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Roberg, Karin
Publications (10 of 58) Show all publications
Melissaridou, S., Wiechec, E., Magan, M., Jain, M. V., Chung, M. K., Farnebo, L. & Roberg, K. (2019). The effect of 2D and 3D cell cultures on treatment response, EMT profile and stem cell features in head and neck cancer.. Cancer Cell International, 19(16)
Open this publication in new window or tab >>The effect of 2D and 3D cell cultures on treatment response, EMT profile and stem cell features in head and neck cancer.
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2019 (English)In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 19, no 16Article in journal (Refereed) Published
Abstract [en]

Background

Head and Neck Squamous Cell Carcinoma (HNSCC) tumors are often resistant to therapies. Therefore searching for predictive markers and new targets for treatment in clinically relevant in vitro tumor models is essential. Five HNSCC-derived cell lines were used to assess the effect of 3D culturing compared to 2D monolayers in terms of cell proliferation, response to anti-cancer therapy as well as expression of EMT and CSC genes.

Methods

The viability and proliferation capacity of HNSCC cells as well as induction of apoptosis in tumor spheroids cells after treatment was assessed by MTT assay, crystal violet- and TUNEL assay respectively. Expression of EMT and CSC markers was analyzed on mRNA (RT-qPCR) and protein (Western blot) level.

Results

We showed that HNSCC cells from different tumors formed spheroids that differed in size and density in regard to EMT-associated protein expression and culturing time. In all spheroids, an up regulation of CDH1, NANOG and SOX2 was observed in comparison to 2D but changes in the expression of EGFR and EMT markers varied among the cell lines. Moreover, most HNSCC cells grown in 3D showed decreased sensitivity to cisplatin and cetuximab (anti-EGFR) treatment.

Conclusions

Taken together, our study points at notable differences between these two cellular systems in terms of EMT-associated gene expression profile and drug response. As the 3D cell cultures imitate the in vivo behaviour of neoplastic cells within the tumor, our study suggest that 3D culture model is superior to 2D monolayers in the search for new therapeutic targets.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Cancer stem cells; Drug response; Epithelial–mesenchymal transition; Head and Neck Squamous Cell Carcinoma; Spheroids
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-153947 (URN)10.1186/s12935-019-0733-1 (DOI)000455593400001 ()30651721 (PubMedID)2-s2.0-85059943217 (Scopus ID)
Note

Funding agencies: Korea-Sweden Joint Research Programme; Swedish Cancer Society [2017/301]; County Council of Ostergotland; Research Funds of Linkoping University Hospital; Cancer Foundation of Ostergotland

Available from: 2019-01-21 Created: 2019-01-21 Last updated: 2019-03-29Bibliographically approved
Jedlinski, A., Garvin, S., Johansson, A.-C., Edqvist, P.-H., Pontén, F. & Roberg, K. (2017). Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction of EGFR, pEGFR, and pSrc. Journal of Oral Pathology & Medicine (9), 717-724
Open this publication in new window or tab >>Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction of EGFR, pEGFR, and pSrc
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2017 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, no 9, p. 717-724Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The aim of this study was to validate in vitro drug sensitivity testing of head and neck squamous cell carcinoma (HNSCC)cell lines in an in vivo xenograft model, and to identify treatment-induced changes in the EGFR signaling pathway that could be used as markersfor cetuximab treatment response.

METHODS: The in vitro cetuximab sensitivity of two HNSCC cell lines, UT-SCC-14 and UTSCC-45, was assessed using a crystal violet assay. In order to determine the corresponding in vivo sensitivity, UT-SCC-14 and UT-SCC-45 xenografts were generated in female BALB/c (nu/nu) nude mice. Mice were given three injections of intraperitoneal cetuximab or PBS and the tumor volume was recorded continuously. The expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR (pEGFR), phosphorylated Src (pSrc), and Ki67 was investigated by immunohistochemistry.

RESULTS: The treatment sensitive UT-SCC-14 cells were found to have an intrinsic cetuximab sensitivity (ICmabS) of 0.15 whereas the ICmabS of the insensitive cell line UT-SCC-45 was 0.78. The corresponding size ratio between untreated and cetuximab treated xenografts was 0.22 and 0.83 for UT-SCC-14 and UT-SCC-45, respectively. UT-SCC-14 cells had a higher baseline expression of pEGFR as compared to UT-SCC-45. Furthermore, in UT-SCC-14 xenografts there was a decrease in EGFR, pEGFR and pSrc upon cetuximab treatment. In contrast, a slight cetuximab-induced increase in EGFR, pEGFR and pSrc was observed in treatment-resistant UT-SCC-45 xenografts.

