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Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oesophageal cancer is a malignant and aggressive disease with very poor survival. The aim of this thesis was to evaluate novel therapeutic targets in oesophageal cancer.

In paper I, Hsp90 was expressed in all 81 oesophageal cancer tissues and also in nine oesophageal cancer cell lines. A specific Hsp90 inhibitor, 17-AAG, could efficiently inhibit cell proliferation, cell survival and sensitise oesophageal cancer cells to gamma photon irradiation. By inhibition of Hsp90 using 17-AAG, EGFR- and IGF-1R-mediated signalling was downregulated.

In paper II, tumour samples from 80 oesophageal cancer patients were investigated for the expression of EGFR and LRIG1-3. Based on a total score of intensity and expression fraction a trend towards survival differences was found for LRIG2 (p=0.18) and EGFR (p=0.09). Correlation analysis revealed a correlation between expression of EGFR and LRIG3 (p=0.0007). Significant correlations were found between LRIG1 mRNA expression levels and sensitivity to cisplatin (r = –0.74), docetaxel (r = –0.69), and vinorelbine (r = –0.82).

In paper III, microtubule targeting drugs podophyllotoxin (PPT), vincristine and docetaxel inhibited survival and proliferation of oesophageal cancer cells. Unexpectedly, experiments showed that microtubule destabilising agents inhibited EGFR phosphorylation and signalling. A tyrosine phosphatase inhibitor, sodium orthovanadate, was able to reverse the EGFR dephosphorylation.

In paper IV, imetelstat, a telomerase antagonist, inhibited telomerase activity, colony formation ability and decreased proliferation of oesophageal cancer cells. Inhibition of telomerase activity by imetelstat led to an increase of 53BP1 foci indicating induction of DSBs. Furthermore, the fraction and size of radiation-induced 53BP1 foci were increased by imetelstat pre-treatment.

In conclusion, Hsp90 and telomerase represent potential therapeutic targets in oesophageal cancer. And, the implication of EGFR and LRIG as prognostic factors is limited. Furthermore, disruption of the microtubule network may activate a protein tyrosine phosphatase that can regulate EGFR phosphorylation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 680
Keyword [en]
Hsp90, EGFR, LRIG, microtubule, telomerase, oesophageal cancer, imetelstat, DNA double-strand break, 17-AAG, radiation, prognosis, radiosensitisation, microtubule targeting agents
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-152614ISBN: 978-91-554-8100-1OAI: oai:DiVA.org:uu-152614DiVA: diva2:414126
Public defence
2011-06-14, Auditorium Minus, Gustavianum, Akademigatan 3, 75310, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-05-24 Created: 2011-04-28 Last updated: 2011-07-01Bibliographically approved
List of papers
1. Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin
Open this publication in new window or tab >>Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin
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2009 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 2, 334-343 p.Article in journal (Refereed) Published
Abstract [en]

Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer. In squamous cell carcinoma, a marked upregulation of Hsp90 could be noted in dysplastic epithelium and invasive cancer compared with normal epithelium. In adenocarcinoma, Hsp90 was expressed in neoplastic epithelium and also in normal non-neoplastic glands weakly. The inhibition of Hsp90 using 17-AAG led to a significant decrease in cell proliferation and viability in human oesophageal cancer cell lines. Using a clonogenic cell survival assay, Hsp90 inhibition significantly sensitised the cells for gamma-photon irradiation. Heat shock protein 90 was found to be critical for proper signalling induced by both epidermal growth factor and insulin-like growthfactor -1, in which the inhibition of signalling by 17-AAG correlated with the observed reduction in cell proliferation and viability. These results showed that Hsp90 was selectively expressed in oesophageal cancer tissue compared with the corresponding normal tissue, and the inhibition of Hsp90 resulted in decreased proliferation and viability as well as radiosensitisation of oesophageal cancer cells. Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy.

Keyword
oesophageal cancer, Hsp90, 17-AAG, EGF, IGF-1, radiation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102928 (URN)10.1038/sj.bjc.6604855 (DOI)000262637800017 ()19142186 (PubMedID)
Available from: 2009-05-12 Created: 2009-05-12 Last updated: 2011-07-01Bibliographically approved
2. Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity
Open this publication in new window or tab >>Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity
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2012 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, 69-76 p.Article in journal (Refereed) Published
Abstract [en]

Background. Leucine-rich and immunoglobulin-like domains 1-3 (LRIG1-3) proteins have been implicated in the regulation of EGFR signalling. In the present study, we investigated the clinical implications of the expression of EGFR and LRIG1-3 in oesophageal carcinoma, as well as the correlation between their expression levels and the chemosensitivity of oesophageal carcinoma cell lines.

Patients and methods. Tumours from 80 patients with oesophageal carcinoma were investigated for the expression of EGFR and LRIG proteins by immunohistochemistry. Oesophageal carcinoma cell lines were investigated for their expression of EGFR and LRIG1, 2, and 3 by quantitative real time RT-PCR and for their sensitivity to commonly used chemotherapeutics by a cytotoxicity assay.

Results and discussion: Based on a total score of intensity and expression rates, a trend towards survival difference was found for EGFR (p = 0.09) and LRIG2 (p = 0.18) whereas for LRIG1 and -3 there was no trend towards any association with survival. Correlation analysis revealed a correlation with the clinical expression of EGFR and LRIG3 (p = 0.0007). Significant correlations were found between LRIG1 expression levels and sensitivity to cisplatin (r = -0.74), docetaxel (r = -0.69), and vinorelbine (r = -0.82) in oesophageal carcinoma cell lines. EGFR and the LRIG proteins may be functionally involved in oesophageal carcinoma, but larger materials are needed to fully elucidate the clinical implication.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-152606 (URN)10.3109/0284186X.2011.562239 (DOI)000298002000010 ()21417672 (PubMedID)
Available from: 2011-04-28 Created: 2011-04-28 Last updated: 2012-02-15Bibliographically approved
3. Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylation
Open this publication in new window or tab >>Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylation
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Microtubules are important structures for a range of cellular functions including cell division. Drugs that interfere with microtubule function can prevent cells from mitosis and various microtubule targeting drugs are used in a clinical setting. In the current study we investigated the sensitivity of oesophageal cancer cells to different microtubule targeting agents. As expected, experiments demonstrated that these agents in a dose-dependent manner inhibited survival and proliferation of oesophageal cancer cells and disrupted the microtubule network. Unexpectedly, experiments showed that microtubule destabilising agents inhibited phosphorylation and activation of the EGF-receptor, and that a tyrosine phosphatase inhibitor, sodium orthovanadate, could reverse the EGFR dephosphorylation. We propose a model in which disruption of the microtubule network leads to activation of a protein tyrosine phosphatase that can regulate EGFR phosphorylation and activation, indicating an additional mechanism of action of microtubule targeting agents.

Identifiers
urn:nbn:se:uu:diva-152763 (URN)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2011-07-22Bibliographically approved
4. The effect of the telomerase antagonist Imetelstat in esophageal carcinoma
Open this publication in new window or tab >>The effect of the telomerase antagonist Imetelstat in esophageal carcinoma
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, Imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that Imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only one week of Imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with Imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Cell cycle analysis demonstrated that short-term treatment with Imetelstat resulted in increased percentage of cells in G1 phase. Short-term Imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with Imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1 h of repair whereas the increase of foci size was prominent later on. This study supports the potential of Imetelstat as a therapeutic agent for the treatment of esophageal cancer.

Identifiers
urn:nbn:se:uu:diva-152761 (URN)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2011-07-01

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