detection of E5 transcripts in clinical samples indicates that E5 is a possible target of immunotherapy. Data from pre-clinical model demonstrate that E5 genetic immunization is feasible, efficacious and could be utilized in clinical trials.

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Section: Discussionmentioning

confidence: 99%

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Paolini¹,

Curzio²,

Cordeiro

et al. 2016

Human Vaccines & Immunotherapeutics

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“…In the HPV16-containing W12 cervical keratinocyte cell line, which mimics the CIN-invasive carcinoma spectrum in vitro, HPV16 integration with consequent disruption/deletion of E2 leads to increased expression of the viral oncogenes (62). Cells containing integrated high-risk HPV acquire a strong growth advantage over cells harboring episomal high-risk HPV, and they undergo clonal expansion (30,32). These cells also show increased genomic instability and therefore have a greater probability of acquiring the secondary genomic abnormalities that may drive malignant progression (61).…”

Section: Hpv Compromises Innate Defenses In Keratinocytesmentioning

confidence: 99%

Epithelial Cell Responses to Infection with Human Papillomavirus

2012

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SUMMARY Human papillomavirus (HPV) infection of the genital tract is common in young sexually active individuals, the majority of whom clear the infection without overt clinical disease. Most of those who do develop benign lesions eventually mount an effective cell-mediated immune (CMI) response, and the lesions regress. Regression of anogenital warts is accompanied histologically by a CD4 + T cell-dominated Th1 response; animal models support this and provide evidence that the response is modulated by antigen-specific CD4 + T cell-dependent mechanisms. Failure to develop an effective CMI response to clear or control infection results in persistent infection and, in the case of the oncogenic HPVs, an increased probability of progression to high-grade intraepithelial neoplasia and invasive carcinoma. Effective evasion of innate immune recognition seems to be the hallmark of HPV infections. The viral infectious cycle is exclusively intraepithelial: there is no viremia and no virus-induced cytolysis or cell death, and viral replication and release are not associated with inflammation. HPV globally downregulates the innate immune signaling pathways in the infected keratinocyte. Proinflammatory cytokines, particularly the type I interferons, are not released, and the signals for Langerhans cell (LC) activation and migration, together with recruitment of stromal dendritic cells and macrophages, are either not present or inadequate. This immune ignorance results in chronic infections that persist over weeks and months. Progression to high-grade intraepithelial neoplasia with concomitant upregulation of the E6 and E7 oncoproteins is associated with further deregulation of immunologically relevant molecules, particularly chemotactic chemokines and their receptors, on keratinocytes and endothelial cells of the underlying microvasculature, limiting or preventing the ingress of cytotoxic effectors into the lesions. Recent evidence suggests that HPV infection of basal keratinocytes requires epithelial wounding followed by the reepithelization of wound healing. The wound exudate that results provides a mechanistic explanation for the protection offered by serum neutralizing antibody generated by HPV L1 virus-like particle (VLP) vaccines.

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“…Furthermore, the integration process has not been systematically studied in primary human keratino-cytes-the natural host for HPV infection. Conclusions about the consequences of integration in the host cell have been largely based on studies of established cell lines derived from cervical cancers, such as SiHa, HeLa, and CaSki, or lines derived from other sources (12), cell lines derived from cervical intraepithelial neoplasia (CIN) lesions (W12E [19] or CIN612 [14]), or spontaneously immortalized epithelial cells (such as NIKS 3]) that exhibit inherent chromosomal instability and altered growth phenotypes compared to primary mucosal keratinocytes.…”

mentioning

confidence: 99%

Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Lace

Anson

Klußmann

et al. 2011

J Virol

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Many human papillomavirus (HPV)-positive high-grade lesions and cancers of the uterine cervix harbor integrated HPV genomes expressing the E6 and E7 oncogenes from chimeric virus-cell mRNAs, but less is known about HPV integration in head and neck cancer (HNC).Mucosal high-risk (HR) human papillomavirus (HPV) types are found in nearly 100% of carcinomas of the uterine cervix, many anogenital cancers, and ϳ25% of head and neck cancers (HNC) (9, 13, 42). The most common HR HPV is type 16, found in over 50% of cervical cancers and 90 to 95% of HPVpositive HNCs. In persistent infection, HPV genomes are maintained as circular, unintegrated plasmids that persist in the nuclei of infected cells (see Fig. 1A). In contrast, HR HPV DNA found in cervical cancer specimens is frequently disrupted and integrated in the cellular genome in a way that potentially alters the expression program of the viral early gene region and/or the host genome (2,5,8,21,23,24,31,43). The integrated HR HPV fragments in high-grade precancerous cervical lesions, cervical carcinomas, and derived cell lines express the viral transforming genes E6 and E7 from chimeric virus-cell mRNAs, while the downstream early genes that are required for viral replication and regulated viral gene expression are disrupted or silenced (33,37,47,55). Further, chimeric virus-cell mRNAs may be more stable than the viral early mRNAs, which harbor a 3Ј destabilization motif (20,53). In addition, some integration sites in cervical cancer and precursor lesions have been found near potential growth control genes (11,40,55).Advances in keratinocyte culture techniques have permitted the study of the life cycle of HR HPV types that replicate efficiently and persist in primary human keratinocytes, such as 34,35), and to a more limited extent 36). However, relatively little is known about the progression of the infected cell toward a malignant phenotype in vivo or in culture. While some cervical cancers have been shown to harbor extrachromosomal HPV DNA, it is apparent that integration of viral DNA accompanied by disruption of the integrity of the HR HPV genomes represents a common, albeit not absolutely obligatory, step associated with carcinogenic progression associated with the genital tract (42, 57). The majority of cervical carcinomas caused by the two most common HR HPV types, HPV-16 and -18, contain integrated viral sequences (52) that express E6-E7 from chimeric, spliced virus-cell transcripts. However, the genetic structure and expres-

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In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

Cited by 74 publications

References 43 publications

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Epithelial Cell Responses to Infection with Human Papillomavirus

Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

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