HPV Strains and Oncogenicity

HPV is Both a Necessary and a Sufficient Cause of Cervical Cancer

"A recent report that 93 percent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an understatement," due to underdetection. On reanalysis of the specimens, HPV was found in most supposedly HPV-negative cases, and "the worldwide HPV prevalence in cervical carcinomas is 99.7 percent." (Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. JM Walboomers et al. J Pathol 1999 Sep;189(1):12-19).

The human papillomavirus type 16 E6 gene alone is sufficient to induce carcinomas in transgenic animals. S Song, HC Pitot, PF Lambert. J Virol 1999 Jul;73(7):5887-5893. "We generated K14E6 transgenic mice in which the HPV16 E6 gene was expressed in the basal layer of epithelia, using the hK14 promoter. Expression of E6 increased cell proliferation and induced epidermal hyperplasia. Skin tumors developed in adult K14E6 mice with an incidence of about 7% at 1 year of age. In contrast to the tumors derived from K14E7 transgenic mice, which were primarily benign, tumors derived from K14E6 transgenic mice were mostly malignant, indicating that E6 alone not only is sufficient to induce tumors but may contribute to the development of malignancy in animals." "Inactivation of p53, however, may not be the only mechanism for E6-induced carcinogenesis. The K14E6 mice that developed tumors also displayed hyperplastic changes in the epidermis, a property that, as discussed above, cannot be ascribed to E6's inactivation of p53. It is likely that the hyperproliferation induced by E6 is important for its carcinogenesis. Another activity that may contribute to E6-associated carcinogenesis is its apparent inhibition of cellular differentiation. Cancer cells usually lack the ability to terminally differentiate. In this study, we found that the suprabasal compartment of the K14E6 transgenic epidermis stained for K14, indicating that E6 may also perturb cellular differentiation; this perturbation was caused by p53-independent activities of E6."

The Discovery of HPV 16

A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. M Durst, L Gissmann, H Ikenberg, H Zur Hausen. Proceedings of the National Academy of Sciences 1983 Jun 15;80(12):3812-3815. 61.1% of cervical carcinomas carried an HPV DNA sequence which had little or no resemblance to those of known HPV types. It was designated HPV 16.

HPV Strains and Oncogenicity

The effect of functional inactivation of TP53 by HPV-E6 transformation on the induction of chromosome aberrations by gamma rays in human tumor cells. JL Schwartz, KJ Russell. Radiat Res 1999 Apr;151(4):385-390. "While aberration frequencies were similar at early harvest times, there was evidence for a subpopulation of more heavily damaged cells in the E6-transformed cells that cycled into late mitosis. Holding cells noncycling for 24 h to allow repair of potentially lethal damage eliminated this subpopulation of more heavily damaged cells. The E6-transformed cells also had higher levels of chromatid-type aberrations and sister chromatid exchanges, consistent with an additional defect in kinetics of repair of base damage that is associated with the E6 transformation. Holding cells noncycling for 24 h eliminated the elevated levels of chromatid-type aberrations and sister chromatid exchanges. These studies demonstrate that E6 transformation of human tumor cells will influence both the frequency and types of chromosome aberrations observed after radiation exposure, and that these effects are related to the expression of potentially lethal damage."

Relationships between 80 human papillomavirus genotypes and different grades of cervical intraepithelial neoplasia: association and causality. T Matsukura, M Sugase. Virology 2001 Apr 25;283(1):139-147. 38 skin and 42 genital HPV types were sought in 386 biopsy samples. "[S]ingle genital, but no skin's HPVs were identified with more than 10 copies per cell in 354 CIN (88 CIN I, 94 CIN II, and 172 CIN III). HPVs 40, 42, 43, 54, 62, or 71 was found in 10 CIN I, while HPVs 18, 30, 39, 51, 56, 59, 66, 68, 69, or 82 was found in 35 CIN I, 20 CIN II, or 8 CIN III. On the other hand, HPVs 16, 31, 33, 35, 52, 58, or 67 was identified in 43 CIN I, 74 CIN II, or 164 CIN III. The results are strongly indicative that most genital HPVs have potency to induce CIN I; however, HPV 16 and its closely related types are able to efficiently induce CIN III. We discuss the definition of causal HPV for CIN with regard to viral prevalence and viral load."

Variation in the E2-binding domain of HPV 16 is associated with high-grade squamous intraepithelial lesions of the cervix. A Gainnoudis, M Duin, PJ Snijders, CS Herrington. Br J Cancer 2001 Apr;84(8):1058-1063. "[D]isruption of the regions of E2 analysed was significantly more frequent in high-grade lesions, and there was a significant association between the 3684C-A variant in the E2 DNA binding domain and high-grade histology suggesting that this variant may be important in progression to high-grade intraepithelial disease."

Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study. J Berumen, RM Ordonez, E Lazcano, J Salmeron, SC Galvan, RA Estrada, E Yunes, A Garcia-Carranca, G Gonzalez-Lira, A Madrigal De- La Campa. J Natl Cancer Inst 2001 Sep 5;93(17):1325-1330; and: Aggressive HPV variant common among Mexican women with cervical cancer. Medscape - Reuters Health 2001 Sep 4.

CpG Methylation of Human Papillomavirus Type 16 DNA in Cervical Cancer Cell Lines and in Clinical Specimens: Genomic Hypomethylation Correlates with Carcinogenic Progression. V Badal, LS Chuang, EH Tan, S Badal, LL Villa, CM Wheeler, BF Li, HU Bernard. J Virol 2003 Jun;77(11):6227-6234. "In 81 patients from two different cohorts, the LCR and the E6 gene of HPV-16 DNA were found to be hypermethylated in 52% of asymptomatic smears, 21.7% of precursor lesions, and 6.1% of invasive carcinomas. This suggests that neoplastic transformation may be suppressed by CpG methylation, while demethylation occurs as the cause of or concomitant with neoplastic progression.... Two speculative and opposing views might explain this observation. The cell may have an antiviral defense that senses viral DNA as foreign and targets it for transcriptional repression. Alternatively, DNA methylation may be yet another example of the numerous strategies developed by HPVs that favor a subclinical, long-term maintenance of the viral infection. Such a model would be reminiscent of the life cycle of Epstein-Barr virus, which includes DNA methylation-dependent silencing of a specific promoter during one form of latency."

Human papillomavirus type 16 E6 and E7 genotypes in head-and-neck carcinomas. M Hoffmann, C Lohrey, A Hunziker, T Kahn, E Schwarz. Oral Oncol 2004 May;40(5):520-524. "Sequence analysis of the E6-E7 segments revealed three different HPV16 E6-E7 genotypes: the HPV16 prototype (6 of 21 cases), the E6 variant T350G (8 of 21 cases), and the E6-E7 variant A131G/C712A (7 of 21 cases). The E6 variants T350G and A131G have been associated with increased oncogenic potential in cervical cancer patients depending on host genetic factors. Their high prevalence in the HNSCC samples studied indicates that they may be important also in HNSCC development."

