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  • 1.
    Ansell, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, R
    Karolinska Institute, Institute Environm Med, Div Biochem Toxicol and Expt Canc Research, S-10401 Stockholm, Sweden .
    Grenman, R
    Turku University, Department Otorhinolaryngol Head and Neck Surg, Cent Hospital, Turku, Finland .
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Matrix metalloproteinase-7 and-13 predict response to cisplatin in head and neck cancer in ORAL ONCOLOGY, vol , issue , pp 94-942009Inngår i: ORAL ONCOLOGY, 2009, s. 94-94Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 2.
    Ansell, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, Rebecca
    Karolinska Institute, Stockholm, Sweden.
    Grafström, Roland
    VTT Technical Research Centre of Finland.
    Grénman, Reidar
    VTT Technical Research Centre of Finland.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.2009Inngår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, nr 10, s. 866-871Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 3.
    Ansell, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, Rebecca
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institution, Stockholm, Sweden.
    Grénman, Reidar
    Department of Otorhinolaryngology, Head & Neck Surgery, Turku University Central Hospital, Finland.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Matrix metalloproteinase-7 and -13 predict response to cisplatin in head and neck cancerManuskript (Annet vitenskapelig)
    Abstract [en]

    Purpose: To identify gene ontology categories and key regulators with impact on the intrinsic cisplatin sensitivity (ICS) in head and neck squamous cell carcinoma (HNSCC).

    Experimental design: The ICS was determined in 35 HNSCC cell lines. Three of these cell lines, one sensitive and two resistant, were selected for microarray analysis. Gene Ontology (GO) categories were assessed using the gene ontology tree machine (GOTM) tool, and transcripts included in these categories were further analyzed using Ingenuity Pathway Analysis (IPA) for detection of key regulator genes. A group of key regulators were verified at protein level by Western blot analysis and on mRNA level using quantitative real-time PCR (qPCR).

    Results: 781 transcripts were detected as significantly differently expressed for the resistant cell lines compared to the sensitive cell line. A total of ten different categories were enriched in GOTM by these transcripts and a transcriptional profile was made from the 20 key regulators identified in the IPA analysis. Five key regulator genes, apolipoprotein E (APOE), catenin beta1 (CTNNB1), matrix metalloproteinase-7 (MMP-7), matrix metalloproteinase-13 (MMP-13), and thrombospondin 1 (THBS1), were verified in 25 HNSCC cell lines on mRNA level using qPCR. The results confirmed MMP-7 (p=0.0013) and implied MMP-13 (p=0.058) as potential biomarkers of ICS.

    Conclusions: We conclude that genome-wide transcriptional analysis and appropriate bioinformatics enable the identification of genes with impact on treatment response. Furthermore, we propose MMP-7 and MMP-13 as predictive markers of cisplatin resistance in HNSCC.

  • 4.
    Bivik Eding, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Domer, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Wäster, Petra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Rosdahl, Inger
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Melanoma Growth and Progression After Ultraviolet A Irradiation: Impact of Lysosomal Exocytosis and Cathepsin Proteases2015Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 95, nr 7, s. 792-797Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ultraviolet (UV) irradiation is a risk factor for development of malignant melanoma. UVA-induced lysosomal exocytosis and subsequent cell growth enhancement was studied in malignant melanoma cell lines and human skin melanocytes. UVA irradiation caused plasma membrane damage that was rapidly repaired by calcium-dependent lysosomal exocytosis. Lysosomal content was released into the culture medium directly after irradiation and such conditioned media stimulated the growth of non-irradiated cell cultures. By comparing melanocytes and melanoma cells, it was found that only the melanoma cells spontaneously secreted cathepsins into the surrounding medium. Melanoma cells from a primary tumour showed pronounced invasion ability, which was prevented by addition of inhibitors of cathepsins B, D and L. Proliferation was reduced by cathepsin L inhibition in all melanoma cell lines, but did not affect melanocyte growth. In conclusion, UVA-induced release of cathepsins outside cells may be an important factor that promotes melanoma growth and progression.

  • 5.
    Farnebo, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, Rebecca
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Grafström, Roland C
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Vainikka, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Grénman, Reidar
    Medical Biochemistry, University of Turku, Finland.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines2011Inngår i: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, nr 10, s. 739-746Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines.

    METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse.

    RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001).

    CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.