CONCLUSIONS: The in vitro treatment sensitivity was reproduced in the in vivo model and cetuximab sensitivity was found to associate with a treatment-induced reduction in pEGFR and pSrc.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
National Category
Medical and Health Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113742 (URN)10.1111/jop.12545 (DOI)000412303500009 ()28036101 (PubMedID)
Note

Funding agencies: Foundation of Ake Wiberg; County Council of Ostergotland; Research Funds of Linkoping University Hospital; Cancer Foundation of Ostergotland; Foundation of Magn. Bergvall; The Swedish Cancer Society [2010/545]

The previous status of this publication was Manuscript

Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2018-05-03Bibliographically approved
Wiechec, E., Tiefenböck Hansson, K., Alexandersson, L., Jönsson, J.-I. & Roberg, K. (2017). Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells.. International Journal of Molecular Sciences, 18(5)
Open this publication in new window or tab >>Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells.
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2017 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, no 5Article in journal (Refereed) Published
Abstract [en]

Despite advances in the head and neck squamous cell carcinoma (HNSCC) treatment modalities, drug resistance and cancer recurrence are often reported. Hypoxia signaling through hypoxia-inducible factor 1 (HIF-1) promotes angiogenesis and metastasis by inducing epithelial-mesenchymal-transition (EMT). The aim of this study was to evaluate the impact of hypoxia on response to therapy as well as EMT and expression of stem cell markers in HNSCC cells. Five HNSCC cell lines (UT-SCC-2, UT-SCC-14, LK0412, LK0827, and LK0923) were selected for this study. The treatment sensitivity for radiation, cisplatin, cetuximab, and dasatinib was assessed by crystal violet assay. Gene expression of EMT and cancer stem cell (CSC) markers as well as protein level of EGFR signaling molecules were analyzed by qPCR and western blotting, respectively. Unlike UT-SCC-14 and LK0827, the LK0412 cell line became significantly more sensitive to cetuximab in hypoxic conditions. This cetuximab sensitivity was efficiently reversed after suppression of HIF-1α with siRNA. Additionally, hypoxia-induced EMT and expression of stem cell markers in HNSCC cells was partially revoked by treatment with cetuximab or knockdown of HIF-1α. In summary, our study shows that hypoxia might have a positive influence on the anti-EGFR therapy effectiveness in HNSCC. However, due to heterogeneity of HNSCC lesions, targeting HIF-1α may not be sufficient to mediate such a response. Further studies identifying a trait of hypoxia-specific response to cetuximab in HNSCC are advisable.

Place, publisher, year, edition, pages
M D P I AG, 2017
Keywords
HIF-1α; cancer stem cells (CSC); cetuximab; cisplatin; epithelial-mesenchymal transition (EMT); head and neck tumors; hypoxia; radiotherapy
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-137276 (URN)10.3390/ijms18050943 (DOI)000404113900050 ()28468237 (PubMedID)2-s2.0-85018414799 (Scopus ID)
Note

Funding agenceis: County Council of Ostergotland; Research Funds of Linkoping University Hospital; Cancer Foundation of Ostergotland; Swedish Cancer Society; Swedish Research Council

Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2018-05-02Bibliographically approved
Ansell, A., Jedlinski, A., Johansson, A.-C. & Roberg, K. (2016). Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells. Journal of Oral Pathology & Medicine, 45(1), 9-16
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, p. 9-16Article 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
Keywords
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
Jangamreddy, J. R., Jain, M. V., Hallbeck, A.-L., Roberg, K., Lotfi, K. & Los, M. J. (2015). Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death. OncoTarget, 6(12), 10134-10145
Open this publication in new window or tab >>Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, p. 10134-10145Article in journal (Refereed) Published
Abstract [en]

Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2015
Keywords
Glucose starvation, 2DG, 2FDG, Normoxia and Hypoxia, Differential Stress Response, autophagy, Akt, Tricirabine, Salinomycin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-113707 (URN)000358874600039 ()
Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2018-01-11Bibliographically approved
Garvin, S., Tiefenböck, K., Farnebo, L., Thunell, L., Farnebo, M. & Roberg, K. (2015). Nuclear expression of WRAP53 beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma. Oral Oncology, 51(1), 24-30
Open this publication in new window or tab >>Nuclear expression of WRAP53 beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma
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2015 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 51, no 1, p. 24-30Article in journal (Refereed) Published
Abstract [en]

