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  • 1.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Potential for clinical radionuclide-based imaging and therapy of common cancers expressing EGFR-family receptors2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no 3, 653-659 p.Article in journal (Refereed)
    Abstract [en]

    High expression of epidermal growth factor receptor (EGFR)-family receptors, especially EGFR, HER2, and HER3, makes them interesting for targeted radionuclide-based imaging and therapy of disseminated cancer. The expression in some commonly occurring cancers such as breast, prostate, colorectal, and urinary bladder cancers is summarized. Possible strategies for radionuclide-based imaging and therapy are briefly discussed, especially in relation to the receptor expression in metastases.

  • 2.
    Ekerljung, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Steffen, Ann-Charlott
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Effects of HER2-binding affibody molecules on intracellular signaling pathways2006In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 27, no 4, 201-210 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: HER2, which is overexpressed in 25-30% of human breast cancers, is a tyrosine kinase receptor critical for the signal transduction network that regulates proliferation, migration and apoptosis of cells. METHOD: We report the effects of two novel HER2-binding affibody molecules (Affibody), (ZHER2:4)2 and ZHER2:342, on intracellular signal transduction pathways (Erk1/2, Akt and PLCgamma1) using quantitative immunoblotting techniques and their biological effects in cell culture. The clinically approved antibody trastuzumab (Herceptin) was used as reference substance. RESULTS: Our data showed that, although all substances target HER2, the effects on the receptor and signaling molecules differed. For example, HER2 phosphorylation was induced by trastuzumab and (ZHER2:4)2 but inhibited by ZHER2:342. The effects these substances had on signal transduction correlated to some degree with changes in growth and migration, e.g. (ZHER2:4)2 stimulated phosphorylation of Erk1/2 and PLCgamma1, as well as growth and migration, while ZHER2:342 did not. ZHER2:342 even inhibited phosphorylation of PLCgamma1 and migration. CONCLUSION: Our data suggest that ZHER2:342 is a promising small agent (7 kDa) that may be used as an alternative, or complement, to trastuzumab. If radiolabelled, it can hopefully also be used for HER2 imaging and radionuclide therapy.

  • 3.
    Gedda, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Nuclisome: targeting the tumor cell nucleus2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no 3, 661-667 p.Article in journal (Refereed)
    Abstract [en]

    The Nuclisome concept builds on a novel two-step targeting strategy with the aim to deliver short-range Auger-electron-emitting radionuclides to nuclear DNA of tumor cells. The concept is based on the use of Nuclisome-particles, i.e., tumor-targeted PEG-stabilized liposomes loaded with a unique DNA-intercalating compound that enables specific and effective delivery of radionuclides to DNA. The specific and potent two-step targeting leads to eradication of tumor cells while toxicity to normal organs is reduced to a minimum. Results of in vitro and in vivo studies point towards the Nuclisome concept as a promising strategy for the treatment of small tumor masses and, in particular, for the elimination of spread single cells and micrometastases.

  • 4.
    Gronowitz, Simon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Nisman, B.
    Peretz, Tamar
    Total body cell division the ultimate biomarker for personalized medicine in cancer?2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no S1, 107-107 p.Article in journal (Other academic)
  • 5.
    Hahn-Strömberg, Victoria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala Univ, Dept Med Cell Biol, SE-75105 Uppsala, Sweden..
    Askari, Shlear
    Orebro Univ, Fac Med & Hlth, Dept Clin Res, Orebro, Sweden..
    Ahmad, Abrar
    Orebro Univ, Fac Med & Hlth, Dept Clin Res, Orebro, Sweden..
    Befekadu, Rahel
    Orebro Univ, Fac Med & Hlth, Dept Clin Res, Orebro, Sweden.;Orebro Univ, Fac Med & Hlth, Dept Lab Med, Orebro, Sweden..
    Nilsson, Torbjörn K.
    Umea Univ, Dept Med Biosci, Div Clin Chem, Umea, Sweden..
    Expression of claudin 1, claudin 4, and claudin 7 in colorectal cancer and its relation with CLDN DNA methylation patterns2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 4Article in journal (Refereed)
    Abstract [en]