Enhanced oncogenicity of Asian-American human papillomavirus 16 is associated with impaired E2 repression of E6/E7 oncogene transcription. RM Ordonez, AM Espinosa, DJ Sanchez-Gonzalez, J Armendariz-Borunda, J Berumen. J Gen Virol 2004 Jun;85(Pt 6):1433-1444. "AA variants confer a nine times higher risk than E variants for cervical cancer... The low repression activity of E2 suggests that increased expression of E6/E7 oncogenes may occur much earlier in AA tumours. Therefore, the time period between viral infection and the emergence of a frankly invasive cancer may be decreased. This hypothesis could explain the association of the AA-c variant with patients 11 years younger than those with E variants (Berumen et al., 2001)."

The National Toxicology Program (NTP) belatedly classifies HPVs as known human carcinogens, 2004

Human papillomaviruses: Some genital-mucosal types. "Known to be a human carcinogen. First listed in the Eleventh Report on Carcinogens (2004)."

DNA aneuploidy and integration of human papillomavirus type 16 e6/e7 oncogenes in intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri. P Melsheimer, S Vinokurova, N Wentzensen, G Bastert, M von Knebel Doeberitz. Clin Cancer Res 2004 May 1;10(9):3059-3063. "RESULTS: DNA aneuploidy and viral genome integration were both associated with increasing dysplasia (P < 0.001, chi(2) test for trend). In addition, DNA aneuploidy was associated with increased viral integration (P < 0.01, Fisher's exact test). Nineteen of 20 (95%) lesions with integrated viral genomes had aneuploid cell lines; however, only 19 of 32 (59%) lesions with aneuploid cell lines had integrated viral genomes. CONCLUSIONS: These data support the hypothesis that aneuploidization precedes integration of HR-HPV genomes in the progression of cervical dysplasia. Accordingly, deregulated viral oncogene expression appears to result first in chromosomal instability and aneuploidization and is subsequently followed by integration of HR-HPV genomes in the affected cell clones."

Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line. CC Ragin, SC Reshmi, SM Gollin. Int J Cancer 2004 Jul 10;110(5):701-709. "Disruption of the E2 gene sequence due to viral integration results in upregulation of E6 and E7, which promote tumorigenesis by abrogating p53 and pRb functions.... Sequential FISH and spectral karyotyping identified integration sites on chromosomes 3, 6, 9q, 13q and t(1;8)(q;?). Restriction site-polymerase chain reaction (RS-PCR) was performed to identify the viral-cellular junctions. Sequence analyses confirmed integration sites at 9q31.1 and 6p21 and revealed a novel junction at 16p12.3. Subsequent chromosome breakage studies suggested that the observed viral-cellular integration sites may have occurred within common fragile sites. Additional studies using RT-PCR for E6--E7 viral transcripts showed oncoprotein expression from episomal and integrated viral sequences. Our results suggest that viral integration of HPV in SCCHN appears to occur nonrandomly through targeting specific chromosomal sequences prone to breakage."

Mechanisms of human papillomavirus-induced oncogenesis. K Munger, A Baldwin, KM Edwards, H Hayakawa, CL Nguyen, M Owens, M Grace, KW Huh. Journal of Virology 2004 Nov;78(21):11451-11460. Minireview. The oncogenic E6 and E7 protein-expressing sequences of human papillomavirus are integrated into human genes, and continue to express their proteins; while the E2 protein-expressing sequence, which supresses transcription, is often lost or its expression is disturbed. The E6 proteins bind to and degrade the cell's p53 tumor suppressor protein, and prevent it from causing the death of damaged or mutated cells. HPV E6 proteins also have independent transforming abilities. The E7 protein inactivates the cell's pRb protein, which results in excessive cell proliferation. The E6 and E7 proteins also collaborate to induce telemerase activity which immortalizes the cell, and they cause centrosome abnormalities during cell division as well.

Papillomavirus capsid mutation to escape dendritic cell-dependent innate immunity in cervical cancer. R Yang, CM Wheeler, X Chen, S Uematsu, K Takeda, S Akira, DV Pastrana, RP Viscidi, RBS Roden. J Virol 2005 Jun;79(11):6741-6750. Mutations occuring in high-grade CIN and cervical cancer evade recognition by the immune system.

The carcinogenicity of human papillomavirus types reflects viral evolution. M Schiffman, R Herrero, R Desalle, A Hildesheim, S Wacholder, AC Rodriguez, MC Bratti, ME Sherman, J Morales, D Guillen, M Alfaro, M Hutchinson, TC Wright, D Solomon, Z Chen, J Schussler, PE Castle, RD Burk. Virology 2005 Jun 20;337(1):76-84. Population-based study of 10,000 women in Costa Rica. "HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration.... Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence [emphasis added]. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5."

Two distinct activities contribute to human papillomavirus 16 E6's oncogenic potential. SJ Simonson, MJ Difilippantonio, PF Lambert. Cancer Res 2005 Sep 15;65(18):8266-8273. "A very different finding was made when we monitored carcinoma development, a measure of progression. Here, we found that, compared with nontransgenic mice, a significantly greater percentage of mice in both K14E6WT (P = 0.005) and K14E6146-151 (P = 0.002) groups developed carcinomas (Fig. 2B). This result indicates that, although E6's interactions with PDZ domain proteins correlate with E6's ability to act in the promotion stage of carcinogenesis, these PDZ interactions are not required for E6's progression activity in carcinogenesis. This is the first evidence showing that the contribution of E6 to the multiple stages of carcinogenesis can be mechanistically separated." "This provides the first direct evidence that distinct activities of E6 contribute to distinct stages in carcinogenesis. We suspect that this other property is E6's inactivation of p53, as mice deficient for p53 specifically show an enhanced rate and incidence of progression but no increase in initiation or promotion."

Worldwide Genomic Diversity of the High-Risk Human Papillomavirus Types 31, 35, 52, and 58, Four Close Relatives of Human Papillomavirus Type 16. IE Calleja-Macias, LL Villa, JC Prado, M Kalantari, B Allan, A-L Williamson, L-P Chung, RJ Collins, RE. Zuna, ST Dunn, T-Y Chu, HA Cubie, K Cuschieri, M von Knebel-Doeberitz, CR Martins, GI Sanchez, FX Bosch, N Munoz, H-U Bernard. Journal of Virology, 2005 Nov;79(21):13630-13640.