  • 6.
    Farnebo, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Vainikka, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Grénman, Reidar
    Department of Otorhinolaryngology, Head and Neck Surgery, Central Hospital and University of Turku and Medical Biochemistry, University of Turku, Finland.
    Norberg-Spaak, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.2008Inngår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 20, nr 2, s. 453-461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study was aimed at establishing a method that combines multiple factors of protein and genetic changes that enables prediction of radiosensitivity in the head and neck squamous cell carcinoma (HNSCC) cell lines. In nine HNSCC cell lines, the quantity of protein expression and the type of genetic alterations were translated into a point system, called the Number of Negative Points. The expression of 14 proteins involved in growth control and/or apoptosis was quantified using a densitometric assessment of Western blots. The blots were adjusted to actin and standardised to normal oral keratinocytes classifying them into four groups depending on the amount of protein expressed (0-3 points). Mutations of the p53 gene were classified into three groups and each mutation was given one point. Since the cell lines each had a known intrinsic radiosensitivity, a multivariate statistical calculation could then be performed to select for the combination of factors having the strongest correlation to radiosensitivity. The strongest correlation of the investigated factors was the combination of epidermal growth factor receptor, survivin and splice site/missense p53 mutations (R=0.990 and P<0.0001). No single factor had a significant correlation to the intrinsic radiosensitivity. Since a significant correlation to the intrinsic radiosensitivity was achieved only when two or more factors were combined, we conclude that a method such as the Number of Negative Points is necessary for prediction of treatment response. We present a novel method to combine factors which enables the prediction of radiosensitivity of HNSCC cell lines.

  • 7.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma2008Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and yearly include 500 000 new cases worldwide. The outcomes for these patients have not been significantly improved over the last decades and the five year survival is still around 50 %. Establishing predictive markers of treatment response will have great impact on the clinical management of this disease.

    The aim of this thesis was to elucidate markers of intrinsic response to radiotherapy and cisplatin. Combining expression patterns of 14 proteins and identifying mutations in the p53 gene, we were able to incorporate both protein and genetic changes to create a predictive model termed Number of Negative Points (NNP). We used the NNP model to statistically calculate the combination of factors that had the best correlation to intrinsic radiosensitivity (IR). We established that a panel of three markers, epidermal growth factor receptor (EGFR), survivin and splice site/missence mutations of p53, had the best correlation to IR (R=0.990, p<0.0001).

    We also conducted gene expression analysis to investigate what genes and gene ontologies that are different between cell lines with varying IR. Furthermore, we wanted to identify key regulator genes with central positions of molecular networks, which were generated from the transcripts included in the deregulated gene ontologies. A transcriptional profile of 28 key regulator genes was generated. Immunoblot analysis supported deregulation at the protein level of three markers implicated from the transcriptional profile. We propose that these proteins, notch1, thrombospondin 1, and pai‐1 are predictive markers of IR.

    Finally, on a subset of cell lines with sensitivity or resistance to cisplatin, we performed gene expression analysis. Markers of intrinsic cisplatin sensitivity (ICS) such as gene ontologies and key regulators of molecular networks were proposed and five genes, APOE, CTNNB1, MMP7, MMP13, and THBS1 were selected for further analysis. Quantitative polymerase chain reaction (qPCR) analysis of these genes in 25 cell lines established that MMP7 (p=0.0013) and MMP13 (p=0.058) are possible predictive markers of ICS.

    The markers of IR and ICS presented here could, if confirmed in a clinical setting, guide clinicians in the choice of treatment and thus give a more individualized and effective therapy for patients with HNSCC.

    Delarbeid
    1. Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.
    Åpne denne publikasjonen i ny fane eller vindu >>Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.
    Vise andre…
    2008 (engelsk)Inngår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 20, nr 2, s. 453-461Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The present study was aimed at establishing a method that combines multiple factors of protein and genetic changes that enables prediction of radiosensitivity in the head and neck squamous cell carcinoma (HNSCC) cell lines. In nine HNSCC cell lines, the quantity of protein expression and the type of genetic alterations were translated into a point system, called the Number of Negative Points. The expression of 14 proteins involved in growth control and/or apoptosis was quantified using a densitometric assessment of Western blots. The blots were adjusted to actin and standardised to normal oral keratinocytes classifying them into four groups depending on the amount of protein expressed (0-3 points). Mutations of the p53 gene were classified into three groups and each mutation was given one point. Since the cell lines each had a known intrinsic radiosensitivity, a multivariate statistical calculation could then be performed to select for the combination of factors having the strongest correlation to radiosensitivity. The strongest correlation of the investigated factors was the combination of epidermal growth factor receptor, survivin and splice site/missense p53 mutations (R=0.990 and P<0.0001). No single factor had a significant correlation to the intrinsic radiosensitivity. Since a significant correlation to the intrinsic radiosensitivity was achieved only when two or more factors were combined, we conclude that a method such as the Number of Negative Points is necessary for prediction of treatment response. We present a novel method to combine factors which enables the prediction of radiosensitivity of HNSCC cell lines.

