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  • 1.
    Ahlén, Karina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ring, Patrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tomasini-Johansson, Bianca
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Holmqvist, Kristina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Magnusson, Karl-Eric
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Platelet-derived growth factor-BB modulates membrane mobility of beta1 integrins.2004In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 314, no 1, p. 89-96Article in journal (Refereed)
  • 2. Berg, Ansgar
    et al.
    Hultgård Ekwall, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Kristofer
    Stjernschantz, Johan
    Reed, Rolf
    Effects of PGE1, PGI2 and PGF2a analogs on collagen gel compaction in vitro and interstitial fluid pressure in vivo1998In: American Journal of Physiology, ISSN 0363-6135, Vol. 274, no Heart Circ. Physiol. 43, p. H663-H671Article in journal (Refereed)
  • 3.
    Burmakin, Mikhail
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    van Wieringen, Tijs
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England..
    Olsson, P. Olof
    Lund Univ, Dept Lab Med, S-22363 Lund, Sweden..
    Stuhr, Linda
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Åhgren, Aive
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Reed, Rolf K.
    Univ Bergen, Dept Biomed, Bergen, Norway.;Univ Bergen, Ctr Canc Biomarkers CCBIO, Bergen, Norway..
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Lund Univ, Dept Lab Med, S-22363 Lund, Sweden.;Lund Univ, Dept Expt Med Sci, BMC D10, S-22381 Lund, Sweden..
    Hellberg, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England..
    Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma2017In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, article id 47Article in journal (Refereed)
    Abstract [en]

    Background: Imatinib causes increased turnover of stromal collagen, reduces collagen fibril diameter, enhances extracellular fluid turnover and lowers interstitial fluid pressure (IFP) in the human colonic carcinoma KAT-4/HT-29 (KAT-4) xenograft model. Methods: We compared the effects of imatinib on oxygen levels, vascular morphology and IFP in three experimental tumor models differing in their content of a collagenous extracellular matrix. Results: Neither the KAT4 and CT-26 colonic carcinoma models, nor B16BB melanoma expressed PDGF beta-receptors in the malignant cells. KAT-4 tumors exhibited a well-developed ECM in contrast to the other two model systems. The collagen content was substantially higher in KAT-4 than in CT-26, while collagen was not detectable in B16BB tumors. The pO(2) was on average 5.4, 13.9 and 19.3 mmHg in KAT-4, CT-26 and B16BB tumors, respectively. Treatment with imatinib resulted in similar pO(2)-levels in all three tumor models but only in KAT-4 tumors did the increase reach statistical significance. It is likely that after imatinib treatment the increase in pO(2) in KAT-4 tumors is caused by increased blood flow due to reduced vascular resistance. This notion is supported by the significant reduction observed in IFP in KAT-4 tumors after imatinib treatment. Vessel area varied between 4.5 and 7% in the three tumor models and was not affected by imatinib treatment. Imatinib had no effect on the fraction of proliferating cells, whereas the fraction of apoptotic cells increased to a similar degree in all three tumor models. Conclusion: Our data suggest that the effects of imatinib on pO(2)-levels depend on a well-developed ECM and provide further support to the suggestion that imatinib acts by causing interstitial stroma cells to produce a less dense ECM, which would in turn allow for an increased blood flow. The potential of imatinib treatment to render solid tumors more accessible to conventional treatments would therefore depend on the degree of tumor desmoplasia.

  • 4.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Franck-Larsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kalamajski, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Type I interferon system activation and association with disease manifestations in systemic sclerosis2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 7, p. 1396-1402Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study the presence of interferogenic autoantibodies in systemic sclerosis (SSc) and their correlation with clinical manifestations, serum levels of interferon alpha (IFNalpha) and chemokines of importance in the disease process. METHODS: Peripheral blood mononuclear cells (PBMCs) or purified plasmacytoid dendritic cells (pDCs) from healthy donors were stimulated with sera from patients with SSc (n=70) or healthy individuals (n=30), together with necrotic or apoptotic cell material. The IFNalpha produced and serum levels of IFNalpha, IFN-inducible protein-10 (IP-10)/chemokine (C-X-C motif) ligand 10, monocyte chemoattractant protein-1 (MCP-1)/(C-C motif) ligand-2 (CCL-2), macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL-3 and RANTES/CCL-5 were measured and correlated with the presence of autoantibodies and clinical manifestations in the patients with SSc. RESULTS: Sera from both diffuse SSc and limited SSc contained interferogenic antibodies, which correlated with the presence of anti-ribonucleoprotein and anti-Sjögren syndrome antigen autoantibodies. The pDCs were responsible for the IFNalpha production which required interaction with FcgammaRII and endocytosis. Increased serum levels of IP-10 were associated with vascular manifestations such as cardiac involvement (p=0.027) and pulmonary arterial hypertension (p=0.036). Increased MCP-1 or IFNalpha serum levels were associated with lung fibrosis (p=0.019 and 0.048, respectively). Digital ulcers including digital loss were associated with increased serum levels of IFNalpha (p=0.029). CONCLUSION: An activated type I IFN system previously seen in several other systemic autoimmune diseases is also present in SSc and may contribute to the vascular pathology and affect the profibrotic process.

