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Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
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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.

Place, publisher, year, edition, pages
2009. Vol. 100, no 2, 334-343 p.
Keyword [en]
oesophageal cancer, Hsp90, 17-AAG, EGF, IGF-1, radiation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-102928DOI: 10.1038/sj.bjc.6604855ISI: 000262637800017PubMedID: 19142186OAI: oai:DiVA.org:uu-102928DiVA: diva2:217051
Available from: 2009-05-12 Created: 2009-05-12 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase
Open this publication in new window or tab >>Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase
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
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:nbn:se:uu:diva-152614 (URN)978-91-554-8100-1 (ISBN)
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

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