    Altered claudin expression has been described in colon, prostatic, ovarian, and breast carcinoma. However, the role of epigenetic modifications in these genes and their role in colorectal cancer is unknown. We aimed our study to investigate whether claudin protein expression and methylation of CLDN can influence the tumorigenesis of colorectal cancer. A total of 31 patients diagnosed with colorectal carcinoma was used in this study. Immunohistochemical staining was used to study protein expression in both tumor and the adjacent nonneoplastic mucosa of claudin 1, 4, and 7. To detect the DNA methylation pattern of CLDN1, 4, and 7, genomic DNA was extracted from both the tumor and the adjacent nonneoplastic mucosa. Methylation analysis was carried out using bisulfite pyrosequencing. Cell membrane staining intensity of all claudins was found significantly lower in colorectal cancer tissues when compared to paired normal mucosa (p = 0.001). For claudin 4, the percentage of cells staining positively was also significantly reduced (p = 0.04). In normal mucosa, cytoplasm showed no staining for claudins in any patient, whereas in paired colorectal cancer tissues, significant cytoplasmic staining appeared both for claudin 1 (p = 0.04) and claudin 4 (p = 0.01). Tumor samples were significantly hypomethylated in CLDN1 (p < 0.05). In conclusion, our results show that CLDN1 is significantly hypomethylated in tumor samples and that the membrane staining intensity for claudin 1, 4, and 7 is significantly lower in colorectal cancer tissues than in adjacent nonneoplastic tissue. Colorectal cancer cells showed dystopic cytoplasmic location of claudins.

  • 6.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gustafsson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Pendekanti, Prathyusha N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    The influence of AKT isoforms on radiation sensitivity and DNA repair in colon cancer cell lines2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 4, 3525-3534 p.Article in journal (Refereed)
    Abstract [en]

    In response to ionizing radiation, several signaling cascades in the cell are activated to repair the DNA breaks, prevent apoptosis, and keep the cells proliferating. AKT is important for survival and proliferation and may also be an activating factor for DNA-PKcs and MRE11, which are essential proteins in the DNA repair process. AKT (PKB) is hyperactivated in several cancers and is associated with resistance to radiotherapy and chemotherapy. There are three AKT isoforms (AKT1, AKT2, and AKT3) with different expression patterns and functions in several cancer tumors. The role of AKT isoforms has been investigated in relation to radiation response and their effects on DNA repair proteins (DNA-PKcs and MRE11) in colon cancer cell lines. The knockout of AKT1 and/or AKT2 affected the radiation sensitivity, and a deficiency of both isoforms impaired the rejoining of radiation-induced DNA double strand breaks. Importantly, the active/phosphorylated forms of AKT and DNA-PKcs associate and exposure to ionizing radiation causes an increase in this interaction. Moreover, an increased expression of both DNA-PKcs and MRE11 was observed when AKT expression was ablated, yet only DNA-PKcs expression influenced AKT phosphorylation. Taken together, these results demonstrate a role for both AKT1 and AKT2 in radiotherapy response in colon cancer cells involving DNA repair capacity through the nonhomologous end joining pathway, thus suggesting that AKT in combination with DNA-PKcs inhibition may be used for radiotherapy sensitizing strategies in colon cancer.

  • 7.
    Jamalpour, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mostoslavsky, Gustavo
    Center for Regenerative Medicine (CReM), Department of Medicine, School of Medicine, Boston University..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 10Article in journal (Refereed)
    Abstract [en]

    Objective: The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Methods: Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines. Results: Despite a low frequency of SHB gene mutations, many tumors overexpressed SHB mRNA compared with normal myeloid blood cells. AML patients with tumors expressing low SHB mRNA displayed longer survival times. A subgroup of AML exhibiting a favorable prognosis, acute promyelocytic leukemia (APL) with a PMLRARA translocation, expressed less SHB mRNA than AML tumors in general. When examining genes co-expressed with SHB in AML tumors, four other genes (PAX5, HDAC7, BCORL1, TET1) related to leukemia were identified. A network consisting of these genes plus SHB was identified that relates to certain phenotypic characteristics, such as immune cell, vascular and apoptotic features. SHB knockdown in the APL PMLRARA cell line NB4 and the monocyte/macrophage cell line MM6 adversely affected proliferation, linking SHB gene expression to tumor cell expansion and consequently to patient survival. Conclusions: It is concluded that tumor SHB gene expression relates to AML survival and its subgroup APL. Moreover, this gene is included in a network of genes that plays a role for an AML phenotype exhibiting certain immune cell, vascular and apoptotic characteristics.