The Human DEK Proto-Oncogene Is a Senescence Inhibitor and an Upregulated Target of High-Risk Human Papillomavirus E7. TM Wise-Draper, HV Allen, MN Thobe, EE Jones, KB Habash, K Münger, and SI Wells. J Virology, 2005 Nov;79(22): 14309-14317.

Genome wide expression analysis in HPV16 cervical cancer: Identification of altered metabolic pathways. C Perez-Plasencia, G Vazquez-Ortiz, R Lopez-Romero, P Pina-Sanchez, J Moreno, M Salcedo. Infectious Agents and Cancer 2007;2(16): in progress. "We found 2,067 genes significantly up or down-modulated (at least 2-fold) in tumor clinical samples compared to normal tissues, representing ~ 3.7% of analyzed genes. Cervical carcinoma was associated with an important up-regulation of Wnt signaling pathway, which was validated by in situ hybridization in clinical samples. Other up-regulated pathways were those of calcium signaling and MAPK signaling, as well as cell cycle-related genes. There was down-regulation of focal adhesion, TGF-beta signaling, among other metabolic pathways."

Genomic integration of oncogenic HPV and gain of the human telomerase gene TERC at 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer. AH Hopman, W Theelen, PP Hommelberg, MA Kamps, CS Herrington, LE Morrison, EJ Speel, F Smedts, FC Ramaekers. J Pathol 2006 Dec;210(4):412-419. "Recently proposed events associated with the progression of cervical intraepithelial neoplasia (CIN) 2/3 to cervical carcinoma include integration of human papillomavirus (HPV) into the host genome, genomic instability, and an increase in chromosome 3q copy number. In particular, the gene coding for the RNA component of telomerase (TERC) at 3q26 has been implicated as a possible candidate gene.... The TERC gene was increasingly gained with progression of CIN 2/3 (3 of 17) through CIN 3&mCA (7 of 13) to invCA (5 of 7). In the lesions exhibiting gain of TERC, the virus was predominantly integrated. This was seen in eight of ten diploid lesions, indicating that these events can occur prior to aneuploidization and are strongly associated with the progression of CIN 3 to mCA and invCA (p < 0.001). With progression to carcinoma, a number of these lesions show polyploidization, resulting in aneuploidy and high TERC gene copy numbers."

Human papillomavirus causes an angiogenic switch in keratinocytes which is sufficient to alter endothelial cell behavior. W Chen, F Li, L Mead, H White, J Walker, DA Ingram, A Roman. Virology 2007 Oct 10;367(1):168-174. "Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation."

The Fraud of IARC Monograph 90, Human Papillomaviruses: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 90 (2007). Human Papillomaviruses.

Chapter 4. Molecular Mechanisms of HPV-induced Carcinogenesis.

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 90 (2007). Human Papillomaviruses. Chapter 5. Summary of Data Reported and Evaluation. "Cancer of the Cervix: ... Strong epidemiological evidence confirmed the previous evaluation that HPV types 16 and 18 are carcinogenic to humans. The evidence for carcinogenicity was strongest for HPV 16. In addition, a convincing association, mainly from case–control studies, was found for HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66. HPV types 26, 68, 73 and 82 were associated with cervical cancer in some case–control studies but were rarely found in case series and were not associated with an increase in risk in prospective studies; overall, the epidemiological data for these types were not considered to show a consistent association. Despite a large amount of HPV type-specific data that failed to demonstrate an association, HPV 6 and 11 have been reported in very rare cases, but they did not contribute meaningfully to the burden of cervical cancer. Fewer data were available for other HPV types." This is not fraudulent. The fraud commences when they deal with the subject of smoking and cancers caused by HPV.

Note the bias of this report concernign HPV and lung cancer: They claim that "At present, there is a lack of evidence from case–control studies to support a possible involvement of HPV infections in tumours of these organs." However, there have been more than fifty laboratory studies, and the same high-risk HPV types have been implicated in lung cancer as in cervical cancer; and there is no reason to suppose that HPV functions any differently in the lung than in the cervix. Furthermore, the existing studies indicate that HPV is involved in ten times more lung cancers than the anti-smoking charlatans pretend - on the basis of nothing but lifestyle questionnaires! - are caused by secondhand smoke. The lack of case-control studies of HPV and lung cancer, despite the major health implications of the evidence, in contrast to the comparatively massive expenditure of resources of scientifically-specious lifestyle-questionnaire studies whose object is to serve the political purpose of banning smoking, is proof of corruption of the scientific process by the anti-smokers, and their deliberate neglect of research on infection.

They also demonstrate their bias by their shoddy and negligent handling of the issue of confounding by the extraordinarily high odds ratios that are associated with infection by high-risk human paillomaviruses. In cervical cancer, they exceed 300! Odds ratios of this magnitude must not be handled in the same casual manner as the trivial odds ratios found in lifestyle questionnaire studies! In lifestyle questionnaire studies, the inclusion or exclusion of some purported non-infectious "risk factor" never alters the odds ratio by more a few tenths of a point. In contrast, the failure to accurately detect exposure to a causal factor with an odds ratio of 300 is guaranteed to result in spurious ratios odds of two or more more, any time that there is a difference between the comparison groups in the amount and duration of their exposure to the pathogen. Their failure to cite the mathematical demonstration of Phillips and Smith, and deal with the issues that it raises, is proof of their negligence, especially on the part of Xavier Bosch, who corresponded with Phillips and Smith on this subject and confirmed it in his own data set. Their specious blow-off is an outrage: "The risk estimates for this association were consistently in the range of 2.0 regardless of the study design (retrospective versus prospective), the restriction criteria employed (any HPV type-positive versus high-risk HPV-positive) and the covariates included in the model" (Ch. 5, p. 471), because this subject requires and deserves a detailed analysis of all the potential routes for confounding, not just a superficial glance at a pile of inadequate studies which concludes that the findings are legitimate on the grounds of the height of the pile! Simply detecting "any HPV" or "high-risk HPV-positive" is not sufficient because infection by multiple strains multiplies the risk. Furthermore, the infectious status of the partner influences the amount of exposure, and the risk of development of cervical cancer. In fact, they have willfully failed to subject their claim about smoking and cervical cancer to the same degree of scrutiny which they applied to HPV, particularly including "lack of a reliable measurement of lifetime exposure to HPV infection" (Ch. 2. Studies of Cancer in Humans, (b) Impact of Study Design, p. 2), which differs between smokers and non-smokers for socioeconomic reasons. IN FACT, given that the potential routes for confounding make it a virtual certainty, any pretense that smoking increases the risk of cervical cancer ought to have been summarily dismissed, and the burden of proof placed where it rightfully belongs, on the anti-smokers, to demonstrate convincingly that they have eliminated potential confounding.

p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy. Y Liu, SA Heilman, D Illanes, G Sluder, JJ Chen. Cancer Res 2007 Mar 15;67(6):2603-2610. "Polyploidy is often an early event during cervical carcinogenesis, and it predisposes cells to aneuploidy, which is thought to play a causal role in tumorigenesis.... We found that E6 expression does not affect the spindle checkpoint. Instead, we provide direct evidence that E6 is capable of abrogating the subsequent G(1) arrest after adaptation of the mitotic stress. E6 targets p53 for degradation, and previous studies have shown an important role for p53 in modulation of the G(1) arrest after mitotic stress. Importantly, we have discovered that E6 mutants defective in p53 degradation also induce polyploidy, although with lower efficiency. These results suggest that E6 is able to induce polyploidy via both p53-dependent and p53-independent mechanisms."