    Emneord
    Predictive markers, p53, epidermal growth factor receptor, survivin, squamous cell carcinoma
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-19558 (URN)10.3892/or_00000028 (DOI)18636211 (PubMedID)
    Tilgjengelig fra: 2009-06-26 Laget: 2009-06-26 Sist oppdatert: 2018-09-11bibliografisk kontrollert
    2. Identification of Key Regulator Genes Linked to Radioresistance in Head and Neck Squamous Cell Carcinoma by Bioinformatic Processing of Transcript Data
    Åpne denne publikasjonen i ny fane eller vindu >>Identification of Key Regulator Genes Linked to Radioresistance in Head and Neck Squamous Cell Carcinoma by Bioinformatic Processing of Transcript Data
    Vise andre…
    (engelsk)Manuskript (Annet vitenskapelig)
    Abstract [en]

    Purpose: We analyzed basal expression patterns of cell lines with different intrinsic radiosensitivity to discover predictive markers of radiotherapy response.

    Experimental Design: Five head and neck squamous cell carcinoma (HNSCC) cell lines were selected for microarray analysis. Two cell lines showed high resistance to radiation, two cell lines showed an intermediate resistance and one cell line was sensitive and therefore used as reference to other cell lines. Three gene lists were generated from this analysis; one list with commonly deregulated genes in all cell lines compared to the reference and two lists with deregulated genes for the intermediate and highly resistant cell lines compared to the reference, respectively. Gene Ontology enrichment profiling and Ingenuity Pathway Analysis was applied on all gene lists. Key transcript findings were verified at the protein level by Western blot.

    Results: Expression analysis of the high and intermediate resistant cell lines compared to the reference resulted in approximately 1300 significantly altered transcripts, respectively; 552 transcripts were found commonly differently expressed. The deregulated transcripts enriched several GO-categories under biological process, cellular component and molecular function as well as multiple molecular networks in Ingenuity Pathway Analysis. A transcriptional profile of 28 key-regulator genes from the molecular networks was generated from the four resistant lines compared to the reference. Finally, immunoblot analysis supported deregulation at the protein level of markers implicated from the transcriptional-profile.

    Conclusions: Novel markers for prediction of radiation sensitivity could be proposed from bioinformatic processing of gene-expression profiles in HNSCC carcinoma cells.

    Emneord
    Microarray, Radiotherapy, Predictive biomarkers, Gene Ontology, Pathway analysis
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-19570 (URN)
    Tilgjengelig fra: 2009-06-29 Laget: 2009-06-29 Sist oppdatert: 2010-01-14bibliografisk kontrollert
    3. Matrix metalloproteinase-7 and -13 predict response to cisplatin in head and neck cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Matrix metalloproteinase-7 and -13 predict response to cisplatin in head and neck cancer
    Vise andre…
    (engelsk)Manuskript (Annet vitenskapelig)
    Abstract [en]

    Purpose: To identify gene ontology categories and key regulators with impact on the intrinsic cisplatin sensitivity (ICS) in head and neck squamous cell carcinoma (HNSCC).

    Experimental design: The ICS was determined in 35 HNSCC cell lines. Three of these cell lines, one sensitive and two resistant, were selected for microarray analysis. Gene Ontology (GO) categories were assessed using the gene ontology tree machine (GOTM) tool, and transcripts included in these categories were further analyzed using Ingenuity Pathway Analysis (IPA) for detection of key regulator genes. A group of key regulators were verified at protein level by Western blot analysis and on mRNA level using quantitative real-time PCR (qPCR).