  • 5.
    Fortin, Marc-André
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Salnikov, Alexei V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Immuno-PET of undifferentiated thyroid carcinoma with radioiodine-labelled antibody cMAb U36: application to antibody tumour uptake studies2007In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 34, no 9, p. 1376-1387Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We tested the suitability of the chimeric monoclonal anti-human CD44 splice version 6 antibody (cMAb U36) for targeting and visualising human anaplastic thyroid carcinoma with PET. We also performed experiments aimed at elucidating the relation between tumour interstitial fluid pressure (TIFP) and the tumour uptake of antibodies. METHODS: The affinity and specificity of the cMAb U36 for KAT-4 cells were evaluated in vitro, as was the Na+/I- symporter (NIS) expression. Biodistribution studies were performed on KAT-4 carcinoma-bearing mice injected with 124I-cMAb U36 or free iodine. Biodistribution studies were also performed in animals treated with the specific TGF-beta1 and -beta3 inhibitor Fc:TbetaRII, which lowers TIFP. Treated and non-treated animals were scanned by microPET. RESULTS: Cultured human undifferentiated/anaplastic thyroid carcinoma KAT-4 cells expressed low levels of NIS and uptake of free iodine was insignificant. The cMAb U36 expressed an affinity (KD) of 11+/-2 nM. Tumour radioactivity uptake reached maximum values 48 h after injection of 124I-cMAb U36 (approximately 22%IA/g). KAT-4 carcinomas were readily identified in all 124I-immuno-PET images. Radioactivity tumour uptake in Fc:TbetaRII-treated animals was significantly lower at 24 and 48 h after injection, and five times higher thyroid uptake was also noted. CONCLUSION: We successfully used 124I-cMAb U36 to visualise CD44v6-expressing human anaplastic thyroid carcinoma. Given the lack of NIS expression in KAT-4, tumour visualisation is not due to free iodine uptake. Lowering the TIFP in KAT-4 carcinomas did not increase the uptake of mAbs into tumour tissue.

  • 6.
    Friman, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsson, Renata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stuhr, Linda B.
    Chidiac, Jean
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Reed, Rolf K.
    Oldberg, Åke
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Increased Fibrosis and Interstitial Fluid Pressure in Two Different Types of Syngeneic Murine Carcinoma Grown in Integrin β3-Subunit Deficient Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34082-Article in journal (Refereed)
    Abstract [en]

    Stroma properties affect carcinoma physiology and direct malignant cell development. Here we present data showing that alpha(V)beta(3) expressed by stromal cells is involved in the control of interstitial fluid pressure (IFP), extracellular volume (ECV) and collagen scaffold architecture in experimental murine carcinoma. IFP was elevated and ECV lowered in syngeneic CT26 colon and LM3 mammary carcinomas grown in integrin beta(3)-deficient compared to wild-type BALB/ c mice. Integrin beta(3)-deficiency had no effect on carcinoma growth rate or on vascular morphology and function. Analyses by electron microscopy of carcinomas from integrin beta(3)-deficient mice revealed a coarser and denser collagen network compared to carcinomas in wild-type littermates. Collagen fibers were built from heterogeneous and thicker collagen fibrils in carcinomas from integrin beta(3)-deficient mice. The fibrotic extracellular matrix (ECM) did not correlate with increased macrophage infiltration in integrin beta(3)-deficient mice bearing CT26 tumors, indicating that the fibrotic phenotype was not mediated by increased inflammation. In conclusion, we report that integrin beta(3)-deficiency in tumor stroma led to an elevated IFP and lowered ECV that correlated with a more fibrotic ECM, underlining the role of the collagen network for carcinoma physiology.

