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Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) poses a major health problem in the world with approximately 600 000 new cases yearly. Treatment resistance is a major problem within this patient group and despite advances in treatment strategies the overall survival rate has unfortunately not increased.

One of the major components of the tumor microenvironment is the cancer associated fibroblasts (CAFs) which can modulate the treatment sensitivity, tumor growth, and the invasive potential of tumor cells.

The aim of this thesis was to identify predictive markers for treatment response in HNSCC and to study the crosstalk between tumor cells and CAFs that may underlie treatment resistance.

In paper I, we identified gene expression differences between one cisplatin sensitive cell line and two cisplatin resistant cell lines, by microarray analysis, and found that a high expression of matrix metalloproteinase (MMP) -7 was associated with resistance to cisplatin. In paper II, the epidermal growth factor (EGF) receptor ligands EGF, amphiregulin, and epiregulin were evaluated regarding their potential use as predictive biomarkers for cetuximab treatment response in tongue cancer cell lines and it was shown that EGF may serve as a marker for poor cetuximab response. In paper III and IV, we investigated the influence of CAFs on the proliferation, migration, gene expression, and cetuximab response of tumor cells. It was found that CAFs induced resistance to cetuximab in a MMP-dependent manner. In addition, a microarray analysis, comparing tumor cells co-cultured with CAFs and tumor cells cultured alone, revealed that CAFs induced multiple gene expression changes in tumor cells some of which are related to epithelial to mesenchymal transition. Some of these changes were found to be dependent on cell-cell contact.

Taken together, we here suggest MMP-7 and EGF to be predictive markers of cisplatin and cetuximab response, respectively. We also show that CAFs protect HNSCC cells from cetuximab treatment; however, the factor responsible for the protective effect is yet to be discovered.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. , 89 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1382
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-100734DOI: 10.3384/diss.diva-100734ISBN: 978-91-7519-492-9 (print)OAI: oai:DiVA.org:liu-100734DiVA: diva2:663329
Public defence
2013-11-29, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2013-11-11Bibliographically approved
List of papers
1. Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.
Open this publication in new window or tab >>Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.
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2009 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, no 10, 866-871 p.Article in journal (Refereed) Published
Abstract [en]

Concomitant chemoradiotherapy is a common treatment for advanced head and neck squamous cell carcinomas (HNSCC). Cisplatin is the backbone of chemotherapy regimens used to treat HNSCC. Therefore, the aim of this study was to identify predictive markers for cisplatin treatment outcome in HNSCC. The intrinsic cisplatin sensitivity (ICS) was determined in a panel of tumour cell lines. From this panel, one sensitive and two resistant cell lines were selected for comparative transcript profiling using microarray analysis. The enrichment of Gene Ontology (GO) categories in sensitive versus resistant cell lines were assessed using the Gene Ontology Tree Machine bioinformatics tool. In total, 781 transcripts were found to be differentially expressed and 11 GO categories were enriched. Transcripts contributing to this enrichment were further analyzed using Ingenuity Pathway Analysis (IPA) for identification of key regulator genes. IPA recognized 20 key regulator genes of which five were differentially expressed in sensitive versus resistant cell lines. The mRNA level of these five genes was further assessed in a panel of 25 HNSCC cell lines using quantitative real-time PCR. Among these key regulators, MMP-7 and MMP-13 are implicated as potential biomarkers of ICS. Taken together, genome-wide transcriptional analysis identified single genes, GO categories as well as molecular networks that are differentially expressed in HNSCC cell lines with different ICS. Furthermore, two novel predictive biomarkers for cisplatin resistance, MMP-7 and MMP-13, were identified.

Place, publisher, year, edition, pages
Elsevier, 2009
Keyword
Predictive markers; Gene Ontology; Head and neck cancer; Cisplatin; Microarray; MMPs
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-21436 (URN)10.1016/j.oraloncology.2009.02.008 (DOI)000270022000005 ()19442568 (PubMedID)
Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2017-12-13Bibliographically approved
2. Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells
Open this publication in new window or tab >>Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells
2016 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 45, no 1, 9-16 p.Article in journal (Refereed) Published
Abstract [en]

Background: Epidermal growth factor receptor (EGFR) is a target for treatment in tongue cancer. Here, EGFR ligands were evaluated for their potential uses as predictive biomarkers of cetuximab treatment response.