  • 8. Kahata, Kaoro
    et al.
    Shahidi Dadras, Mahsa
    Moustakas, Aristidis
    TGF-β family signaling in epithelial differentiation and epithelial-mesenchymal transition2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380Article in journal (Refereed)
  • 9.
    Kareem, Heewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sandström, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Elia, Ronny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Blocking EGFR in the liver improves the tumor-to-liver uptake ratio of radiolabeled EGF2010In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 31, no 2, 79-87 p.Article in journal (Refereed)
    Abstract [en]

    Overexpression of epidermal growth factor receptor (EGFR) in several types of malignant tumors correlates with disease progression. EGFR could, therefore, be an excellent candidate for targeted radionuclide diagnostics. However, the high natural expression of EGFR in the liver may be problematic. The aim of this study was to improve the tumor-to-liver ratio of radiolabeled epidermal growth factor (EGF) by blocking its uptake by the liver with a nonradiolabeled EGFR-targeting molecule in tumorbearing mice. Intraperitoneally injected nonradiolabeled EGF was first evaluated as a blocking agent, preadministered at various time intervals before intravenous injection of 125I-labeled EGF. The anti-EGFR Affibody molecule (ZEGFR:955)2 was then assessed as a blocking agent of 111In-labeled EGF in a dual isotope study (50, 100, and 200μg, preadministered 30 or 60 min before 111In-EGF). The 30-min preadministration of nonradiolabeled EGF significantly decreased 125I-EGF uptake in the liver, whereas uptake in the tumor remained unchanged. Furthermore, preadministration of only 50μg (ZEGFR:955)2 as a blocking agent 30 min before the 111In-EGF decreased the uptake of 111In-EGF by the liver and increased its uptake by the tumor, thereby increasing the tumor-to-liver ratio sixfold. We conclude that the Affibody molecule (ZEGFR:955)2 shows promise as a blocking agent that could enhance the outcome of radionuclide-based EGFRexpressing tumor diagnostics and imaging.

  • 10.
    Kundu, S K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Targeted therapy in head and neck cancer2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no 3, 707-721 p.Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) of multi-factorial etiopathogenesis is rising worldwide. Treatment-associated toxicity problems and treatment failure in advanced disease stages with conventional therapies have necessitated a focus on alternative strategies. Molecular targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. In an attempt to improve outcomes in HNSCC, targeted therapeutic strategies have been developed. These strategies are focusing on the molecular biology of HNSCC in an attempt to target selected pathways involved in carcinogenesis. Inhibiting tumor growth and metastasis by focusing on specific protein or signal transduction pathways or by targeting the tumor microenvironment or vasculature are some of the new approaches. Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors (Cetuximab, Panitumumab, Zalutumumab), EGFR tyrosine kinase inhibitors (Gefitinib, Erloitinib), VEGFR inhibitors (Bevacizumab, Vandetanib), and various inhibitors of, e.g., Src-family kinase, PARP, proteasome, mTOR, COX, and heat shock protein. Moreover, targeted molecular therapy can also act as a complement to other existing cancer therapies. Several studies have demonstrated that the combination of targeting techniques with conventional current treatment protocols may improve the treatment outcome and disease control, without exacerbating the treatment related toxicities. Some of the targeted approaches have been proved as promising therapeutic potentials and are already in use, whereas remainder exhibits mixed result and necessitates further studies. Identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from targeted treatment.