  • 7.
    Friman, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsson, Renata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stuhr, Linda
    Chidiac, Jean
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Reed, Rolf
    Oldberg, Åke
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Integrin αVβ3 restrains fibrosis and elevated interstitial fluid pressure in syngeneic mouse carcinoma: Integrin β3-ablation affects tumor microenvironmentManuscript (preprint) (Other academic)
  • 8.
    Gullberg, Donald
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Tingström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Thuresson, A C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Olsson, L
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Zoology.
    Terracio, L
    Borg, T K
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Beta 1 integrin-mediated collagen gel contraction is stimulated by PDGF1990In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 186, no 2, p. 264-272Article in journal (Refereed)
  • 9.
    Gustafsson, Renata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Friman, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Burmakin, Mikhail
    Hellberg, Carina
    Heldin, Carl-Henrik
    Oldberg, Åke
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stromal effects of PDGFR inhibition by STI571 in experimental carcinoma: Altered collagen fibrils and reduction of a specific stromal cell populationManuscript (preprint) (Other academic)
  • 10.
    Hakelius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Koskela, Anita
    Ivarsson, Mikael
    Grenman, Reidar
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Keratinocytes and Head and Neck Squamous Cell Carcinoma Cells Regulate Urokinase-type Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Fibroblasts2013In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 33, no 8, p. 3113-3118Article in journal (Refereed)
    Abstract [en]

    Background: To investigate possible differences in the effects of soluble factors from oral squamous cell carcinoma (SCC) cells (UT-SCC-87) and normal oral keratinocytes (NOK) on fibroblast expression of genes involved in tumor stroma turnover. Materials and Methods: Transwell co-cultures with fibroblasts in collagen gels, and SCC cells or NOK in inserts were carried out. Fibroblast gene expression was measured with real-time polymerase chain reaction (PCR). Results: The expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) was up-regulated in co-cultures with SCC cells but not with NOK. In contrast, both SCC cells and NOK regulated matrix metalloproteinase-1 (MMP1) and -3, and tissue inhibitor of metalloproteinases-2 (TIMP2) and -3 to a similar extent, while MMP2 and TIMP1 were largely unaffected. Interleukin 1 alpha (IL1 alpha) up-regulated both MMP1 and MMP3 and down-regulated PAI-1, TIMP2 and -3. Conclusion: SCC and NOK regulate fibroblast expression of genes involved in tumor stroma turnover differentially in vitro. These observations may contribute to a better understanding of the mechanisms behind extracellular matrix turnover in tumors.

  • 11.
    Hakelius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Koskela, Anita
    Reyhani, Vahid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ivarsson, Mikael
    Grenman, Reidar
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Interleukin-1-mediated effects of normal oral keratinocytes and head and neck squamous carcinoma cells on extracellular matrix related gene expression in fibroblasts2012In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 48, no 12, p. 1236-1241Article in journal (Refereed)
    Abstract [en]

    Objectives: The composition of tumor stroma and the activity of tumor associated fibroblasts are important for tumor growth. Interactions between carcinoma cells and fibroblasts regulate the turnover of extracellular matrix (ECM). Here, the in vitro effects of oral squamous cell carcinoma (SCC) cells (UT-SCC-30 and UT-SCC-87) on fibroblast expression of genes for ECM components and connective tissue growth factor (CTGF/CCN2), were compared to those of normal oral keratinocytes (NOK). Materials and Methods: Cocultures with fibroblasts in collagen gels and keratinocytes with the two cell types separated by a semi permeable membrane were used, and relative gene expression was measured with real-time PCR. Results: All investigated genes were regulated by NOK and the SCCs. The downregulation of pro-collagens alpha 1(I) and alpha 1(III) was more pronounced in cocultures with NOK, while the expression of CCN2 and fibronectin was downregulated by both NOK and the SCCs to a similar extent. UT-SCC-87, but not UT-SCC-30, secreted significantly more IL-1 alpha than NOK. A recombinant interleukin-1 receptor antagonist reversed many of the observed effects on fibroblast gene expression suggesting involvement of IL-1 in cocultures with NOK as well as with SCCs. Conclusion: The observed differential effects on fibroblast gene expression suggest that NOK are more antifibrotic compared to UT-SCC-30 and UT-SCC-87. These findings may contribute to a better understanding of the mechanisms behind ECM turnover in tumors.