Methods: In three tongue cancer cell lines the influences of epidermal growth factor (EGF), amphiregulin (AR), and epiregulin (EPR) on tumour cell proliferation and cetuximab response were evaluated by the addition of recombinant human (rh) proteins or the siRNA-mediated downregulation of endogenous ligand production.

Results: EGF or AR downregulation suppressed the proliferation of all investigated cell lines. Furthermore, all cell lines displayed increased cetuximab resistance upon the addition of rhEGF, whereas EGF silencing resulted in an improved cetuximab response in one cell line.

Conclusions: Our data suggest that EGF and AR are critical components of the EGFR signalling network required for full proliferative potential. Moreover, EGF is a potential predictive biomarker of poor cetuximab response and a possible treatment target.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016
Keyword
Head and neck cancer; Tongue cancer; Erbitux; EGFR ligands; treatment response
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-100675 (URN)10.1111/jop.12310 (DOI)000369990100003 ()
Note

Funding agencies: Foundation of Ake Wiberg; Swedish Cancer Society [2008/552, 2010/545]; County Council of Ostergotland; Linkoping University Hospital; Foundation of Magnus Bergvall; Cancer Foundation of Ostergotland

Vid tiden för disputation förelåg publikationen endast som manuskript

Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2017-05-03
3. Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
Open this publication in new window or tab >>Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
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2012 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 10, no 9, 1158-1168 p.Article in journal (Refereed) Published
Abstract [en]

A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86135 (URN)10.1158/1541-7786.MCR-12-0030 (DOI)000310648300003 ()
Note

Funding Agencies|Johan and Jakob Soderberg Foundation||Foundation Olle Engqvist Byggmastare||Swedish Laryng Foundation||Borgholm Rotary Club||Swedish National Board of Health and Welfare||Lions Research Foundation||Lars Hierta Memorial Foundation||Tore Nilsson Foundation for Medical Research||Swedish Society for medical research||County Council of Ostergotland||Cancer Foundation of Ostergotland||Merck Serono||Swedish Research Council|349-2008-6578|Swedish Cancer Society|CAN 2009/1136CAN 2010/545|

Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2017-12-07
4. Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts
Open this publication in new window or tab >>Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Cancer-associated fibroblasts (CAFs) are one of the main components of the tumor stroma and are known to increase tumor growth and stimulate  invasion and metastasis. Increasing evidence suggests that CAFs may also be an important determinant of the response to various treatments. In this study we aimed to characterize the molecular cross-talk between CAFs and head and neck squamous cell carcinoma (HNSCC) cells.

HNSCC cell lines were co-cultured with their patient-matched CAFs for seven days, after which the gene expression of tumor cells was investigated by Affymetrix microarray. 58 protein coding genes were found to be differentially expressed (Q≤0.05) in tumor cells cocultured with CAFs when compared to tumor cells cultured alone. The top functions of these genes were cancer, cellular movement, and embryonic development as analyzed by Ingenuity Pathway Analysis. Nine genes were upregulated by ≥1.5-fold while the expression of 35 genes was found to be reduced by ≤ 0.67-fold. Several of the differentially expressed genes have been associated with epithelial-to-mesenchymal transition (EMT). The change in the expression of POSTN, GREM1, COL1A2, VIM, and MMP7 was verified by qPCR analysis. Moreover, the influence of CAFs on the proliferation, migration and cetuximab sensitivity of tumor cells was investigated, and was found to vary among the tumor cell-CAF pairs.

In conclusion, we demonstrate that CAF-derived signals cause changes in the expression of multiple genes, several of which are associated with an EMT phenotype of tumor cells. Furthermore, CAFs modulate the proliferation, migration and cetuximab treatment response of tumor cells.

Keyword
Head and neck cancer; Tongue cancer; Erbitux; EGFR ligands; treatment response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100678 (URN)
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2013-11-11Bibliographically approved

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