Comparative study of histologic and chromosomal abnormalities in cervical neoplasia

Kirkland, James A.; Stanley, Margaret; Cellier, K. M.

doi:10.1002/1097-0142(196711)20:11<1934::aid-cncr2820201122>3.0.co;2-4

Cited by 61 publications

(6 citation statements)

References 23 publications

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“…Cells containing integrated high-risk HPV acquire a strong growth advantage over cells harbouring episomal high-risk HPV and undergo clonal expansion. These cells also show increased genomic instability [30,31] and therefore have a greater probability of acquiring the secondary genomic abnormalities that may drive malignant progression [32].…”

Section: Ifn Response and Progression In Cervical Neoplasiamentioning

confidence: 99%

HPV: from infection to cancer

Stanley

Pett

Coleman

2007

Biochemical Society Transactions

202

167

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Infection with HPV (human papillomavirus) 16 is the cause of 50% or more of cervical cancers in women. HPV16 infection, however, is very common in young sexually active women, but the majority mount an effective immune response and clear infection. Approx. 10% of individuals develop a persistent infection, and it is this cohort who are at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma. Effective evasion of innate immune recognition seems to be the hallmark of HPV infections, since the infectious cycle is one in which viral replication and release is not associated with inflammation. Furthermore, HPV infections disrupt cytokine expression and signalling with the E6 and E7 oncoproteins particularly targeting the type I IFN (interferon) pathway. High doses of IFN can overcome the HPV-mediated abrogation of signalling, and this may be the basis for the therapeutic effects on HPV infections of immune-response modulators such as the imidazoquinolones that induce high levels of type I IFNs by activation of TLR (Toll-like receptor) 7. Using the unique W12 model of cervical carcinogenesis, some of these IFN-related interactions and their relevance in the selection of cells with integrated viral DNA in cancer progression have been investigated. Our data show that episome loss associated with induction of antiviral response genes is a key event in the spontaneous selection of cervical keratinocytes containing integrated HPV16. Exogenous IFN-beta treatment of W12 keratinocytes in which the majority of the population contain episomes results only in the rapid emergence of IFN-resistant cells, loss of episome-containing cells and a selection of cells containing integrated HPV16 in which the expression of the transcriptional repressor E2 is down-regulated, but in which E6 and E7 are up-regulated.

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Section: Ifn Response and Progression In Cervical Neoplasiamentioning

confidence: 99%

HPV: from infection to cancer

Stanley

Pett

Coleman

2007

Biochemical Society Transactions

202

167

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“…More likely, these tumors arise from an initial tetraploidization event that is followed by frequent chromosome loss (Shackney et al, 1989). Indeed, tetraploid nuclei and supernumerary centrosomes have been noted in the early stages of some solid tumors (Reid et al, 1996; Kirkland et al, 1967). Importantly, tetraploidization after chemically-induced cytokinesis failure has been shown to promote tumorigenesis in p53-deficient mouse mammary epithelial cells (Fujiwara et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Telomere-Driven Tetraploidization Occurs in Human Cells Undergoing Crisis and Promotes Transformation of Mouse Cells

2012

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SUMMARY Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide DNA damage. We now report that endoreduplication and mitotic failure occur during telomere crisis in human fibroblasts and mammary epithelial cells and document the role of p53 and Rb in repressing tetraploidization. Using an inducible system to generate transient telomere damage, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Similar to human solid cancers, the resulting tumors evolved subtetraploid karyotypes. These data establish that telomere-driven tetraploidization is induced by critically short telomeres and has the potential to promote tumorigenesis in early cancerous lesions.

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“…Genomic instability, producing specific genomic aberrations, is also associated with the development and progression of cervical carcinomas (13)(14)(15)(16). The temporal relationship between integration of HR-HPV and acquisition of a genetically unstable environment has not previously been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

et al. 2004

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Whereas two key steps in cervical carcinogenesis are integration of high-risk human papillomavirus (HR-HPV) and acquisition of an unstable host genome, the temporal association between these events is poorly understood. Chromosomal instability is induced when HR-HPV E7 oncoprotein is overexpressed from heterologous promoters in vitro. However, it is not known whether such events occur at the "physiologically" elevated levels of E7 produced by deregulation of the homologous HR-HPV promoter after integration. Indeed, an alternative possibility is that integration in vivo is favored in an already unstable host genome. We have addressed these issues using the unique human papillomavirus (HPV) 16-containing cervical keratinocyte cell line W12, which was derived from a low-grade squamous intraepithelial lesion and thus acquired HPV16 by "natural" infection. Whereas W12 at low passage contains HPV16 episomes only, long-term culture results in the emergence of cells containing integrated HPV16 only. We show that integration of HPV16 in W12 is associated with 3 deletion of the E2 transcriptional repressor, resulting in deregulation of the homologous promoter of the integrant and an increase in E7 protein levels. We further demonstrate that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein. Whereas intermediate E7 levels are associated with numerical chromosomal abnormalities, maximal levels are associated with both numerical and structural aberrations. HR-HPV integration is likely to be a critical event in cervical carcinogenesis, preceding the development of chromosomal abnormalities that drive malignant progression.

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Comparative study of histologic and chromosomal abnormalities in cervical neoplasia

Cited by 61 publications

References 23 publications

HPV: from infection to cancer

HPV: from infection to cancer

Telomere-Driven Tetraploidization Occurs in Human Cells Undergoing Crisis and Promotes Transformation of Mouse Cells

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

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