  • 12.
    Hakelius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Reyhani, Vahid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Normal oral keratinocytes and head and neck squamous carcinoma cells induce an innate response in fibroblasts2016In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 36, no 5, p. 2131-2137Article in journal (Other academic)
    Abstract [en]

    Background: Tumor stroma is similar to the connective tissue of chronic inflammation. The extracellular matrix of tumors is formed by cancer-associated fibroblasts that also modulate the inflammatory response. Materials and Methods: We studied the ability of oral keratinocytes (NOK) and oral squamous cell carcinoma cells (SCC) to induce an innate immune response in fibroblasts. Co-cultures with fibroblasts in collagen gels and keratinocytes in inserts were used. Pentraxin 3 (PTX3) was used as an indicator of an innate immune response. Results: SCC and NOK up-regulated fibroblast mRNA expression and protein release of PTX3. mRNA levels were more pronounced in cultures with malignant cells. The induction of PTX3 was abrogated by an interleukin-1 receptor antagonist Conclusion: Keratinocytes have the capacity to induce an interleukin-1-dependent innate immune response by fibroblasts in vitro. This could be important for subsequent fibroblast modulation of the inflammatory reaction in non-malignant and malignant disease processes.

  • 13.
    Hakelius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Saiepour, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Göransson, Hanna Kultima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Differential Gene Regulation in Fibroblasts in Co-culture with Keratinocytes and Head and Neck SCC Cells2015In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 6, p. 3253-3265Article in journal (Refereed)
    Abstract [en]

    Background: While carcinoma-associated fibroblasts (CAFs) support tumorigenesis, normal tissue fibroblasts suppress tumor progression. Mechanisms behind conversion of fibroblasts into a CAF phenotype are largely unrevealed. Materials and Methods: Transwell co-cultures with fibroblasts in collagen gels and squamous-cell carcinoma (SCC) cells or normal oral keratinocytes (NOKs) in inserts. Differences in fibroblast global gene expression were analyzed using Affymetrix arrays and subsequent functional annotation and cluster analysis, as well as gene set enrichment analysis were performed. Results: There were 52 up-regulated and 30 down-regulated transcript IDs (>2-fold, p<0.05) in fibroblasts co-cultured with SCC compared to NOKs. Functional analysis demonstrated an enrichment of collagen-related genes. There were similarities with gene sets reflecting a non-specific, innate-type response with activation of both interferon pathways and connective tissue turnover. Conclusion: There were distinct differences in fibroblast gene expression between the co-culture types. Many were in genes related to an innate-type of response and to connective tissue turnover.

  • 14.
    Heldin, Carl-Henrik
    et al.
    Ludwiginstitutet för Cancerforskning.
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pietras, Kristian
    Ludwiginstitutet för Cancerforskning.
    Östman, Arne
    Ludwiginstitutet för Cancerforskning.
    High interstitial fluid pressure - an obstacle in cancer therapy.2004In: Nat Rev Cancer, ISSN 1474-175X, Vol. 4, no 10, p. 806-13Article in journal (Refereed)
    Abstract [en]

    Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.

  • 15.
    Heuchel, Rainer
    et al.
    Ludwiginstitutet för Cancerforskning.
    Berg, Ansgar
    Tallquist, Michelle
    Åhlén, Karina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Reed, Rolf K
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Claesson-Welsh, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Carl-Henrik
    Ludwiginstitutet för Cancerforskning.
    Soriano, Philippe
    Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3' kinase signaling1999In: Proc Natl Acad Sci U S A, Vol. 96, no 20, p. 11410-5Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) isoforms lead to mitogenic, survival, and chemotactic responses in a variety of mesenchymal cell types during development and in the adult. We have studied the importance of phosphatidylinositol-3' kinase (PI3K) signaling in these responses by mutating the PI3K-binding sites in the PDGF-beta receptor by gene targeting in embryonic stem cells. Homozygous mutant mice developed normally; however, cells derived from the mutants were less chemotactic and had largely lost their ability to contract collagen gels in response to PDGF. Injection of a mast cell degranulating agent in mice led to a decrease in interstitial fluid pressure resulting in edema formation. In contrast to wild-type mice, mutant mice were unable to normalize the pressure after treatment with PDGF. Taken together, these observations suggest a function for PDGF signaling through PI3K in interstitial fluid homeostasis by modulating the tension between cells and extracellular matrix structures.