Objectives: Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under-and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53 beta (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53 beta can predict response to radiotherapy in patients with HNSCC. Materials and methods: Tumor biopsies from patients with HNSCC classified as responders or non-responders to radiotherapy were examined for the expression of the WRAP53 beta protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53 beta on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. Results: Nuclear expression of WRAP53 beta was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53 beta with siRNA in vitro enhanced cellular resistance to radiation. Conclusions: Our findings suggest that nuclear expression of WRAP53 beta promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Head and neck cancer; Radiotherapy; Predictive factors; Survivin; WRAP53
National Category
Cancer and Oncology Otorhinolaryngology
Identifiers
urn:nbn:se:liu:diva-113161 (URN)10.1016/j.oraloncology.2014.10.003 (DOI)000346210900007 ()25456005 (PubMedID)
Note

Funding Agencies|Swedish Laryng Foundation; Ake Wiberg Foundation; Swedish Cancer Society [2008/552, 2010/545]; County Council of Ostergotland; Research Funds of Linkoping University Hospital

Available from: 2015-01-14 Created: 2015-01-12 Last updated: 2017-12-05
Jerhammar, F., Johansson, A.-C., Ceder, R., Welander, J., Jansson, A., Grafstrom, R. C., . . . Roberg, K. (2014). YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Oral Oncology, 50(9), 832-839
Open this publication in new window or tab >>YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer
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2014 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 50, no 9, p. 832-839Article in journal (Refereed) Published
Abstract [en]

Objectives: Targeted therapy against the epidermal growth factor receptor (EGFR) only variably represents a therapeutic advance in head and neck squamous cell carcinoma (HNSCC). This study addresses the need of biomarkers of treatment response to the EGFR-targeting antibody cetuximab (Erbitux (R)). Materials and Methods: The intrinsic cetuximab sensitivity of HNSCC cell lines was assessed by a crystal violet assay. Gene copy number analysis of five resistant and five sensitive cell lines was performed using the Affymetrix SNP 6.0 platform. Quantitative real-time PCR was used for verification of selected copy number alterations and assessment of mRNA expression. The functional importance of the findings on the gene and mRNA level was investigated employing siRNA technology. The data was statistically evaluated using Mann-Whitney U-test and Spearmans correlation test. Results: Analysis of the intrinsic cetuximab sensitivity of 32 HNSCC cell lines characterized five and nine lines as cetuximab sensitive or resistant, respectively. Gene copy number analysis of five resistant versus five sensitive cell lines identified 39 amplified protein-coding genes, including YAP1, in the genomic regions 11q22.1 or 5p13-15. Assessment using qPCR verified that YAP1 amplification associated with cetuximab resistance. Amplification of YAP1 correlated to higher mRNA levels, and RNA knockdown resulted in increased cetuximab sensitivity. Assessment of several independent clinical data sets in the public domain confirmed YAP1 amplifications in multiple tumor types including HNSCC, along with highly differential expression in a subset of HNSCC patients. Conclusion: Taken together, we provide evidence that YAP1 could represent a novel biomarker gene of cetuximab resistance in HNSCC cell lines.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Head and neck cancer; SCCHN; YAP1; Predictive marker; Treatment response; Gene copy number; Drug resistance
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-110268 (URN)10.1016/j.oraloncology.2014.06.003 (DOI)000340267300011 ()24993889 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2008/552, 2010/545]; Ake Wiberg foundation; National board of health and welfare; Ostergotland county council; Foundation of Olle Engkvist; Swedish Cancer and Allergy Fund; Swedish Research Council; Swedish Fund for Research

Available from: 2014-09-05 Created: 2014-09-05 Last updated: 2017-12-05
Jedlinski, A., Ansell, A., Johansson, A.-C. & Roberg, K. (2013). EGFR status and EGFR ligand expression influence the treatment response of head and neck cancer cell lines. Journal of Oral Pathology & Medicine, 42(1), 26-36
Open this publication in new window or tab >>EGFR status and EGFR ligand expression influence the treatment response of head and neck cancer cell lines
2013 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 42, no 1, p. 26-36Article in journal (Refereed) Published
Abstract [en]