    Results: 781 transcripts were detected as significantly differently expressed for the resistant cell lines compared to the sensitive cell line. A total of ten different categories were enriched in GOTM by these transcripts and a transcriptional profile was made from the 20 key regulators identified in the IPA analysis. Five key regulator genes, apolipoprotein E (APOE), catenin beta1 (CTNNB1), matrix metalloproteinase-7 (MMP-7), matrix metalloproteinase-13 (MMP-13), and thrombospondin 1 (THBS1), were verified in 25 HNSCC cell lines on mRNA level using qPCR. The results confirmed MMP-7 (p=0.0013) and implied MMP-13 (p=0.058) as potential biomarkers of ICS.

    Conclusions: We conclude that genome-wide transcriptional analysis and appropriate bioinformatics enable the identification of genes with impact on treatment response. Furthermore, we propose MMP-7 and MMP-13 as predictive markers of cisplatin resistance in HNSCC.

    Emneord
    Predictive markers, chemotherapy, microarray and intrinsic cisplatin resistance
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-19571 (URN)
    Tilgjengelig fra: 2009-06-29 Laget: 2009-06-29 Sist oppdatert: 2010-01-14bibliografisk kontrollert
  • 8.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Head and neck cancer is a common malignancy with approximately 600 000 new cases yearly. Disappointingly, the overall survival has not increased over the last decades. The concept of personalized medicine, i.e. to treat every patient with an individually planned treatment regime has gathered increased interest, but requires the establishment of novel biomarkers that can predict treatment response.

    The aim of this thesis is to propose novel predictive single markers or combinations of markers of response to radiation, cisplatin and cetuximab. The general methodology is to evaluate common differences of cell lines resistant to radiation, cisplatin or cetuximab compared to sensitive counterparts.

    In paper I, we analysed the expression of 14 proteins involved in growth control and/or apoptosis by western blot and related them to intrinsic radiosensitivity (IR) in nine cell lines. No factor had a significant correlation to IR on its own. A combination of EGFR, survivin, Bak, Smad4, and Hsp70 had the best correlation to IR (R=0.886, p=0.001). Additionally, we analysed the presence of p53 mutations in the cell lines. All cell lines had at least one missense, splice site or loss of transcript mutation. To be able to combine protein expression and presence of p53 mutations we created a system designated the number of negative points (NNP). With this system we could extract that expression of EGFR, survivin, and p53 missense or splice site mutations had the best correlation to IR (R=0.990, p<0.001).

    In paper II we conducted a gene expression microarray analysis of three cell lines, from which common deregulations in two cisplatin resistant cell lines was compared to a cisplatin sensitive cell line. From a bioinformatic approach of gene ontology and molecular network analysis, we defined a transcriptional profile of 20 genes. Finally, key findings were analysed in a larger panel of cell lines, where high MMP-7 expression correlated with higher cisplatin resistance.

    Paper III compared 4 cell lines with high IR to a radiosensitive equivalent. Using a similar bioinformatic approach as paper II, we established a transcriptional profile of 14 genes. Analysis in a larger panel of cell lines revealed that FN1 expression predicts higher IR.

    Paper IV establishes the cetuximab sensitivity of 35 cell lines of which 12 were resistant and five were sensitive to cetuximab. After whole genome gene copy number analysis of five cetuximab resistant and five cetuximab sensitive cell lines, and verification of key findings in a larger cell line panel, the results show that the amplification of the YAP1 gene is coupled to cetuximab resistance.

    In summary, this thesis proposes a number of novel markers of resistance to radiation, cisplatin, and cetuximab which could influence treatment choice in the future, following verifications in primary tumor material.

    Delarbeid
    1. Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.
    Åpne denne publikasjonen i ny fane eller vindu >>Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.
    Vise andre…
    2008 (engelsk)Inngår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 20, nr 2, s. 453-461Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The present study was aimed at establishing a method that combines multiple factors of protein and genetic changes that enables prediction of radiosensitivity in the head and neck squamous cell carcinoma (HNSCC) cell lines. In nine HNSCC cell lines, the quantity of protein expression and the type of genetic alterations were translated into a point system, called the Number of Negative Points. The expression of 14 proteins involved in growth control and/or apoptosis was quantified using a densitometric assessment of Western blots. The blots were adjusted to actin and standardised to normal oral keratinocytes classifying them into four groups depending on the amount of protein expressed (0-3 points). Mutations of the p53 gene were classified into three groups and each mutation was given one point. Since the cell lines each had a known intrinsic radiosensitivity, a multivariate statistical calculation could then be performed to select for the combination of factors having the strongest correlation to radiosensitivity. The strongest correlation of the investigated factors was the combination of epidermal growth factor receptor, survivin and splice site/missense p53 mutations (R=0.990 and P<0.0001). No single factor had a significant correlation to the intrinsic radiosensitivity. Since a significant correlation to the intrinsic radiosensitivity was achieved only when two or more factors were combined, we conclude that a method such as the Number of Negative Points is necessary for prediction of treatment response. We present a novel method to combine factors which enables the prediction of radiosensitivity of HNSCC cell lines.

