disease markers 23 (2007) 197–198 ios press...

Disease Markers 23 (2007) 197–198 197IOS Press

Foreword

Magnus von Knebel Doeberitz∗ and Nicolas WentzensenGuest EditorsUniversity of Heidelberg, Germany

The year 2006 was marked by an important event incancer prevention: 30 years after Harald zur Hausen forthe first time hypothesized that human papillomavirus-es may be associated with the development of cervicalcancer, a prophylactic vaccine against certain types ofthese viruses was launched to the market in Mexico,the US, Canada, Australia, and several European coun-tries. Initially, the very rare malignant conversion ofcondylomata accuminata tempted zur Hausen to spec-ulate that infectious genital warts and cervical cancermay have a similar infectious causes. These considera-tions were strongly supported by observations made byAlexander Meisels in Toronto who found that replicat-ing HPV infections led to the formation of “koilocytes”that are found in condylomata but also in early cervicalintraepithelial lesions (CIN 1), the early precursors ofinvasive cervical cancer. Shortly thereafter, the papillo-mavirus genotypes 6 and 11 were isolated from condy-lomata and were used as molecular probes to identifyrelated viral genomes in cell lines and biopsies of cer-vical cancers. These experiments led to the successfuldetection of HPV 16 and 18 in the early 1980ies. Sub-sequent research revealed that oncogenic HPV genesare present in almost all cervical cancers, that the viralgenes E6 and E7 are continuously expressed in all can-cer cells, that these genes confer transforming activi-ties once they are expressed in cultured human epithe-lial cells in vitro and, importantly, that the inhibitionof the expression of these genes results in loss of theneoplastic growth of cervical cancer cells. Since thena tremendous amount of knowledge has been gatheredby many scientists, including epidemiologists, pathol-ogists, clinicians and public health physicians on theglobal distribution of oncogenic papillomaviruses andtheir disease causing role. It turned out that these virus-

∗Corresponding author. E-mail: [email protected].

es are abundant agents infecting the majority of all hu-mans at least once in their lifetime. They use an elegantreplication strategy that permits high level expressionof viral genes and multiplication of the viral genomewith capsid formation only in terminally differentiatedepithelial cells at the very surface of the epithelium thatare going to be exfoliated as cellular debris anyhow.Thus, they cause little or almost no damage within theinfected tissues and replicate usually unrecognized bythe host. Danger occurs only when after a rather pro-longed period of latent infection some basal cells losemolecular control mechanisms that restrain the virusand usually prevent active expression of viral genes inthe basal cells. Uncontrolled expression of the viraloncogenes may then induce chromosomal instabilityand initiate a dangerous cascade of events that drivethe cells through a series of pre-neoplastic lesions intoinvasive cancer cells.

All this knowledge was combined to design a plan todefeat this cancer-causing virus: Empty viral capsidsthat resemble normal virus particles, but lacking theirdangerous genetic information, have been producedand were injected subcutaneously to stimulate the im-mune system of vaccinees to produce neutralizing an-tibodies that prevent the entry of infectious virus parti-cles in the basal cells at risk of being infected by onco-genic papillomaviruses. Initial animal experiments andlater large worldwide clinical trials showed excellentprotection of the vaccinated individuals in almost 100% against infectious papillomavirus particles. Thus,the development of these vaccines crowns the 30 yearlong discovery of human papillomaviruses as cancercausing agents that are responsible for at least the sec-ond most frequent cancer in women world wide andthus represent after smoking the second most importantcarcinogen on earth.

Despite all this success a word of caution: we havenot yet reached all the goals. Cervical cancer still is an

ISSN 0278-0240/07/$17.00 2007 – IOS Press and the authors. All rights reserved

198 M. von Knebel Doeberitz and N. Wentzensen / Foreword

important and costly issue and the prevention approachwill only work if at least most women in the world willhave access to these vaccines. To achieve this, we willcertainly need a lot of time, effort and money. Theworst thing to do now would be to neglect the verysuccessful screening programs for cervical cancer thatmade cervical cancer the prime paradigm for success-ful cancer prevention strategies. About 60 years agoGeorge Papanicolaou developed a simple cytologicalstaining technique that allowed to identify preneoplas-tic cells in cytological specimens taken by a little swab,brush or broom from the uterine cervix. Because of itssimplicity this method became the most wide spreaddiagnostic test in oncology and led to reduction of theincidence of cervical cancer by about 70%. The vac-cine has to compete with this success and there clearlywill be a time period in that we will not be willing toabandon the one or the other.

For the time being, vaccination and screening haveto go hand in hand. It is clear that screening needs tobe adapted to the new demands. There is a lot of roomfor improvement in cervical cancer screening and a lotof opportunities to render it more cost-effective. Theintroduction of costly vaccines together with a costlyand ineffective screening program is surely not accept-able. In this issue we have addressed these problemsfrom many points of view covering all timely issuesof HPV-related disease, screening techniques, molecu-lar biomarkers as well as therapeutic and prophylacticvaccination approaches.

Jenkins summarizes the various histo- und cyto-pathological features associated with acute and persis-tent HPV-infections and provides the reader with the es-sential knowledge to understand how HPV gene prod-ucts alter shape and function of normal epithelial cells.

Bosch and de Sanjose present a current and ex-tensive survey of HPV and cervical cancer epidemi-ology. Moscicki gives an overview of HPV infec-tions, screening, triage, and treatment in adolescentsthat is highly relevant for vaccination programs, sinceadolescents represent the primary target populationand HPV infection in young girls emerges as a newproblem. Shah and Westra provide an up-to-date re-view of HPV associated disease in the aerodigestivetract, including the benign recurrent respiratory papi-

llomatosis as well as head and neck cancers. Nindland colleagues have summarized biological and clini-cal data on the role of human papillomviruses in non-melanoma skin cancer. Palefsky contributes a com-prehensive overview of HPV infections in men withrespect to disease patterns observed in men, transmis-sion of the virus to women and the related issues con-cerning the possible vaccination of women and men.Moving towards new approaches in screening, Meijerand colleagues present an extensive survey of differentHPV detection methods including genotyping and mR-NA detection together with different possible scenar-ios of their application. Pagliusi contributes an impor-tant article on the international standardization of HPVtesting.

Further articles address the emerging research onnew biomarkers for cervical cancer screening that ap-pear to help to overcome several of the important limi-tations of the current cancer early detection strategies.Doorbar extensively reviews molecular processes intransition from viral infection to the development ofhigh grade disease and cervical cancer. A special focusis put on the changes of the viral life cycle with effectson cellular genes and proteins. Wentzensen and vonKnebel Doeberitz summarize the current state of themost promising biomarkers that have been identified sofar for revised cervical cancer screening and triage pro-grams and potential clinical applications. The last twoarticles finally deal with the exciting topic of prophy-lactic and therapeutic vaccines. Muller and Gissmanncontribute an exciting historical essay of the discoveryof HPV and the highly interesting process of develop-ment of therapeutic and prophylactic vaccines. Kastand colleagues present an excellent and very timelysurvey on therapeutic vaccines against HPV and asso-ciated disease with a detailed description of the lessonslearned from the limitations of previous vaccinationtrials and of novel promising approaches.

We like to express our sincere thanks to all colleaguesand scientists who took the effort to contribute to thisselection of papers and very much hope that this issuewill be an informative source of valuable informationparticularly for the growing group of people joining thefield now and decided to help for their part to defeat hu-man papillomavirus infections and associated cancers.

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