  • 16.
    Hultgård Ekwall, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Couloigner, Vincent
    Rubin, Kristofer
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Network organization of interstitial connective tissue cells in the human endolymphatic duct2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, Vol. 51, no 11, p. 1491-1500Article in journal (Refereed)
  • 17.
    Hultgård Ekwall, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg, Jens
    Rubin, Kristofer
    Prostaglandin E1 stimulates phosphorylation of caldesmon and depolymerizes F-actin in a cAMP- and PKA dependent manner in human dermal fibroblastsManuscript (Other academic)
  • 18. Hultgård-Ekwall, Anna-Karin H
    et al.
    Couloigner, Vincent
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Network organization of interstitial connective tissue cells in the human endolymphatic duct2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, no 11, p. 1491-500Article in journal (Refereed)
    Abstract [en]

    The human endolymphatic duct (ED) and sac of the inner ear have been suggested to control endolymph volume and pressure. However, the physiological mechanisms for these processes remain obscure. We investigated the organization of the periductal interstitial connective tissue cells and extracellular matrix (ECM) in four freshly fixed human EDs by transmission electron microscopy and by immunohistochemistry. The unique surgical material allowed a greatly improved structural and epitopic preservation of tissue. Periductal connective tissue cells formed frequent intercellular contacts and focally occurring electron-dense contacts to ECM structures, creating a complex tissue network. The connective tissue cells also formed contacts with the basal lamina of the ED epithelium and the bone matrix, connecting the ED with the surrounding bone of the vestibular aqueduct. The interstitial connective tissue cells were non-endothelial and non-smooth muscle fibroblastoid cells. We suggest that the ED tissue network forms a functional mechanical entity that takes part in the control of inner ear fluid pressure and endolymph resorption.

  • 19.
    Hultgård-Ekwall, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mayerl, Christina
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wick, Georg
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    An interstitial network of podoplanin-expressing cells in the human endolymphatic duct2006In: Journal of the Association for Research in Otolaryngology, ISSN 1525-3961, E-ISSN 1438-7573, Vol. 7, no 1, p. 38-47Article in journal (Refereed)
    Abstract [en]

    The human endolymphatic duct (ED) with encompassing interstitial connective tissue (CT) is believed to be important for endolymph resorption and fluid pressure regulation of the inner ear. The periductal CT cells are interconnected via numerous cellular extensions, but do not form vessel structures. Here we report that the periductal CT is populated by two distinct cell phenotypes; one expressing podoplanin, a protein otherwise found on lymph endothelia and on epithelia involved in fluid fluxes, and a second expressing a fibroblast marker. A majority of the interstitial cells expressed podoplanin but not the lymphatic endothelial cell markers hyaluronan receptor (LYVE-1) or vascular endothelial growth factor receptor-3 (VEGFR-3). The fibroblast marker positive cells were found close to the ED epithelium. In the mid- and distal parts of the ED, these cells were enriched under folded epithelia. Furthermore, subepithelial CT cells were found to express activated platelet derived growth factor (PDGF)-beta receptors. Cultured CT cells from human inner ear periductal and perisaccular explant tissues were identified as fibroblasts. These cells compacted a three-dimensional collagen lattice by a process that could be promoted by PDGF-BB, a factor involved in interstitial fluid pressure regulation. Our results are compatible with the notion that the periductal CT cells are involved in the regulation of inner ear fluid pressure. By active compaction of the periductal CT and by the formation of villous structures, the CT cells could modulate fluid fluxes over the ED epithelium as well as the longitudinal flow of endolymph in the ED.