    Emneord
    Predictive markers, p53, epidermal growth factor receptor, survivin, squamous cell carcinoma
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-19558 (URN)10.3892/or_00000028 (DOI)18636211 (PubMedID)
    Tilgjengelig fra: 2009-06-26 Laget: 2009-06-26 Sist oppdatert: 2018-09-11bibliografisk kontrollert
    2. Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.
    Åpne denne publikasjonen i ny fane eller vindu >>Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.
    Vise andre…
    2009 (engelsk)Inngår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, nr 10, s. 866-871Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    Elsevier, 2009
    Emneord
    Predictive markers; Gene Ontology; Head and neck cancer; Cisplatin; Microarray; MMPs
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-21436 (URN)10.1016/j.oraloncology.2009.02.008 (DOI)000270022000005 ()19442568 (PubMedID)
    Tilgjengelig fra: 2009-10-01 Laget: 2009-10-01 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma
    Åpne denne publikasjonen i ny fane eller vindu >>Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma
    Vise andre…
    2010 (engelsk)Inngår i: CANCER BIOLOGY and THERAPY, ISSN 1538-4047, Vol. 10, nr 12, s. 1244-1251Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Radiotherapy remains the backbone of head and neck cancer therapy but response is sometimes impeded by tumor radioresistance. Identifying predictive biomarkers of radiotherapy response is a crucial step towards personalized therapy. The aim of this study was to explore gene expression data in search of biomarkers predictive of the response to radiotherapy in head and neck squamous cell carcinoma (HNSCC). Microarray analysis was performed on five cell lines with various intrinsic radiosensitivity, selected from a panel of 29 HNSCC cell lines. The bioinformatics approach included Gene Ontology (GO) enrichment profiling and Ingenuity Pathway Analysis (IPA). The GO-analysis detected 16 deregulated categories from which development, receptor activity and extracellular region represented the largest groups. Fourteen hub genes (CEBPA, CEBPB, CTNNB1, FN1, MYC, MYCN, PLAU, SDC4, SERPINE1, SP1, TAF4B, THBS1, TP53 and VLDLR) were identified from the IPA network analysis. The hub genes in the highest ranked network, (FN1, SERPINE1, THBS1 and VLDLR) were further subjected to qPCR analysis in the complete panel of 29 cell lines. Of these genes, high FN1 expression associated to high intrinsic radiosensitivity (p = 0.047). In conclusion, gene ontologies and hub genes of importance for intrinsic radiosensitivity were defined. The overall results suggest that FN1 should be explored as a potential novel biomarker for radioresistance.

    sted, utgiver, år, opplag, sider
    Landes Bioscience, 2010
    Emneord
    head and neck cancer, predictive markers, radiotherapy, microarray, gene ontology, pathway analysis, fibronectin 1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-64243 (URN)10.4161/cbt.10.12.13432 (DOI)000285388400007 ()
    Tilgjengelig fra: 2011-01-17 Laget: 2011-01-17 Sist oppdatert: 2012-03-29bibliografisk kontrollert
    4. YAP1 Gene Amplification is a Marker for Cetuximab Resistance in Head and Neck Cancer
    Åpne denne publikasjonen i ny fane eller vindu >>YAP1 Gene Amplification is a Marker for Cetuximab Resistance in Head and Neck Cancer
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is commonly overexpressed in head and neck squamous cell carcinomas (HNSCC). The monoclonal antibody cetuximab (Erbitux®) inhibits its signaling and has been approved for treatment of HNSCC. However, since many patients do not benefit from cetuximab treatment, predictive biomarkers of cetuximab response are required. The present study aims at finding novel markers of cetuximab resistance.

    The intrinsic cetuximab sensitivity of 35 HNSCC cell lines was determined, and revealed a great variation in the response between cell lines. Five cell lines (14%) were cetuximab sensitive, and 12 (34%) were resistant. Interestingly, two cell lines proliferated after cetuximab treatment.

