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Biomolecular markers in head and neck cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck cancer is a heterogeneous group of tumours, of which certain subgroups such as cancer of the mobile tongue frequently are associated with a relatively poor prognosis due to the high risk of regional failure and mortality rates that haven’t improved in a significant way over the last 3 decades, despite advancements in both diagnostics and treatment.

Today we lack means to assess the biological aggressiveness of each individual tumour, which varies largely. Treatment comprises of surgery with additional radiotherapy and medical therapies in more advanced tumours.

The focus in this thesis is on molecular biomarker expression in head and neck cancer and especially in association with radiotherapy. Increased knowledge paves the way to a more individualized cancer treatment aiming for better outcome and less overtreatment and sequelae.

The aims of this thesis was:

  • To map the effects of radiotherapy in both tumour and adjacent tissue for the possible markers hyaluronan, EGFR and mast cells.
  • To investigate whether the expression of hyaluronan in the epithelium and connective tissue stroma and EGFR in the tumour correlates with the risk for developing cervical metastasis in N0 patients, and to find out whether the 3-year tumour-specific survival rates correlates with the expression of HA in the epithelium and EGFR in the tumour.
  • To establish an animal model for radiation-induced mucositis and to use that model to examine the pattern of invading inflammatory cells.
  • To investigate whether the expression of podoplanin in tongue cancer correlates with the risk for cervical metastasis and to determine whether the total amount of lymph vessels in the diagnostic biopsy has any impact on the clinical outcome.
  • To investigate the differences in the metabolome of tongue cancer cell lines with different radiosensitivity.

The most important findings of this thesis were:

  • The expression of EGFR and hyaluronan hade the same pattern of expression in both tumour and adjacent tissues before radiotherapy. The expression of EGFR was increased in the epithelium of the adjacent tissue close to the tumour after radiotherapy.
  • The intensity of the staining of hyaluronan was correlated to the 3-year survival rates in patients with tongue cancer.
  • An experimental model for radiation-induced oral mucositis in rat was established and in this model a temporal pattern of macrophage invasion with two different subtypes of macrophages was found.
  • There were no correlation between the expression of podoplanin in the tumour tissue and the cervical metastasis rate in patients with tongue cancer, but the younger patients were more likely to have a higher expression of podoplanin in their tumour than elder patients.
  • Tongue cancer cell lines with different radiosensitivity respond to irradiation with different patterns of metabolic expressions. 
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , p. 106
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1305
Keywords [en]
Head and neck cancer, Biomolecular markers, Radiation, Radiation-induced mucositis, Oral Tongue Squamous Cell Carcinoma, Metabolomics, EGFR, Hyaluronan, Mast cells, Neutrophils
National Category
Otorhinolaryngology
Research subject
Oto-Rhino-Laryngology
Identifiers
URN: urn:nbn:se:uu:diva-306126ISBN: 978-91-554-9835-1 (print)OAI: oai:DiVA.org:uu-306126DiVA, id: diva2:1077319
Public defence
2017-04-21, Skoog-salen, Ingång 78-79 Akademiska sjukhuset, Uppsala, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2017-03-28 Created: 2017-02-27 Last updated: 2017-03-30
List of papers
1. Effect of radiotherapy on expression of hyaluronan and EGFR and presence of mast cells in squamous cell carcinoma of the head and neck.
Open this publication in new window or tab >>Effect of radiotherapy on expression of hyaluronan and EGFR and presence of mast cells in squamous cell carcinoma of the head and neck.
2012 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 4, no 6Article in journal (Refereed) Published
Abstract [en]

Head and neck squamous cell carcinoma is a common form of cancer, and despite improvements in treatment during the last decades, survival rates have not significantly increased. There is therefore a need to better understand how these tumours and the adjacent tissues react to radiotherapy, the most common type of treatment for this group of tumours. In order to improve this understanding, the expression of hyaluronan (HA) and epidermal growth factor receptor (EGFR) and the presence of mast cells were mapped before and after radiotherapy using immunohistochemistry. The results showed HA and EGFR to have similar expression patterns in tumour tissue and histologically normal squamous epithelium prior to radiotherapy. Following radiotherapy, EGFR increased in histologically normal epithelium. An increased number of mast cells were also observed as a result of radiotherapy. No expression of EGFR was observed in the connective tissue either prior to or following radiotherapy.