Genomic instability of the host cell induced by the human papillomavirus replication machinery. M Kadaja, A Sumerina, T Verst, M Ojarand, E Ustav, M Ustav. EMBO J 2007 Apr 18;26(8):2180-2191. "We show that HPV replication proteins E1 and E2 are capable of inducing overamplification of the genomic locus where HPV origin has been integrated. Clonal analysis of the cells in which the replication from integrated HPV origin was induced showed excision, rearrangement and de novo integration of the HPV containing and flanking cellular sequences."

The Human Papillomavirus E7 Protein Deregulates Mitosis via an Association with the Nuclear Mitotic Apparatus Protein-1 (NuMA). CL Nguyen, K Münger. J Virol 2009 Feb;83(4):1700-1707. "We previously observed that high-risk human papillomavirus type 16 (HPV16) E7 expression leads to the delocalization of dynein from mitotic spindles (C. L. Nguyen, M. E. McLaughlin-Drubin, and K. Munger, Cancer Res. 68:8715-8722, 2008). Here, we show that HPV16 E7 associates with nuclear mitotic apparatus protein 1 (NuMA) and that NuMA binding and the ability to induce dynein delocalization map to similar carboxyl-terminal sequences of E7. Additionally, we show that the delocalization of dynein from mitotic spindles by HPV16 E7 and the interaction between HPV16 E7 and NuMA correlate with the induction of defects in chromosome alignment during prometaphase even in cells with normal centrosome numbers. Furthermore, low-risk HPV6b and HPV11 E7s also associate with NuMA and also induce a similar mitotic defect. It is possible that the disruption of mitotic events by HPV E7, via targeting of the NuMA/dynein complex and potentially other NuMA-containing complexes, contributes to viral maintenance and propagation potentially through abrogating the differentiation program of the infected epithelium. Furthermore, in concert with activities specific to high-risk HPV E6 and E7, such as the inactivation of the p53 and pRB tumor suppressors, respectively, the disruption of the NuMA/dynein network may result in mitotic errors that would make an infected cell more prone to the accumulation of aneuploidy even in the absence of supernumerary centrosomes."

Abrogation of the Postmitotic Checkpoint Contributes to Polyploidization in HPV E7 Expressing Cells. SA Heilman, JJ Nordberg, Y Liu, G Sluder, JJ Chen. J Virol. 2009 Mar;83(6):2756-2764. "Cells expressing the oncogene E7 from high-risk HPVs have a high incidence of polyploidy, which has been shown to occur as an early event in cervical carcinogenesis and predisposes the cells to aneuploidy.... We find that E7 expressing cells undergo normal mitoses with an intact spindle assembly checkpoint, and that they are able to complete cytokinesis. Our results also exclude DNA re-replication as a major mechanism of polyploidization in E7 expressing cells upon microtubule disruption. Instead, we have shown that while normal cells arrest at the postmitotic checkpoint after adaptation to the spindle assembly checkpoint, E7 expressing cells replicate their DNA and propagate as polyploid cells. Thus, abrogation of the postmitotic checkpoint leads to polyploidy formation in E7 expressing human epithelial cells. Our results suggest that down-regulation of pRb is important for E7 to induce polyploidy and abrogation of the postmitotic checkpoint."

Mechanism of genomic instability in cells infected with the high-risk human papillomaviruses. M Kadaja, H Isok-Paas, T Laos, E Ustav, M Ustav. PLoS Pathogens 2009 Apr;5(4). "We used immunofluorescence analysis to show that the DNA repair/recombination centers are assembled at the sites of the integrated HPV replication. These centers recruit viral and cellular replication proteins, the MRE complex, Ku70/80, ATM, Chk2, and, to some extent, ATRIP and Chk1 (S317). In addition, the synthesis of histone γH2AX, which is a hallmark of DNA double strand breaks, is induced, and Chk2 is activated by phosphorylation in the HPV–replicating cells.... We show that HPV replication proteins expressed at the physiological level from the viral extrachromosomal genome are capable of replicating episomal and integrated HPV simultaneously. Unscheduled replication of the integrated HPV induces a variety of changes in the host genome, such as excision, repair, recombination, and amplification, which also involve the flanking cellular DNA."

Association of p73 G4C14-to-A4T14 polymorphism with human papillomavirus type 16 status in squamous cell carcinoma of the head and neck in non-Hispanic whites. X Ji, EM Sturgis, C Zhao, CJ Etzel, Q Wei, G Li. Cancer 2009 Apr 15;115(8):1660-1668. 202 non-Hispanic white patients with squamous cell carcinoma of the head and neck . "Compared with the p73 GC/GC genotype, the AT/AT and combined GC/AT + AT/AT variant genotypes were associated significantly with HPV-16-positive tumor status among patients with SCCHN (adjusted OR, 5.32; 95% CI, 1.32-21.4; adjusted OR, 1.91; 95% CI, 1.03-3.53, respectively)."

Detection Methodologies

Development of a sensitive and specific assay combining multiplex PCR and DNA microarray primer extension to detect high-risk mucosal human papillomavirus types. T Gheit, S Landi, F Gemignani, PJ Snijders, S Vaccarella, S Franceschi, F Canzian, M Tommasino. J Clin Microbiol 2006 Jun;44(6):2025-2031. "The importance of assays for the detection and typing of human papillomaviruses (HPVs) in clinical and epidemiological studies has been well demonstrated. Several accurate methods for HPV detection and typing have been developed. However, comparative studies showed that several assays have different sensitivities for the detection of specific HPV types, particularly in the case of multiple infections. Here, we describe a novel one-shot method for the detection and typing of 19 mucosal high-risk (HR) HPV types (types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, 73, and 82). This assay combines two different techniques: multiplex PCR with HPV type-specific primers for amplification of viral DNA and array primer extension (APEX) for typing. This novel method has been validated with artificial mixtures of HPV DNAs and clinical samples that were already analyzed for the presence of mucosal HPV types by a different consensus PCR method, i.e., GP5+/GP6+. Our data showed a very good agreement between the results from the multiplex PCR/APEX assay and those from the GP5+/GP6+ PCR (overall rates of HPV positivity, 63.0 and 60.9%, respectively). Whereas the GP5+/GP6+ PCR was slightly more sensitive for the detection of HPV type 16 (HPV-16), multiplex PCR-APEX found a higher number of infections with HPV-33, HPV-53, and multiple HPV types."