    10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR  verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant.

    YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-76151 (URN)
    Tilgjengelig fra: 2012-03-29 Laget: 2012-03-29 Sist oppdatert: 2012-03-29bibliografisk kontrollert
  • 9.
    Jerhammar, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, Rebecca
    Karolinska Institute, Stockholm.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Grenman, Reidar
    Turku University Hospital, Finland.
    C Grafstrom, Roland
    Karolinska Institute, Stockholm.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma2010Inngår i: CANCER BIOLOGY and THERAPY, ISSN 1538-4047, Vol. 10, nr 12, s. 1244-1251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radiotherapy remains the backbone of head and neck cancer therapy but response is sometimes impeded by tumor radioresistance. Identifying predictive biomarkers of radiotherapy response is a crucial step towards personalized therapy. The aim of this study was to explore gene expression data in search of biomarkers predictive of the response to radiotherapy in head and neck squamous cell carcinoma (HNSCC). Microarray analysis was performed on five cell lines with various intrinsic radiosensitivity, selected from a panel of 29 HNSCC cell lines. The bioinformatics approach included Gene Ontology (GO) enrichment profiling and Ingenuity Pathway Analysis (IPA). The GO-analysis detected 16 deregulated categories from which development, receptor activity and extracellular region represented the largest groups. Fourteen hub genes (CEBPA, CEBPB, CTNNB1, FN1, MYC, MYCN, PLAU, SDC4, SERPINE1, SP1, TAF4B, THBS1, TP53 and VLDLR) were identified from the IPA network analysis. The hub genes in the highest ranked network, (FN1, SERPINE1, THBS1 and VLDLR) were further subjected to qPCR analysis in the complete panel of 29 cell lines. Of these genes, high FN1 expression associated to high intrinsic radiosensitivity (p = 0.047). In conclusion, gene ontologies and hub genes of importance for intrinsic radiosensitivity were defined. The overall results suggest that FN1 should be explored as a potential novel biomarker for radioresistance.

  • 10.
    Jerhammar, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, Rebecca
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Grénman, Reidar
    Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Central Hospital, University of Turku, Turku, Finland/Department of Medical Biochemistry, University of Turku, Turku, Finland.
    Grafström, Roland C.
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Identification of Key Regulator Genes Linked to Radioresistance in Head and Neck Squamous Cell Carcinoma by Bioinformatic Processing of Transcript DataManuskript (Annet vitenskapelig)
    Abstract [en]

    Purpose: We analyzed basal expression patterns of cell lines with different intrinsic radiosensitivity to discover predictive markers of radiotherapy response.

    Experimental Design: Five head and neck squamous cell carcinoma (HNSCC) cell lines were selected for microarray analysis. Two cell lines showed high resistance to radiation, two cell lines showed an intermediate resistance and one cell line was sensitive and therefore used as reference to other cell lines. Three gene lists were generated from this analysis; one list with commonly deregulated genes in all cell lines compared to the reference and two lists with deregulated genes for the intermediate and highly resistant cell lines compared to the reference, respectively. Gene Ontology enrichment profiling and Ingenuity Pathway Analysis was applied on all gene lists. Key transcript findings were verified at the protein level by Western blot.

    Results: Expression analysis of the high and intermediate resistant cell lines compared to the reference resulted in approximately 1300 significantly altered transcripts, respectively; 552 transcripts were found commonly differently expressed. The deregulated transcripts enriched several GO-categories under biological process, cellular component and molecular function as well as multiple molecular networks in Ingenuity Pathway Analysis. A transcriptional profile of 28 key-regulator genes from the molecular networks was generated from the four resistant lines compared to the reference. Finally, immunoblot analysis supported deregulation at the protein level of markers implicated from the transcriptional-profile.

    Conclusions: Novel markers for prediction of radiation sensitivity could be proposed from bioinformatic processing of gene-expression profiles in HNSCC carcinoma cells.