  • 11. Lindberg, Hanna
    et al.
    Hofström, Camilla
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Honorvar, Hadis
    Wållberg, Helena
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Ståhl, Stefan
    Gräslund, Torbjörn
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for 99mTc-labelling at the C terminus2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no 3, 641-651 p.Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are a class of small (ca.7 kDa) robust scaffold proteins with high potential as tracers for radionuclide molecular imaging in vivo. Incorporation of a cysteine-containing peptide-based chelator at the C terminus provides an opportunity for stable labelling with the radionuclide 99mTc. The use of a GGGC chelator at the C terminus has provided the lowest renal radioactivity retention of the previously investigated peptide-based chelators. Previously, it has also been demonstrated that replacement of the His6-tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine-glutamate (HEHEHE)-tag permits purification of affibody molecules by immobilized metal ion affinity chromatography (IMAC) and provides low hepatic accumulation of radioactivity of conjugates site-specifically labelled at the C terminus using several different nuclides. We hypothesized that the combination of a HEHEHE-tag at the N terminus and a GGGC chelator at the C terminus of an affibody molecule would be a favourable format permitting IMAC purification and providing low uptake in excretory organs. To investigate this hypothesis, a (HE)3-ZHER2:342-GGGC affibody molecule was generated. It could be efficiently purified by IMAC and stably labelled with 99mTc. 99mTc-(HE)3-ZHER2:342-GGGC preserved specific binding to HER2-expressing cells. In NMRI mice, hepatic uptake of 99mTc-(HE)3-ZHER2:342-GGGC was lower than the uptake of the control affibody molecules, 99mTc-ZHER2:2395-VDC and 99mTc-ZHER2:342-GGGC. At 1 and 4 h after injection, the renal uptake of 99mTc-(HE)3-ZHER2:342-GGGC was 2–3-fold lower than uptake of 99mTc-ZHER2:2395-VDC, but it was substantially higher than uptake of 99mTc-ZHER2:342-GGGC. Further investigation indicated that a fraction of 99mTc was chelated by the HEHEHE-tag which caused a higher accumulation of radioactivity in the kidneys. Thus, a combination of a HEHEHE-tag and the GGGC chelator in targeting scaffold proteins was found to be undesirable in the case of 99mTc labelling due to a partial loss of site-specificity of nuclide chelation.

  • 12.
    Liu, Minghui
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zhou, Yinghua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression and function of vinculin in neuroendocrine tumors2007In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 28, no 4, 196-204 p.Article in journal (Refereed)
    Abstract [en]

    Transfection of chicken vinculin into highly malignant neuroendocrine tumor cells, vasostatin-transformed (vaso-transformed) Bon cells which expressed low levels of vinculin protein, reversed their malignant behavior and restored expression of tumor suppressor genes. Conversely, small interfering RNA (siRNA)-mediated knockout of vinculin resulted in fast cell growth and augmentation of colony formation in wild-type cells. Moreover, expression of a tight junction protein, claudin 4 (CLD4), was found to be associated with vinculin expression. In the vaso-transformed Bon cells, CLD4 expression was reduced, whereas a significantly increased CLD4 expression was observed in the cells with vinculin overexpression. Furthermore, vinculin knockout brought about CLD4 downregulation in wild-type cells. However, vinculin and CLD4 expression was inversely correlated in neuroendocrine tumors, respectively. Based on these findings, we hypothesize that vinculin plays a role in growth regulation of neuroendocrine tumors. Further studies are necessary to analyze the relationship between the course of the disease, and vinculin and CLD4 expression in large tumor samples.

  • 13.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Effect of cetuximab treatment in squamous cell carcinomas2010In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 31, no 2, 141-147 p.Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to assess the effects of the monoclonal antibody cetuximab in a panel of cultured squamous cell carcinoma cell lines. This antibody, targeting the epidermal growth factor receptor (EGFR), is emerging as a promising agent for treatment of several cancers. As this antibody comes into clinical use, the identification of predictive markers of therapeutic benefit remains a pressing issue. Cells were first characterized according to EGFR expression, cell doubling time, and BRAF and K-ras mutations. The effects of cetuximab on cell-cycle distribution, proliferation, as well as cell growth rate were then evaluated. Cetuximab decreased cell proliferation in three out of four cell lines in a time-dependent manner, and all cell lines were found to exhibit wild type K-ras and BRAF genes. A possible correlation between EGFR expression and cetuximab effect on growth inhibition rate was observed, whereas reduction of cell doubling time seemed to be more dependent on initial growth rate. In addition, other factors may further influence the long-term treatment response of cetuximab. Moreover, the time-dependent manner of cetuximab response demonstrates the importance of long-term measurements for this substance.