Modified General Primer PCR System for Sensitive Detection of Multiple Types of Oncogenic Human Papillomavirus. A Söderlund-Strand, J Carlson, J Dillner. J Clin Microbiol 2009 Mar;47(3):541-546. "The reference method (GP5+/6+) had the desirable high sensitivity (five copies/PCR) for five oncogenic HPV types (HPV type 16 [HPV-16], HPV-18, HPV-56, HPV-59, and HPV-66). The MGP [modified general primer] system was able to detect all 14 oncogenic HPV types at five copies/PCR. In the clinical samples, the MGP system detected a significantly higher proportion of women with more than two concomitant HPV infections than did the GP5+/6+ system (102/592 women compared to 42/592 women [17.2% vs 7.1%]). MGP detected a significantly greater number of infections with HPV-16, -18, -31, -33, -35, -39, -42, -43, -45, -51, -52, -56, -58, and -70 than did GP5+/6+."

Comparison of a Polymer-Based DNA Biochip Platform with a Commercial PCR Followed by Reverse Hybridization for the Detection and Genotyping of Human Papilloma Virus (HPV) in Clinical Samples. T Schenk, T Brandstetter, A Zur Hausen, J Alt-Mörbe, D Huzly, J Rühe. J Clin Microbiol 2009 May;47(5):1428-1435. Comparison of a new hydrogel-based HPV genotyping biochip assay (Biochip) to a commercially available and CE-marked conventional PCR followed by reverse hybridization (GenID-PCR), in 123 samples (101 gynecological, 8 genital warts, 7 otorhinolaryngeal, 5 skin warts, 2 orolabial.) "These molecular methods for HPV genotyping showed comparable sensitivity and specificity. However, 19/123 of the results were discrepant. Specifically, Biochip showed better performance in the detection of multiple infections, especially when more than one high-risk genotype was present. Due to the different probe configurations used in the two assays, GenID-PCR achieves only group-specific detection of many HPV genotypes, whereas Biochip allows for specific identification."

Transmission

HPV group- and type-specific concordance in HPV infected sexual couples. L Giovannelli, C Bellavia, G Capra, MC Migliore, M Caleca, M Giglio, A Perino, D Matranga, P Ammatuna. J Med Virol 2007 Dec;79(12):1882-1888. 45 sexual couples with both partners HPV infected. "Examining individual HPV types, using samples from any male site, concordance was found in 29 (64.4%; P = 0.036) couples; significant concordance was evident for 16 HPV genotypes, the most frequent being HPV-6, -66, -31, -51, and -53."

Transmission of Human Papillomavirus in Heterosexual Couples. BY Hernandez, LR Wilkens, X Zhu, P Thompson, K McDuffie, YB Shvetsov, LE Kamemoto, JK Kileen, L Ning, MT Goodman. Emerg Infect Dis 2008 Jun;14(6):888. "We examined the transmission of human papillomavirus (HPV) in 25 heterosexual, monogamous couples (25 men, 25 women), followed up over an average of 7.5 months. A total of 53 heterosexual transmission events were observed among 16 couples (14 male-to-female and 39 female-to-male). Sexual transmission involved 13 different oncogenic and nononcogenic HPV types; 8% were vaccine-covered types transmitted between partners. The overall rate of HPV transmission from the penis to the cervix was 4.9/100 person-months, which was substantially lower than that from the cervix to the penis (17.4/100 person-months). Transmission between the hands and genitals, as well as apparent self-inoculation events (primarily in men), were also observed. Couples who transmitted HPV were more sexually active and used condoms less frequently." Cervical specimens were taken from the women, and anal, oral, hand, and urine specimens from both sexes.

Chemical carcinogens

Concerning attempts to implicate chemical carcinogens from cigarette smoke as cofactors with HPV: "Attempts to determine the importance of cofactors utilizing in vitro models with human cells and recombinant HPV have been frustrating. In general, there is a marked contrast between the effects of a carcinogen on rodent and human cells. Whereas a number of chemical and physical viral agents are effective in transforming normal rodent cells to the malignant state, they are for the most part ineffective when applied to human cells. The same can be said for cells that have been immortalized with HPV-16 or -18. The addition of diverse chemical carcinogens to HPV-16 immortalized cells has consistently failed to induce malignancy; however, evidence of effects has been obtained as reflected by new chromosomal rearrangements." (Immortalization of keratinocytes by human papillomaviruses. CD Woodworth, JA DiPaolo. In: DNA tumor viruses. Oncogenic mechanisms. G Barbanti-Brodano, M Bendinelli, H Friedman, eds. Plenum Press, 1995, Ch 6, pp 91-109.) Author DiPaolo has been a prominent anti-smoker, and both authors are from the National Cancer Institute. And, since enormous resources are always devoted to attempting to blame chemical carcinogens from tobacco, this failure would not be due to lack of trying. Animal cancers that were blamed on chemical carcinogens in bracken ferns have turned out to be caused by HPV, which resulted from immunosuppression from the toxicity of the substances.

Efficient repair of bulky anti-BPDE DNA adducts from non-transcribed DNA strand requires functional p53 but not p21(waf1/cip1) and pRb. MA Wani, MA El-Mahdy, FM Hamada, G Wani, Q Zhu, QE Wang, AA Wani. Mutat Res 2002 Aug 29;505(1-2):13-25. "[T]he removal of anti-BPDE DNA adducts from the genome overall and NTS by GGR was significantly reduced in HPV-16E6 protein expressing cells as compared to that in normal and HPV-16E7 protein expressing cells, indicating the role of p53 and not pRb in nucleotide excision repair (NER).... the modulation of NER by p53 may be independent of its function in the regulation of cell cycle arrest upon chemically induced DNA damage."