  • 11.
    Jerhammar, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Not Found:Linkoping Univ, Fac Hlth Sci, Dept Clin and Expt Med, Div Otorhinolaryngol and Head and Neck Surg, Linkoping, Sweden .
    Ceder, Rebecca
    Karolinska Institute, Sweden .
    Welander, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Grafstrom, Roland C.
    Karolinska Institute, Sweden VTT Technical Research Centre Finland, Finland .
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer2014Inngår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 50, nr 9, s. 832-839Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 12.
    Jerhammar, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Welander, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    YAP1 Gene Amplification is a Marker for Cetuximab Resistance in Head and Neck CancerManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is commonly overexpressed in head and neck squamous cell carcinomas (HNSCC). The monoclonal antibody cetuximab (Erbitux®) inhibits its signaling and has been approved for treatment of HNSCC. However, since many patients do not benefit from cetuximab treatment, predictive biomarkers of cetuximab response are required. The present study aims at finding novel markers of cetuximab resistance.

    The intrinsic cetuximab sensitivity of 35 HNSCC cell lines was determined, and revealed a great variation in the response between cell lines. Five cell lines (14%) were cetuximab sensitive, and 12 (34%) were resistant. Interestingly, two cell lines proliferated after cetuximab treatment.

    10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR  verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant.

    YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer.

  • 13.
    Jerhammar, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US. Östergötlands Läns Landsting.
    Variation of intrinsic cetuximab sensitivity in head and neck squamous cell carcinomas in EJC SUPPLEMENTS, vol 8, issue 5, pp 50-502010Inngår i: EJC SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2010, Vol. 8, nr 5, s. 50-50Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 14.
    Jerhammar, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Welander, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Johansson, A C
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Gene Copy Number as Predictive Marker for Cetuximab Resistance in Head and Neck Squamous Cell Carcinomas in EUROPEAN JOURNAL OF CANCER, vol 47, issue , pp S571-S5712011Inngår i: EUROPEAN JOURNAL OF CANCER, Elsevier , 2011, Vol. 47, s. S571-S571Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 15.
    Johansson, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Ansell, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Bradic Lindh, Maja
    Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Grenman, Reidar
    Turku University Hospital, Finland University of Turku, Finland .
    Munck-Wikland, Eva
    Karolinska University Hospital, Sweden .
    Ostman, Arne
    Karolinska Institute, Sweden .
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells2012Inngår i: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 10, nr 9, s. 1158-1168Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16.
    Zheng, Lin
    et al.
    Karolinska Inst, NVS, KI Alzheimers Dis Res Ctr, S-14186 Stockholm, Sweden.
    Cedazo-Minguez, Angel
    KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, SE-141 57, Stockholm,Sweden.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Hultenby, Kjell
    Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Geriatriska kliniken.
    Terman, Alexi
    Department of Clinical Pathology and Cytology, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden.
    Intracellular localization of amyloid beta peptide in SH-SY5Y neuroblastoma cells2013Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, nr 4, s. 713-733Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid-beta peptide (A beta), the main component of Alzheimer's disease (AD) senile plaques, has been found to accumulate within the lysosomal compartment of AD neurons. We have previously shown that in differentiated SH-SY5Y neuroblastoma cells cultured under normal conditions, the majority of A beta is localized extralysosomally, while oxidative stress significantly increases intralysosomal A beta content through activation of macroautophagy. It is, however, not clear which cellular compartments contain extralysosomal A beta in intact SH-SY5Y cells, and how oxidative stress influences the distribution of extralysosomal A beta. Using confocal laser scanning microscopy and immunoelectron microscopy, we showed that in differentiated neuroblastoma cells cultured under normal conditions A beta (A beta(40), A beta(42), and A beta oligomers) is colocalized with both membrane-bound organelles (endoplasmic reticulum, Golgi complexes, multivesicular bodies/late endosomes, lysosomes, exocytotic vesicles and mitochondria) and non-membrane-bound cytosolic structures. Neuroblastoma cells stably transfected with A beta PP Swedish KM670/671NL double mutation showed enlarged amount of A beta colocalized with membrane compartments. Suppression of exocytosis by 5 nM tetanus toxin resulted in a significant increase of the amount of cytosolic A beta as well as A beta colocalized with exocytotic vesicles, endoplasmic reticulum, Golgi complexes, and lysosomes. Hyperoxia increased A beta localization in the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes, but not in the secretory vesicles. These results indicate that in SH-SY5Y neuroblastoma cells intracellular A beta is not preferentially localized to any particular organelle and, to a large extent, is secreted from the cells. Challenging cells to hyperoxia, exocytosis inhibition, or A beta overproduction increased intracellular A beta levels but did not dramatically changed its localization pattern.