  • 20.
    Jacobson, Annica
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rahmanian, Mehdi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Paraskevi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ludwiginstitutet för Cancerforskning.
    Expression of hyaluronan synthase 2 or hyaluronidase 1 differentially affect the growth rate of transplantable colon carcinoma cell tumors.2002In: Int J Cancer, Vol. 102, p. 212-Article in journal (Refereed)
    Abstract [en]

    Advanced colorectal cancers are often associated with elevated amounts of hyaluronan. To investigate the importance of hyaluronan in colon carcinoma tumor progression, we have expressed by stable transfection hyaluronan synthase 2 (Has2) and hyaluronidase 1 (Hyal1) in the rat colon carcinoma cell line, PROb. We found that hyaluronan overproduction led to a higher growth rate of tumor cells in vitro, and to a faster development of transplantable tumors in syngeneic rats, compared to the mock-transfectants. Has2 transfected PROb cells gave rise to tumors that were significantly less vascularized, but had a significantly larger viable tumor fraction compared to tumors generated from mock-transfectants. In contrast, Hyal1 overexpression suppressed the growth rate of tumor cells both in vitro and in vivo. Moreover, tumors derived from Hyal1-transfected cells had a significantly larger necrotic area than tumors derived from mock- and Has2-transfectants. Our study demonstrates that Has2 overproduction promotes tumorigenicity, whereas Hyal1 overexpression suppresses tumorigenicity in an experimental model for colon carcinoma.

  • 21.
    Jacobson, Annica
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salnikov, Alexei
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lammerts, Ellen
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Roswall, Pernilla
    Department of Genetics and Pathology.
    Sundberg, Christian
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Paraskevi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ludwiginstitutet för Cancerforskning.
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Nils-Erik
    Department of Genetics and Pathology.
    Hyaluronan content in experimental carcinoma is not correlated to interstitial fluid pressure.2003In: Biochem. Biophys. Res. Commun., Vol. 305, p. 1017-1023Article in journal (Refereed)
    Abstract [en]

    Mechanism(s) for generation of the high tumor interstitial fluid pressure (TIFP) that is characteristic of carcinoma is not known. We investigated the role of hyaluronan, the major water-binding polysaccharide of the extracellular matrix, for the generation of a high TIFP. A human anaplastic thyroid carcinoma (KAT-4) xenografted to athymic mice and a syngeneic rat colon carcinoma (PROb) were used. Neither KAT-4 nor PROb cells produced hyaluronan (HA) in culture, however, both cell lines produced factors that stimulated HA-synthesis by cultured fibroblasts. Modulating hyaluronan levels by transfection of PROb carcinoma cells with hyaluronan synthase-2 revealed no correlation between hyaluronan content and TIFP. Furthermore, lowering of TIFP by treating KAT-4 tumors with a specific inhibitor of TGF-beta 1 and -beta 3 did not change the concentration of hyaluronan in the tumors. In summary, our results suggest that a modulation of hyaluronan content is not a major pathogenetic mechanism for the generation of the characteristically high TIFP in malignant carcinomas.

  • 22.
    Kalamajski, Sebastian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bihan, Dominique
    Bonna, Arkadiusz
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Farndale, Richard W
    Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase.2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 15, p. 7951-60Article in journal (Refereed)
    Abstract [en]

    The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin. Its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase (a major collagen cross-linking enzyme) and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Together, the data suggest a fibromodulin-modulated collagen cross-linking mechanism where fibromodulin binds to a specific part of the collagen domain and also forms a complex with lysyl oxidase, targeting the enzyme toward specific cross-linking sites.

  • 23.
    Kalamajski, Sebastian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Liu, Cuiping
    Tillgren, Viveka
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oldberg, Ake
    Rai, Jyoti
    Weis, MaryAnn
    Eyre, David R.
    Increased C-telopeptide Cross-linking of Tendon Type I Collagen in Fibromodulin-deficient Mice2014In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 27, p. 18873-18879Article in journal (Refereed)
    Abstract [en]

    The controlled assembly of collagen monomers into fibrils, with accompanying intermolecular cross-linking by lysyl oxidase-mediated bonds, is vital to the structural and mechanical integrity of connective tissues. This process is influenced by collagen-associated proteins, including small leucine-rich proteins (SLRPs), but the regulatory mechanisms are not well understood. Deficiency in fibromodulin, an SLRP, causes abnormal collagen fibril ultrastructure and decreased mechanical strength in mouse tendons. In this study, fibromodulin deficiency rendered tendon collagen more resistant to nonproteolytic extraction. The collagen had an increased and altered cross-linking pattern at an early stage of fibril formation. Collagen extracts contained a higher proportion of stably crosslinked alpha 1(I) chains as a result of their C-telopeptide lysines being more completely oxidized to aldehydes. The findings suggest that fibromodulin selectively affects the extent and pattern of lysyl oxidase-mediated collagen cross-linking by sterically hindering access of the enzyme to telopeptides, presumably through binding to the collagen. Such activity implies a broader role for SLRP family members