  • 14. Nisman, B.
    et al.
    Kadouri, L.
    Allweis, T.
    Hamburger, T.
    Gronowitz, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Peretz, T.
    Proliferative background in healthy women carriers of BRCA1/2 mutation2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no S1, 86-86 p.Article in journal (Other academic)
  • 15. Nisman, B.
    et al.
    Nechushtan, H.
    Biran, H.
    Gronowitz, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Peretz, T.
    Evaluation of thymidine kinase 1 activity in the serum of lung cancer (LC) patients2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no S1, 91-91 p.Article in journal (Other academic)
  • 16. Rentoft, Matilda
    et al.
    Coates, Philip John
    Loljung, Lotta
    Wilms, Torben
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nylander, Karin
    Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 5, 4194-4198 p.Article in journal (Refereed)
    Abstract [en]

    Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81 % for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42 % to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue.

  • 17.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Westman-Brinkmalm, Ann
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Davidsson, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas2003In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 24, no 2, 94-99 p.Article in journal (Refereed)
    Abstract [en]

    Little is known about the expression of mitogens and other tumour-related substances in the cerebrospinal fluid (CSF) of glioma patients. The aim of the current study was to determine the presence of aberrant proteins in the CSF of patients with low-grade gliomas. Lumbar puncture was performed in 8 adult patients with supratentorial low-grade gliomas at the time of diagnosis and in 7 controls. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry were used to detect and quantify deviant proteins in the CSF. Two isoforms of alpha(2)-Heremans-Schmid glycoprotein (AHSG) were identified and demonstrated in higher levels in patients with low-grade gliomas compared with the control group consisting of patients with mixed neurological diagnoses (p = 0.001 and p = 0.04, respectively). In 1 patient, the level of AHSG was significantly reduced after gross total resection of the tumour. AHSG appears in the present proteome screening as a novel substance in glioma research. This glycoprotein is expressed in the fetal human brain and is believed to be involved in the embryonic development of the neocortex. Further analyses are planned to determine the significance of the increased levels of AHSG in the CSF of patients with low-grade gliomas.

  • 18.
    Sandström, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Ekberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Engström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Targeting CD44v6 expressed in head and neck squamous cell carcinoma: preclinical characterization of an 111In-labeled monoclonal antibody2008In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 29, no 3, 137-144 p.Article in journal (Refereed)
    Abstract [en]

    In patients with head and neck squamous cell carcinoma (HNSCC) radioimmunodiagnosis could offer a more specific and sensitive tumor diagnostic method.Our aim was to evaluate the labeling and biodistribution of the novel radioimmunoconjugate (111)In-cMAb U36. In this study cMAb U36, targeting CD44v6, and huA33, as a negative control, were labeled with indium-111, using the chelator CHXA''-DTPA. Immunoreactivity assays and binding studies were performed in vitro. Biodistribution and tumor imaging were conducted after intravenous injection of the radioimmunoconjugate to nude mice bearing HNSCC xenografts expressing CD44v6. The immunoreactive fraction was very high and the binding was CD44v6-specific. In vivo results demonstrated a promising biodistribution, with tumors clearly accumulating radioactivity with time. At 168 h postinjection (p.i.) the tumor uptake was 54.7 +/- 16.6% injected dose/g. The cMAb U36 had significantly (p < 0.05) higher uptake in tumors 72 h p.i. compared to huA33. We produced a novel radioimmunoconjugate targeting CD44v6 for possible use in the detection of HNSCC. The conjugate demonstrates no adverse effects from labeling and a favorable biodistribution.