  • 17.
    Zheng, Lin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik.
    Cedazo-Minguez, Angel
    KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, Stockholm, Sweden.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Terman, Alexei
    Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system.2012Inngår i: Translational Neurodegeneration, ISSN 2047-9158, Vol. 1, nr 1, s. 19-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Amyloid beta peptide (Aβ) is the main component of extraneuronal senile plaques typical of Alzheimer’s disease (AD) brains. Although Aβ is produced by normal neurons, it is shown to accumulate in large amounts within neuronal lysosomes in AD. We have recently shown that under normal conditions the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is also suggested that impaired Aβ secretion and resulting intraneuronal increase of Aβ can contribute to AD pathology. However, it is not clear how Aβ is distributed inside normal neurons, and how this distribution is effected when Aβ secretion is inhibited.

    Methods

    Using retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons, we studied intracellular distribution of Aβ by double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers. In addition, we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ.

    Results

    Under normal conditions, Aβ was found in the small cytoplasmic granules in both neurites and perikarya. Only minor portion of Aβ was colocalized with trans-Golgi network, Golgi-derived vesicles, early and late endosomes, lysosomes, and synaptic vesicles, while the majority of Aβ granules were not colocalized with any of these structures. Furthermore, treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβ in both perikarya and neurites. Finally, we found that tetanus toxin increased the levels of intralysosomal Aβ although the majority of Aβ still remained extralysosomally.

    Conclusion

    Our results indicate that most Aβ is not localized to Golgi-related structures, endosomes, lysosomes secretory vesicles or other organelles, while the suppression of Aβ secretion increases intracellular intra- and extralysosomal Aβ.

  • 18.
    Zheng, Lin
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Oto-Rhino-Laryngologi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Jerhammar, Fredrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Marcusson, Jan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Geriatriska kliniken.
    Terman, Alexei
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Autophagy of amyloid beta-protein in differentiated neuroblastoma cells exposed to oxidative stress2006Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 394, nr 3, s. 184-189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidative stress is considered important for the pathogenesis of Alzheimer disease (AD), which is characterized by the formation of senile plaques rich in amyloid beta-protein (Aβ). Aβ cytotoxicity has been found dependent on lysosomes, which are abundant in AD neurons and are shown to partially co-localize with Aβ. To determine whether oxidative stress has any influence on the relationship between lysosomes and Aβ1-42 (the most toxic form of Aβ), we studied the effect of hyperoxia (40% versus 8% ambient oxygen) on the intracellular localization of Aβ1-42 (assessed by immunocytochemistry) in retinoic acid differentiated SH-SY5Y neuroblastoma cells maintained in serum-free OptiMEM medium. In control cells, Aβ1-42 was mainly localized to small non-lysosomal cytoplasmic granules. Only occasionally Aβ1-42 was found in large (over 1 μm) lysosomal-associated membrane protein 2 positive vacuoles, devoid of the early endosomal marker rab5. These large Aβ1-42-containing lysosomes were not detectable in the presence of serum (known to suppress autophagy), while their number increased dramatically (up to 24-fold) after exposure of cells to hyperoxia during 5 days. Activation of autophagy by hyperoxia was confirmed by transmission electron microscopy. Furthermore, an inhibitor of autophagic sequestration 3-methyladenine prevented the accumulation of Aβ1-42-positive lysosomes due to hyperoxia. In parallel experiments, intralysosomal accumulation of Aβ1-40 following oxidative stress has been found as well. The results suggest that Aβ can be autophagocytosed and its accumulation within neuronal lysosomes is enhanced by oxidative stress. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 19.
    Zheng, Lin
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Marcusson, Jan
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Terman, Alexei
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Oxidative Stress Induces Intralysosomal Accumulation of Alzheimer Amyloid β-Protein in Cultured Neuroblastoma Cells2006Inngår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1067, s. 248-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidative stress is considered important for the pathogenesis of Alzheimer's disease (AD), which is characterized by the formation of extracellular senile plaques, mainly composed of amyloid β-protein (Aβ). Aβ also accumulates within AD neurons and is believed to exert cellular toxicity through lysosomal labilization. We report that the exposure of human neuroblastoma cells to hyperoxia (40% vs. 8% ambient oxygen) induced the accumulation of large (over 1 μM) Aβ-containing lysosomes, which were not typical of control cells, showing a distinct localization of Aβ and lysosomal markers. An inhibitor of autophagy, 3-methyladenine, suppressed the effect of hyperoxia. The results suggest a link between the involvement of oxidative stress and lysosomes in AD.

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