Zelluläre Ursachen des unterschiedlichen Ansprechens HPV-assoziierter und Noxen-induzierter Plattenepithelkarzinome der Kopf- Halsregion auf eine kombinierte Radiochemotherapie
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Philipps-Universität Marburg
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Abstract
Head and neck squamous cell carcinoma (HNSCC) are divided into two distinct subgroups. One group is caused by classical risk factors like nicotine and alcohol, the other group is related to an infection with human papillomavirus (HPV). While the incidence for the first group is almost stable the latter one shows a dramatic increase. Clinical trials have shown that HPV-associated HNSCC have a better treatment response, regardless of treatment protocol, and have a favorable prognosis compared to HPV-negative HNSCC. Together with data from next- generation sequencing studies this led to the acceptance that HPV-associated and HPV- negative HNSCC are two biologically distinct etiologies. However, this did not lead to an HPV- adopted stratification for individualized treatment regimes. Today, both HPV-positive and HPV- negative HNSCC patients receive the same therapy that usually consist of definitive or adjuvant simultaneous Cisplatin based radiochemotherapy especially in advanced stage disease. While in ongoing clinical trials a de-escalation of the therapy for HPV-positive HNSCC is studied, the biological mechanisms causing this better response rates are still not fully understood.
This work aims at studying differences in HPV-positive and HPV-negative HNSCC cell lines that contribute to the improved treatment response of HPV-associated HNSCC. Therefore, the response of a panel of four HPV-positive and four HPV-negative cell lines to ionizing radiation and/or Cisplatin incubation was analyzed by measuring proliferation, cell viability, clonogenic survival, cell-cycle progression, expression of onco- and tumor suppressor-proteins, cell death and DNA-damage repair.
In concordance with clinical data, HPV-positive cell lines were sensitive to both ionizing radiation and Cisplatin incubation when compared with HPV-negative cell lines. In addition, in HPV-positive cell lines the radiosensitizing effect of Cisplatin was significantly stronger than in HPV-negative ones. HPV-positive cell lines exhibited a greater and prolonged cell-cycle arrest in G2-phase after irradiation alone and tended to arrest in S-phase after Cisplatin incubation. However, this was not reflected by a higher number of residual DNA double-strand breaks compared to HPV-negative cell lines. Instead, an increase in apoptosis mainly after Cisplatin incubation was found especially in HPV-positive cell lines. In line with this a decreased expression of both viral oncoproteins E6 and E7 was seen when cells where incubated with Cisplatin or a combination of Cisplatin and ionizing radiation. In contrast, irradiation alone led to an increase of both proteins. For tumor suppressor protein p53 no change in expression was found in all cell lines, regardless of treatment and HPV-status.
These data indicate that cell-cycle deregulation together with down-regulation of E6 and E7 leading to increased apoptosis facilitates the higher sensibility of HPV-positive cell lines to combined radio-chemotherapy. Thus, combined effects of radiotherapy and Cisplatin seem to promote the improved response rates of HPV-associated HNSCC. Therefore, adapting the dosage of radiation and Cisplatin might be a more promising strategy than restricting treatment to a single modality.
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Dates
Created: 2017Issued: 2017-03-31Updated: 2017-04-05
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
ZellzyklusregulationE7HNSCCHPVcell-cycle regulationp53HPVE6DSB-ReparaturE7ApoptoseCisplatinp53E6StrahlentherapieHNSCCradiotherapyDSB-repaircisplatinapoptosis
DFG-subjects
Protein p53DNS-ReparaturPlattenepithelcarcinomStrahlentherapieZellzyklusApoptosisHumanes PapillomavirusCisplatin
DDC-Numbers
610
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Ziemann, Frank: Zelluläre Ursachen des unterschiedlichen Ansprechens HPV-assoziierter und Noxen-induzierter Plattenepithelkarzinome der Kopf- Halsregion auf eine kombinierte Radiochemotherapie. : Philipps-Universität Marburg 2017-03-31. DOI: https://doi.org/10.17192/z2017.0210.
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This item has been published with the following license: In Copyright