Keywords
Age; Body mass index; Cytokine; Human; Proximity extension assay (PEA); Cerebrospinal fluid
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-269490 (URN)10.3892/ol.2012.907 (DOI)23205115 (PubMedID)
Available from: 2015-12-16 Created: 2015-12-16 Last updated: 2017-12-01
2. The Micromorphological Course of Irradiation-Induced Oral Mucositis in Rat.
Open this publication in new window or tab >>The Micromorphological Course of Irradiation-Induced Oral Mucositis in Rat.
2015 (English)In: Journal of Clinical & Experimental Oncology, ISSN 2324-9110Article in journal (Refereed) Published
National Category
Otorhinolaryngology
Research subject
Oto-Rhino-Laryngology; Oncology
Identifiers
urn:nbn:se:uu:diva-316200 (URN)10.4172/2324-9110.1000145 (DOI)
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-02-27
3. High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients≤ 40 years but does not correlate with tumour spread
Open this publication in new window or tab >>High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients≤ 40 years but does not correlate with tumour spread
Show others...
2016 (English)In: The journal of pathology. Clinical research, ISSN 2056-4538, no 1, p. 3-8Article in journal (Refereed) Published
Abstract [en]

More than 30% of patients with squamous cell carcinoma (SCC) of the mobile tongue have clinically undetectable lymph node metastasis. Tumour cells can spread as single cells or collectively. A protein known to play a role in both processes is podoplanin, which is expressed in endothelial cells not only in lymph vessels but also in some aggressive tumours with high invasive and metastatic potential. Here we studied samples from 129 patients with primary SCC of the tongue for expression of podoplanin using immunohistochemistry. mRNA levels were analysed in another 27 cases of tongue SCC with adjacent clinically tumour-free tongue tissue and 14 tongue samples from healthy donors. Higher levels of podoplanin were seen in tumours compared to both normal tongue and clinically normal tongue in the tumour vicinity. No association was found between levels of podoplanin, presence of lymph node metastases or other clinical factors. Patients aged 40 or less were more likely to express high levels of podoplanin protein compared to older patients (p = 0.027). We conclude that levels of podoplanin in primary tongue SCCs are not associated with lymph node metastases. However, tongue SCCs arising in young patients (< 40 years of age) are more likely to express high levels of podoplanin than tongue SCCs that arise in the more elderly. The data suggest that podoplanin has a distinctive role in young patients, who are known to have a poor prognosis: these patients may, therefore, benefit from podoplanin inhibitory therapies.

National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-316241 (URN)10.1002/cjp2.28 (DOI)000410840100001 ()27499910 (PubMedID)
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-12-08Bibliographically approved
4. Immunohistochemical analysis of EGFR and hyaluronan in tongue cancer and the development of regional recurrence in patients initially diagnosed N0
Open this publication in new window or tab >>Immunohistochemical analysis of EGFR and hyaluronan in tongue cancer and the development of regional recurrence in patients initially diagnosed N0
2017 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 137, no 8, p. 877-882Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate whether the extent of expression of hyaluronan (HA) and epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the mobile tongue can predict the risk of cervical metastasis and survival. Study design: Retrospective histopathologic study. Methods: Surgical specimens from 64 patients who had undergone surgery for squamous cell carcinoma of the mobile tongue were assessed using immunohistochemistry to investigate the expression of HA and EGFR in the primary tumours, and the data were then correlated to cervical metastasis and survival. Results: There was a significant correlation between the intensity of HA staining and patient survival (p .024), and a weak correlation between the staining proportion of EGFR and the risk for regional recurrence (AUC 66). Conclusions: This study indicates that immunoscoring using HA could be used to provide prognostic tools for tongue cancer, and that it might be of interest to study the prognostic properties of EGFR further concerning the risk for regional recurrence after the primary treatment.

Place, publisher, year, edition, pages
Taylor & Francis, 2017
Keywords
Epidermal growth factor receptor expression, immunoscoring, oral tongue squamous cell carcinoma, prognostic factors, biomarkers
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-316243 (URN)10.1080/00016489.2017.1292049 (DOI)000404684100016 ()28355940 (PubMedID)
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-10-19Bibliographically approved
5. Metabolic profiling of head and neck cancer cell lines with different radiosensitivity using mass spectroscopy provides new insights on the mechanism of radiation response.
Open this publication in new window or tab >>Metabolic profiling of head and neck cancer cell lines with different radiosensitivity using mass spectroscopy provides new insights on the mechanism of radiation response.
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-316244 (URN)
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-02-27

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