Drug resistance argues against mutation theory of cancer. By Robert Sanders. Press Release, UC-Berkeley News, Jun. 26, 2007. Peter Duesberg, professor of molecular and cell biology at theUniversity of California, Berkeley: "'The mutation theory of cancer says that a limited number of genes causes cancer, so cancers should all be more or less the same,' Duesberg said. The chromosomal theory, which he laid out in an article in the May 2007 issue of Scientific American, implies instead that, 'even if cancers are from the same tissue, and are generated with the same carcinogen, they are never the same. There is always a cytogenetic and a biochemical individuality in every cancer.' ...Duesberg proposed in 2000 that the assumption underlying most cancer research today is wrong. That assumption, that cancer results from a handful of genetic mutations that drive a cell into uncontrolled growth, has failed to explain many aspects of cancer, he said, and has led researchers down the wrong path. His alternative theory is that cancer results from aneuploidy - that is, duplication or sometimes loss of one or more of our 46 chromosomes, which throws thousands of genes out of whack. This condition, generated by a defect in the mechanism that duplicates chromosomes during cell growth, leads to more and more chromosomal disorder as the cells divide and proliferate, disrupting even more genes and providing ample opportunity for the development of resistance to drugs being used to control the cancer. 'In this new study and in one published in 2005, we have proved that only chromosomal rearrangements, rather than mutations, can explain the high rates and wide ranges of drug resistance in cancer cells,' he said.... 'The fundamental problem these conventional theories don't address is why it (drug resistance) doesn't happen in normal cells," he said. "Why aren't we all getting resistant to any toxic drug we are exposed to? Why does it happen only in cancer cells? Why do cancer cells become resistant and the patients don't?... They see now, more and more, that aneuploidy cannot be ignored. It is a big elephant compared to their little mutations,' he said."

See also:

Papillomaviruses Cause Cancer in Animals

Cats (Felines)

Papillomavirus infection in association with feline cutaneous squamous cell carcinoma in situ. SM LeClerc, EG Clark, DM Haines. Proc Am Assoc Vet Derm/Am Coll Vet Derm 1997;13:125-126. As reported in Sundberg 2000: "In a large case series of cutaneous squamous cell carcinoma in situ in domestic cats, 30 of 63 biopsies were positive for PV antigens. It is possible that negative tumors in this and other studies were not associated with papillomavirus infections or that they were intermittently productively infected, a phenomenon described for other PV-induced lesions."

Feline papillomas and papillomaviruses. JP Sundberg, M Van Ranst, R Montali, BL Homer, WH Miller, PH Rowland, DW Scott, JJ England, RW Dunstan, I Mikaelian, AB Jenson. Vet Pathol 2000 Jan;37(1):1-10. Review. "In general, the cat lesions, like their human counterparts [epidermodysplasia verruciformis], are planar or flat warts with the clinical appearance of plaques. In the human lesions, those associated with HPV-5 and HPV-8 undergo conversion to malignancy in the presence of ultraviolet light in approximately 30% of individuals. This may be significant because cats frequently develop basal and squamous cell carcinomas."

Clinical, histological and immunohistochemical study of feline viral plaques and bowenoid in situ carcinomas. S Wilhelm, F Degorce-Rubiales, D Godson, C Favrot. Vet Dermatol 2006 Dec;17(6):424-431. "Of the seven cases in the FVP group, six were deemed positive by immunohistology as were all 10 cats in the FVP + BISC group. On the other hand, only one of the nine BISC cats was positive. The presence of both FVP and BISC lesions in some cats and the high detection rate of PV antigens in the FVP and FVP + BISC groups suggest that both conditions might have the same viral cause and that some BISC may evolve from FVP. The low rate of viral antigen detection in the BISC group indicates another cause or a loss of viral replication during the cancerogenesis."

Detection of novel papillomaviruslike sequences in paraffin-embedded specimens of invasive and in situ squamous cell carcinomas from cats. G Nespeca, P Grest, WS Rosenkrantz, M Ackermann, C Favrot. Am J Vet Res 2006 Dec;67(12):2036-2041. "5 of 21 BISC specimens and 4 of 22 invasive SCC specimens were positive for PV DNA on the basis of broad-range PCR assay results. Sequence analysis revealed that only 1 specimen was infected by a virus closely related to classic FePV. In the 8 other specimens positive for PV DNA, DNA of unknown PVs was uncovered. CONCLUSIONS AND CLINICAL RELEVANCE: Bowenoid in situ SCC and invasive SCC of cats may be associated with PVs of genetic diversity."

Detection of papillomaviral sequences in feline Bowenoid in situ carcinoma using consensus primers. JS Munday, M Kiupel, AF French, L Howe, RA Squires. Vet Dermatol 2007 Aug;18(4):241-245. Papillomaviral DNA was amplified from 11 of 18 formalin-fixed samples of BISC, but no controls. "Six amplicons were sequenced; one was homologous with a papillomavirus from a human patient with multiple cutaneous squamous cell carcinomas and the other five showed weak homology to human papillomavirus type 17. These five sequences were > 96% homologous over a 235 bp sequence, indicating the presence in all five BISCs of one papillomavirus type distinct from any previously sequenced and more closely related to human than animal papillomaviruses. The results confirm an association between BISC and papillomaviruses, and as all six papillomavirus sequences identified are closely related to human papillomaviruses, it is possible that the virus is transmitted from humans to cats or vice versa."

Amplification of papillomaviral DNA sequences from a high proportion of feline cutaneous in situ and invasive squamous cell carcinomas using a nested polymerase chain reaction. JS Munday, M Kiupel, AF French, L Howe. Vet Dermatol 2008 Aug 5. [Epub ahead of print]. "Papillomaviral DNA was amplified from 20 of 20 BISC, 17 of 20 invasive SCC and 3 of 17 non-SCC controls. The rate of PV amplification from feline cutaneous SCCs was significantly higher than from non-SCC lesions."

Clinical, histologic, and immunohistochemical analyses of feline squamous cell carcinoma in situ. C Favrot, M Welle, M Heimann, DL Godson, F Guscetti. Vet Pathol 2009 Jan;46(1):25-33. "P53 immunoreactivity was observed in 11/14 (79%) confirmed AK cases and in 4/22 (18%) BISC cases, while papillomavirus antigen was not detected in any confirmed AK case but was detected in 11/23 (48%) BISC cases."

Detection of papillomaviral DNA sequences in a feline oral squamous cell carcinoma. JS Munday, L Howe, A French, RA Squires, H Sugiarto. Res Vet Sci 2009 Apr;86(2):359-361. A papillomavirus similar to human PV type 76 was found in 1/20 feline OSCCs.

Cattle (Bovines)

Bovine papillomavirus E5 oncoprotein binds to the activated form of the platelet-derived growth factor beta receptor in naturally occurring bovine urinary bladder tumours. G Borzacchiello, V Russo, F Gentile, F Roperto, A Venuti, L Nitsch, MS Campo, S Roperto. Oncogene 2006 Feb 23;25(8):1251-1260. "We have shown that BPV-2 DNA is present in the majority of naturally occurring urinary bladder tumours of cattle and that E5 is expressed in the cancer cells. Here we show that the interaction between the platelet-derived growth factor (PDGF) beta receptor and BPV E5, described in vitro in cultured cells, takes place in vivo in bovine urinary bladder cancers. In these cancers, E5 and PDGF beta receptor colocalize, as shown by confocal microscopy, and physically interact, as shown by coimmunoprecipitation. Furthermore, the PDGF beta receptor associated with E5 is highly phosphorylated, suggesting the functional activation of the receptor upon E5 interaction. Our results demonstrate, for the first time, that E5-PDGF beta receptor interaction occurs during the natural history of bovine urinary bladder tumours, suggesting an important role for E5 in carcinogenesis."

