The causal relation between human papillomavirus and cervical cancer

Bosch, F. Xavier; Lörincz, Attila T.; Muñóz, Núbia; Meijer, Chris J.L.M.; Shah, Keerti V.

doi:10.1136/jcp.55.4.244

Cited by 3,005 publications

(2,408 citation statements)

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“…3 Indeed, while the majority of sexually active women become infected with HPV, only a minority develops premalignant cervical lesions or cervical cancer. 4 In these patients, as expected, HPVspecific CTL activity is generally low, 5,6 suggesting that they have mounted a certain degree of immunological tolerance or ignorance for the HPV-derived antigens. It is possible that this tolerance arises peripherally at the level of the epithelial keratinocytes, the target cells for HPV.…”

supporting

confidence: 63%

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fastgrowing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPVtransgenic mice. Gene Therapy (2005) Cervical cancer is the third most common cancer among women worldwide. It is caused by infection with highrisk human papillomavirus (HPV), in particular types 16, 18, 31, 33 or 45. Indeed, in over 99% of all cervical carcinomas, DNA derived from these HPV types is detectable. 1 High-risk HPVs have the capacity to transform cervical epithelial cells by integrating the open reading frames encoding the viral early proteins E6 and E7 into the host cell genome. This integration may lead to constitutive overexpression of E6 and E7, mediating transformation of the cells to a malignant phenotype. 2 Since the continued production of E6 and E7 is required for the maintenance of the transformed phenotype, E6 and E7 in fact represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are potential targets for immunotherapeutic intervention strategies involving induction or stimulation of cytotoxic T lymphocyte (CTL) activity against HPV-transformed cells. 3

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supporting

confidence: 63%

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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“…There is now consistent and convincing evidence that cervical cancer is in fact a rare consequence of infection of the genital tract by some mucosatropic types of HPV [2].…”

Section: What Causes Cervical Cancer ? Human Papillomavirus (Hpv)mentioning

confidence: 96%

“…Despite being a theoretically preventable disease, cervical cancer is still the second most common cancer in women (after breast cancer) worldwide [2], and the fifth most frequent cancer overall, with an estimated prevalence of 1 . 4 million cases.…”

Section: Introductionmentioning

confidence: 99%

Vaccines for cervical cancer

Lowndes¹

2006

Epidemiol. Infect.

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SUMMARYThis review focuses on current and future prevention of invasive cervical cancer (ICC), the second most common cancer among women worldwide. Implementation of population-based cytological screening programmes, using the 'Pap ' smear to detect pre-cancerous lesions in the cervix, has resulted in substantial declines in mortality and morbidity from ICC in North America and some European countries. However, cases of, and deaths from, ICC continue to occur. Primary prevention of infection with high-risk human papillomavirus (HPV) types, the central causal factor of ICC, could further reduce incidence of and mortality from ICC. This is particularly the case in developing countries, which bear 80% of the burden of ICC, and where effective Pap screening programmes are extremely difficult to implement. Very promising results from several trials of synthetic HPV type-specific monovalent (HPV 16) and bivalent (HPV 16 and 18) vaccines have recently been published, showing high efficacy against type-specific persistent HPV infection and development of type-specific pre-cancerous lesions. Large-scale phase III trials of a number of such vaccine candidates are currently underway, and there is real hope that an effective vaccine capable of protecting against infection with HPV types 16 and 18 (which together account for y70% of cervical cancer cases worldwide), and thereby of preventing development of a very significant proportion of cases of ICC, could be available within the next 2 years.

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“…We conclude that condom use blocks sexual HPV transmission by preventing reinfection and development of new penile lesions in men who are susceptible to the same type as present in the female partner. Infection with high-risk types of human papillomavirus (HPV) is the major cause of cervical cancer and its precursor lesions (Schiffman et al, 1993;Walboomers et al, 1999;Bosch et al, 2002;Munoz et al, 2003). Human papillomavirus has also been linked to cancers of the vulva, vagina, anus, and penis (IARC 1995;Melbye and Frisch, 1998).…”

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confidence: 99%

HPV type concordance in sexual couples determines the effect of condoms on regression of flat penile lesions

et al. 2005

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We earlier demonstrated, in a randomised clinical trial, that the regression time of flat penile lsions in male sexual partners of women with cervical intraepithelial neoplasia (CIN) was shorter in men who used condoms compared to those who did not. To further evaluate this finding, we examined whether the effect of condom use on the regression of flat penile lesions depends on the presence of human papillomavirus (HPV) type concordance in sexual couples, as determined in cervical and penile scrapes by GP5 þ /6 þ PCR testing. A Cox model with time-dependent covariates showed a beneficial effect of condoms on regression of flat penile lesions in concordant couples (hazard ratio 2.63, 95% CI 1.07 -6.48) but not in those who were nonconcordant. When both partners harboured different HPV types, no effect of condoms was found (hazard ratio 0.90, 95% CI 0.27 -2.96). Delayed regression of flat penile lesions was associated with either stable lesions or with new penile lesions developing at sites surrounding pre-existing lesions suggesting reinfection of the penile epithelium. We conclude that condom use blocks sexual HPV transmission by preventing reinfection and development of new penile lesions in men who are susceptible to the same type as present in the female partner. Infection with high-risk types of human papillomavirus (HPV) is the major cause of cervical cancer and its precursor lesions (Schiffman et al, 1993;Walboomers et al, 1999;Bosch et al, 2002;Munoz et al, 2003). Human papillomavirus has also been linked to cancers of the vulva, vagina, anus, and penis (IARC 1995;Melbye and Frisch, 1998). Genital HPV types are transmitted sexually and the risk of infection has been associated with numerous parameters involving sexual behaviour (Franco et al, 1995;Bosch et al, 1996;Kjaer et al, 2001).Partner studies have shown that penile lesions are found in more than half of the male partners of women with cervical intraepithelial neoplasia (CIN) (Barrasso et al, 1987;Campion et al, 1988;Hippelainen M et al, 1991;Bleeker et al, 2002). Flat lesions are reported as the most prevalent lesion type and their relationship with HPV has been established (Barrasso et al, 1987;Campion et al, 1988;Hippelainen M et al, 1991;Hippelainen MI et al, 1993b;Bleeker et al, 2002). Since flat penile lesions are only well visible after acetowhitening, their presence remains often unnoticed. This explains why the natural history of penile lesions and HPV infection in men has not been studied extensively and is largely unknown.We have recently shown that the presence of penile HPV is associated with delayed regression whereas condom use revealed accelerated regression . The beneficial effect of condom intervention on regression of penile lesions suggests that a sexual transmittable factor, that is, most likely cervical HPV, influences the clinical course of these lesions. To evaluate this hypothesis, the effect of condom use on regression of flat penile lesions was studied in relation to the presence of HPV type concordance between sexual part...

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The causal relation between human papillomavirus and cervical cancer

Cited by 3,005 publications

References 212 publications

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Vaccines for cervical cancer

HPV type concordance in sexual couples determines the effect of condoms on regression of flat penile lesions

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