  • 19.
    Sooman, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tsakonas, Georgios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Jaiswal, Archita
    Navani, Sanjay
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Mikael
    Wu, Xuping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 5, 4479-4488 p.Article in journal (Refereed)
    Abstract [en]

    Background: The prognosis of high-grade glioma patients is poor and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase, non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients and the epigenetic regulation of the expression of PTPN6 and the role of its expression in chemotherapy resistance in glioma-derived cells.

    Material and methods: PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6 overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite-Pyrosequencing and demethylation of PTPN6 was done with decitabine treatment.

    Results: PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p=0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increased resistance (p<0.05) to the chemotherapeutic drugs bortezomib, cisplatin and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis or autophagy. Low PTPN6 promoter methylation correlated to protein expression and the protein expression was increased upon demethylation in glioma-derived cells.

    Conclusion: PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients and in glioma-derived cells its expression is epigenetically regulated and influences the response to chemotherapy.

  • 20.
    Spiegelberg, Diana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Kuku, Gamze
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Selvaraju, Ram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Characterization of CD44 variant expression in head and neck squamous cell carcinomas2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 3, 2053-2062 p.Article in journal (Refereed)
    Abstract [en]

    CD44 is a complex family of molecules, associated with aggressive malignancies and cancer stem cells. However, the role of CD44 variants in tumor progression and treatment resistance is not clear. In this study, the expression of CD44 and its variants was assessed in head and neck squamous cell carcinomas (HNSCC). Furthermore, subpopulations of cells expressing high amounts of CD44 variants were identified and characterized, for e.g., cell cycle phase and radioresistance. Results revealed high and homogenous CD44 and CD44v7 expression in four cell lines and CD44v4 and CD44v6 in three cell lines. CD44v3 was highly expressed in two cell lines, whereas CD44v5, CD44v7/8, CD44v10, CD133, and CD24 demonstrated no or moderate expression. Moreover, a subpopulation of very high CD44v4 expression was identified, which is independent of cell phase, demonstrating increased proliferation and radioresistance. In cell starvation experiments designed to enrich for cancer stem cells, a large population with dramatically increased expression of CD44, CD44v3, CD44v6, and CD44v7 was formed. Expression was independent of cell phase, and cells demonstrated increased radioresistance and migration rate. Our results demonstrate that the heterogeneity of tumor cells has important clinical implications for the treatment of HNSCC and that some of the CD44 variants may be associated with increased radioresistance. Highly expressed CD44 variants could make interesting candidates for selective cancer targeting.

  • 21. Wei, Qichun
    et al.
    Xu, Jing
    Shen, Li
    Fu, Xianhua
    Zhang, Bicheng
    Zhou, Xiaofeng
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    HER2 expression in primary gastric cancers and paired synchronous lymph node and liver metastases. A possible road to target HER2 with radionuclides2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 7, 6319-6326 p.Article in journal (Refereed)
    Abstract [en]

    Resistance has been reported to human epidermal growth factor receptor 2 (HER2)-targeted therapy with the tyrosine kinase inhibitor lapatinib and the antibody trastuzumab in metastatic gastric cancer. An alternative or complement might be to target the extracellular domain of HER2 with therapy-effective radionuclides. The fraction of patients with HER2 expression in primary tumors and major metastatic sites, e.g., lymph nodes and liver, was analyzed to evaluate the potential for such therapy. Samples from primary tumors and lymph node and liver metastases were taken from each patient within a few hours, and to our knowledge, such sampling is unique. The number of analyzed cases was therefore limited, since patients that had received preoperative radiotherapy, chemotherapy, or HER2-targeted therapy were excluded. From a large number of considered patients, only 29 could be included for HER2 analysis. Intracellular mutations were not analyzed since they are assumed to have no or minor effect on the extracellular binding of molecules that deliver radionuclides. HER2 was positive in nearly 52 % of the primary tumors, and these expressed HER2 in corresponding lymph node and liver metastases in 93 and 100 % of the cases, respectively. Similar values for primary tumors and also good concordance with metastases have been indicated in the literature. Thus, relevant radionuclides and targeting molecules for nuclear medicine-based noninvasive, whole-body receptor analysis, dose planning, and therapy can be applied for many patients; see "Discussion" Hopefully, more patients can then be treated with curative instead of palliative intention.

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