Bovine papillomavirus type-2 DNA and expression of E5 and E7 oncoproteins in vascular tumours of the urinary bladder in cattle. G Borzacchiello, V Russo, C Spoleto, S Roperto, I Balcos, C Rizzo, A Venuti, F Roperto. Cancer Lett 2007 May 18;250(1):82-91. "BPV-2 is present in 100% of the vascular tumours of the urinary bladder examined. Twenty-six out of twenty-seven tumour samples (96%) expressed E5 while 20 out of 27 (74%) tumour samples expressed E7. The two viral oncoproteins were not expressed in normal endothelial cells. Additionally, they co-localize in neoplastic endothelial cells as demonstrated by confocal immunofluorescence. PDGFbeta receptor was also shown to be expressed and co-localizes with E5 in neoplastic blood vessels."

Association of bovine papillomavirus type-2 and urinary bladder tumours in cattle from Romania. LG Balcos, G Borzacchiello, V Russo, O Popescu, S Roperto, F Roperto. Res Vet Sci 2008 Aug;85(1):145-148. Bovine papillomavirus type 2 (BPV-2) DNA was detected by polymerase chain reaction (PCR) in 68% of 90 urinary bladders from slaughtered cows in an area where chronic enzootic hematuria is endemic. E5 expression was not observed in normal mucosa.

Bovine papillomaviruses: their role in the aetiology of cutaneous tumours of bovids and equids. L Nasir, MS Campo. Vet Dermatol 2008 Oct;19(5):243-254. Review. "Cattle papillomas are benign tumours and generally regress without eliciting any serious clinical problems in the host, but occasionally persist and provide the focus for malignant transformation to squamous cell carcinoma, as in the case of cancer of the urinary bladder and cancer of the upper alimentary canal. BPV is the only papillomavirus that jumps species: the virus also infects equids, and gives rise to fibroblastic tumours called sarcoids. Sarcoids very rarely regress, more often they persist and can be locally aggressive. These tumours are the most common dermatological tumour of equids worldwide."

Detection of bovine papillomavirus type 2 in the peripheral blood of cattle with urinary bladder tumours: possible biological role. S Roperto, R Brun, F Paolini, C Urraro, V Russo, G Borzacchiello, U Pagnini, C Raso, C Rizzo, F Roperto, A Venuti. J Gen Virol 2008 Dec;89(Pt 12):3027-3033. "Peripheral blood samples were collected from 78 cattle clinically suffering from a severe chronic enzootic haematuria. Circulating BPV-2 DNA was detected in 61 of them and in two blood samples from healthy cows. Fifty of the affected animals were slaughtered at public slaughterhouses and neoplastic proliferations in the urinary bladder were detected in all of them. BPV-2 DNA was amplified and sequenced in 78 % of urinary bladder tumour samples and in 38.9 % of normal samples as a control. Circulating episomal BPV-2 DNA was detected in 78.2 % of the blood samples. Simultaneous presence of BPV-2 DNA in neoplastic bladder and blood samples was detected in 37 animals."

Dogs (Canines)

Epithelial neoplasms of the skin, the cutaneous mucosa and the transitional epithelium in dogs: an immunolocalization study for papillomavirus antigen. K Schwegler, JH Walter, R Rudolph. Zentralbl Veterinarmed A 1997 Apr;44(2):115-123. 44.2% of 95 papillomas and 27% of 100 diagnosed squamous cell carcinomas reacted with antiserum. "Papillomavirus antigen was detectable in 54.2% of all oral and ocular papillomas and in 37.0% of all cutaneous papillomas. The majority of the squamous cell carcinomas with detectable papillomavirus antigen were considered positive but not without restrictions. The average age of dogs with viral oral and ocular papillomas was 2.3 years, with viral cutaneous papillomas it was 3.2 years. The average age of dogs with virus-positive squamous cell carcinomas was nearly 11 years. Papillomavirus-like particles were demonstrated by means of transmission electron microscopy in three positive oral papillomas, in the positive squamous cell carcinomas virion detection failed."

Detection of canine oral papillomavirus-DNA in canine oral squamous cell carcinomas and p53 overexpressing skin papillomas of the dog using the polymerase chain reaction and non-radioactive in situ hybridization. JP Teifke, CV Löhr, H Shirasawa. Vet Microbiol 1998 Feb 28;60(2-4):119-30. 29 oral and 25 non-oral squamous cell carcinomas of dogs. Fragments of the E6, E7 and L1 gene were amplified by polymerase chain reaction (PCR) from five of eight oral and from five of eight cutaneous papillomas as well as from three oral squamous cell carcinomas. "In three squamous cell carcinomas COPV-DNA was located in nests of the epithelial tumor cells surrounding 'horn pearls' or disseminated in the carcinoma tissue. These observations support the view that COPV may also induce non-oral papillomas in the dog and confirm the opinion that a progression of viral papillomas into carcinomas in dogs may occur."

Detection of novel papillomaviruses in canine mucosal, cutaneous and in situ squamous cell carcinomas. N Zaugg, G Nespeca, B Hauser, M Ackermann, C Favrot. Vet Dermatol 2005 Oct;16(5):290-298. "While approximately 100 human PVs are known, only one single canine oral PV (COPV) has been identified and studied extensively. Therefore, we applied a narrow-range polymerase chain reaction (PCR) suitable for the detection of classical canine and feline PVs, as well as a broad-range PCR, which has been used for the detection of various novel PVs in humans, in order to analyse 42 paraffin-embedded samples, representing three different forms of canine SCCs. Ten samples of skin tissues with various non-neoplastic conditions served as controls. While none of the negative controls reacted positively, PV DNA was discovered in 21% of the tested SCC samples. Interestingly, the classical COPV was amplified from only one sample, while the other positive cases were associated with a variety of thus far unknown PVs. This study suggests that a fraction of canine SCC is infected with PVs and that a genetic variety of canine PVs exists."

An epidermotropic canine papillomavirus with malignant potential contains an E5 gene and establishes a unique genus. H Yuan, S Ghim, J Newsome, T Apolinario, V Olcese, M Martin, H Delius, P Felsburg, B Jenson, R Schlegel. Virology 2007 Mar 1;359(1):28-36. "CfPV-2 establishes a new PV genus, with its closest phylogenetic relatives being amongst the Xi and Gamma genuses. CfPV-2 also has unique biological features; it induces papillomas on footpads and interdigital regions which, if infection is persistent, can progress to highly metastatic squamous cell carcinoma. CfPV-2 does not induce oral papillomas in immunocompetent animals and antibodies generated against COPV and CfPV-2 are type-specific."