Background: Combination treatment (chemoradiotherapy) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems. A high level of epidermal growth factor receptor (EGFR) has been associated with a more aggressive phenotype as well as decreased responsiveness to radio- or chemotherapy. We examined the role of EGFR status and EGFR ligand expression for the treatment response. Methods: Intrinsic sensitivity to radiotherapy, cisplatin, and cetuximab treatments was investigated in 25 HNSCC cell lines. EGFR gene copy number, mRNA and protein expression, EGFR and Akt phosphorylation status, and mRNA expression of the EGFR ligands were analyzed using quantitative PCR and ELISA and assessed for their impact on treatment sensitivity. Results: Different treatment modalities yielded great diversity in outcome; of note, cetuximab treatment stimulated growth in one cell line. When treatments were combined primarily additive effects were observed. While radioresistance tended to be associated with a high level of phosphorylated EGFR (pEGFR; P = 0.09), cetuximab-resistant cells had low levels of pEGFR (P = 0.13). The three most cetuximab-sensitive cell lines had high EGFR gene copy numbers. Furthermore, cetuximab treatment response was significantly correlated with epiregulin mRNA expression (r = -0.408, P = 0.043). Cisplatin-resistant tumor cells expressed significantly lower levels of EGFR protein (P = 0.04) compared to cisplatin-sensitive cells and tended to have lower levels of phosphorylated Akt (pAkt; P = 0.13) and lower expression levels of amphiregulin (P = 0.18). Conclusions: Epidermal growth factor receptor status and ligand expression influence the treatment sensitivity of HNSCC cells and may be useful as predictive markers.

Place, publisher, year, edition, pages
John Wiley and Sons, 2013
Keywords
chemoradiotherapy, EGFR, epiregulin, Erbitux (R), HB-EGF, SCCHN, TGF-a, treatment response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87963 (URN)10.1111/j.1600-0714.2012.01177.x (DOI)000312998500004 ()
Note

Funding Agencies|Swedish Laryng Foundation||Foundation of Olle Engkvist, Building Contractor||Linkoping University Hospital||

Available from: 2013-01-28 Created: 2013-01-28 Last updated: 2017-12-06
Jain, M. V., Paczulla, A. M., Klonisch, T., Dimgba, F. N., Rao, S., Roberg, K., . . . Los, M. J. (2013). Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development. Journal of Cellular and Molecular Medicine (Print), 17(1), 12-29
Open this publication in new window or tab >>Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development
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2013 (English)In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 17, no 1, p. 12-29Article, review/survey (Refereed) Published
Abstract [en]

The rapid accumulation of knowledge on apoptosis regulation in the 1990s was followed by the development of several experimental anticancer- and anti-ischaemia (stroke or myocardial infarction) drugs. Activation of apoptotic pathways or the removal of cellular apoptotic inhibitors has been suggested to aid cancer therapy and the inhibition of apoptosis was thought to limit ischaemia-induced damage. However, initial clinical studies on apoptosis-modulating drugs led to unexpected results in different clinical conditions and this may have been due to co-effects on non-apoptotic interconnected cell death mechanisms and the yin-yang role of autophagy in survival versus cell death. In this review, we extend the analysis of cell death beyond apoptosis. Upon introduction of molecular pathways governing autophagy and necrosis (also called necroptosis or programmed necrosis), we focus on the interconnected character of cell death signals and on the shared cell death processes involving mitochondria (e.g. mitophagy and mitoptosis) and molecular signals playing prominent roles in multiple pathways (e.g. Bcl2-family members and p53). We also briefly highlight stress-induced cell senescence that plays a role not only in organismal ageing but also offers the development of novel anticancer strategies. Finally, we briefly illustrate the interconnected character of cell death forms in clinical settings while discussing irradiation-induced mitotic catastrophe. The signalling pathways are discussed in their relation to cancer biology and treatment approaches.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
Keywords
Bcl2 family, p53, Cancer therapy, Erk, FOXO, PI3-K, Rheb, S6K
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89810 (URN)10.1111/jcmm.12001 (DOI)000314518700002 ()
Note

Funding Agencies|Baden-Wurttemberg Stiftung|P-LS-ASII/11|Natural Sciences and Engineering Council of Canada (NSERC)||

Available from: 2013-03-07 Created: 2013-03-07 Last updated: 2017-12-06
Ansell, A., Kankainen, M., Jönsson, J.-I., Monni, O., Roberg, K. & Johansson, A.-C. (2013). 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.

Keywords
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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