Equids (Horses)

Evaluation of equine papillomas, aural plaques, and sarcoids for the presence of Equine papillomavirus DNA and Papillomavirus antigen. RC Postey, GD Appleyard, BA Kidney. Can J Vet Res 2007 Jan;71(1):28-33. "With IHC testing, 23 of 38 papillomas, 4 of 9 aural plaques, and 0 of 10 sarcoids were positive for PV antigen; EPV DNA was found in 20 of the 38 papillomas and 1 of the 10 sarcoids but 0 of the 9 aural plaques."

High prevalence of bovine papillomaviral DNA in the normal skin of equine sarcoid-affected and healthy horses. L Bogaert, A Martens, M Van Poucke, R Ducatelle, H De Cock, J Dewulf, C De Baere, L Peelman, F Gasthuys. Vet Microbiol 2008 May 25;129(1-2):58-68. "BPV DNA was found in the normal skin of 24 of 42 horses (57%). Mainly sarcoid-affected horses and horses living in contact with cattle were carriers (73%), but BPV DNA was also detected in 50% of the horses living in contact with sarcoid-affected horses and in 30% of the control population. BPV mRNA was detected in 58% of the samples positive for BPV DNA, although in a much lower quantity compared to sarcoids."

Bovine papillomaviruses: their role in the aetiology of cutaneous tumours of bovids and equids. L Nasir, MS Campo. Vet Dermatol 2008 Oct;19(5):243-254. Review. "Cattle papillomas are benign tumours and generally regress without eliciting any serious clinical problems in the host, but occasionally persist and provide the focus for malignant transformation to squamous cell carcinoma, as in the case of cancer of the urinary bladder and cancer of the upper alimentary canal. BPV is the only papillomavirus that jumps species: the virus also infects equids, and gives rise to fibroblastic tumours called sarcoids. Sarcoids very rarely regress, more often they persist and can be locally aggressive. These tumours are the most common dermatological tumour of equids worldwide."

Expression of platelet-derived growth factor-beta receptor and bovine papillomavirus E5 and E7 oncoproteins in equine sarcoid. G Borzacchiello, V Russo, L Della Salda, S Roperto, F Roperto. J Comp Pathol 2008 Nov;139(4):231-237. "BPV DNA was demonstrated in 12/15 tumours collected from different areas of Italy. Nine of these 12 tumours expressed the BPV oncoproteins E5 and E7, but these oncoproteins were not expressed by normal equine cells."

Detection of bovine papillomavirus DNA in sarcoid-affected and healthy free-roaming zebra (Equus zebra) populations in South Africa. E van Dyk, MC Oosthuizen, AM Bosman, PJ Nel, D Zimmerman, EH Venter. J Virol Methods 2009 Jun;158(1-2):141-151. "BPV-1 and -2 DNA (either single or mixed infections) are present in sarcoid tumour, healthy skin and blood of sarcoid-affected and healthy zebras from sarcoid-affected parks as well as in the blood of zebras from parks where no sarcoid has been observed before."

Hamsters

Presence of a novel hamster oral papillomavirus in dysplastic lesions of hamster lingual mucosa induced by application of dimethylbenzanthracene and excisional wounding: molecular cloning and complete nucleotide sequence. T Iwasaki, H Maeda, Y Kameyama, M Moriyama, S Kanai, T Kurata. J Gen Virol 1997 May;78 ( Pt 5):1087-1093. "All dysplastic lesions induced by this combination of DMBA application and excisional wounding contained viral DNA. Although Southern blot hybridization analysis could not detect the HOPV genome, PCR analysis demonstrated the latent HOPV genome in the tongue and skin of an untreated hamster. These results suggest that latently present HOPV genome is reactivated by the DMBA/wounding procedures." Viral particles resembling papillomavirus were detected in the nuclei as far back as 1986.

DNA vaccine against hamster oral papillomavirus-associated oral cancer. H Maeda, K Kubo, Y Sugita, Y Miyamoto, S Komatsu, S Takeuchi, T Umebayashi, S Morikawa, K Kawanishi, Y Kameyama. J Int Med Res 2005 Nov-Dec;33(6):647-653. "Previously we developed a carcinogenesis model involving the combination of 9,10-dimethyl-1,2-benzanthracene (DMBA) application with physical wounding of hamster lingual mucosa. The presence of a novel hamster oral papillomavirus (HOPV) was demonstrated and its genome sequenced.... All control hamsters developed lingual carcinoma, whereas 12 of the L1-vaccinated hamsters showed no lesions." There were 20 vaccinated and 20 control animals.

Mice (Murine)

Cloning and characterization of a papillomavirus associated with papillomas and carcinomas in the European harvest mouse (Micromys minutus). MK O'Banion, ME Reichmann, JP Sundberg. J Virol 1988 Jan;62(1):226-233. "All 17 tumors examined contained large amounts of viral DNA in a supercoiled, unintegrated form as revealed by Southern blot hybridization. Furthermore, many extracts (25 of 35) from normal organs and skin of individuals with lesions elsewhere on their bodies contained viral DNA." "[H]igh copy numbers and the presence of viral antigens indicate that productive infection was occurring in many of these tissues. Although insufficient sample numbers preclude a final conclusion, the observations that no viral antigens were detected in two sebaceous carcinomas and that the viral DNA copy number was low (100 copies) in the one carcinoma examined suggest that productive infection was not occurring in these lesions." Viral DNAs were also detected in many apparently normal tissues from affected individuals.

Rabbits

A transactivator function of cottontail rabbit papillomavirus e2 is essential for tumor induction in rabbits. S Jeckel, E Huber, F Stubenrauch, T Iftner. J Virol 2002 Nov;76(22):11209-11215. "In contrast to the productive virus infection observed in the cottontail rabbit, which is the natural host, infection of New Zealand White rabbits with CRPV causes an abortive infection. As many as 80% of the initially benign epithelial tumors progress to carcinomas within the next 6 to 14 months, and these finally metastasize without the need for cofactors."

Rats

The Mastomys natalensis papillomavirus: nucleotide sequence, genome organization, and phylogenetic relationship of a rodent papillomavirus involved in tumorigenesis of cutaneous epithelia. CH Tan, R Tachezy, M Van Ranst, SY Chan, HU Bernard, RD Burk. Virology 1994 Feb;198(2):534-541. "Mastomys natalensis is a rodent of African origin afflicted with a very high incidence of skin tumors (keratoacanthomas and squamous carcinomas), which are associated with a papillomavirus, M. natalensis papillomavirus (MnPV)." It is similar to several HPV types that are associated with epidermodysplasia verruciformis.

cast 01-11-10