  • 24. Kelkka, Tiina
    et al.
    Pizzolla, Angela
    Laurila, Juha Petteri
    Friman, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsson, Renata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kallberg, Eva
    Olsson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leanderson, Tomas
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salmi, Marko
    Jalkanen, Sirpa
    Holmdahl, Rikard
    Mice Lacking NCF1 Exhibit Reduced Growth of Implanted Melanoma and Carcinoma Tumors2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e84148-Article in journal (Refereed)
    Abstract [en]

    The NADPH oxidase 2 (NOX2) complex is a professional producer of reactive oxygen species (ROS) and is mainly expressed in phagocytes. While the activity of the NOX2 complex is essential for immunity against pathogens and protection against autoimmunity, its role in the development of malignant tumors remains unclear. We compared wild type and Ncf1(m1J) mutated mice, which lack functional NOX2 complex, in four different tumor models. Ncf1(m1J) mutated mice developed significantly smaller tumors in two melanoma models in which B16 melanoma cells expressing a hematopoietic growth factor FLT3L or luciferase reporter were used. Ncf1(m1J) mutated mice developed significantly fewer Lewis Lung Carcinoma (LLC) tumors, but the tumors that did develop, grew at a pace that was similar to the wild type mice. In the spontaneously arising prostate carcinoma model (TRAMP), tumor growth was not affected. The lack of ROS-mediated protection against tumor growth was associated with increased production of immunity-associated cytokines. A significant increase in Th2 associated cytokines was observed in the LLC model. Our present data show that ROS regulate rejection of the antigenic B16-luc and LLC tumors, whereas the data do not support a role for ROS in growth of intrinsically generated tumors.

  • 25.
    Kłosowska-Wardega, Agnieszka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hasumi, Yoko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Burmakin, Mikhail
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Åhgren, Aive
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Stuhr, Linda
    Department of Biomedicine, University of Bergen, Norway.
    Moen, Ingrid
    Department of Biomedicine, University of Bergen, Norway.
    Reed, Rolf K.
    Department of Biomedicine, University of Bergen, Norway.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellberg, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Combined anti-angiogenic therapy targeting PDGF and VEGF receptors lowers the interstitial fluid pressure in a murine experimental carcinoma2009In: PloS one, ISSN 1932-6203, Vol. 4, no 12, p. e8149-Article in journal (Refereed)
    Abstract [en]

    Elevation of the interstitial fluid pressure (IFP) of carcinoma is an obstacle in treatment of tumors by chemotherapy and correlates with poor drug uptake. Previous studies have shown that treatment with inhibitors of platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) signaling lowers the IFP of tumors and improve chemotherapy. In this study, we investigated whether the combination of PDGFR and VEGFR inhibitors could further reduce the IFP of KAT-4 human carcinoma tumors. The tumor IFP was measured using the wick-in-needle technique. The combination of STI571 and PTK/ZK gave an additive effect on the lowering of the IFP of KAT-4 tumors, but the timing of the treatment was crucial. The lowering of IFP following combination therapy was accompanied by vascular remodeling and decreased vascular leakiness. The effects of the inhibitors on the therapeutic efficiency of Taxol were investigated. Whereas the anti-PDGF and anti-VEGF treatment did not significantly inhibit tumor growth, the inhibitors enhanced the effect of chemotherapy. Despite having an additive effect in decreasing tumor IFP, the combination therapy did not further enhance the effect of chemotherapy. Simultaneous targeting of VEGFR and PDGFR kinase activity may be a useful strategy to decrease tumor IFP, but the timing of the inhibitors should be carefully determined.

  • 26. Lammerts, Ellen
    et al.
    Roswall, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundberg, Christian
    Gotwals, Philip
    Koteliansky, Victor
    Reed, Rolf
    Heldin, Nils-Erik
    Rubin, Kristofer
    Interference with TGF-β1 and -β3 in Tumor Stroma Lowers Tumor Interstitial Fluid Pressure Independently of Growth in Experimental Carcinoma2002In: International Journal of Cancer, ISSN 0020-7136, Vol. 102, no 5, p. 453-462Article in journal (Refereed)
  • 27.
    Liden, Åsa
    et al.
    Univ Bergen, Dept Biomed, Bergen, Norway.
    Karlsen, Tine Veronika
    Univ Bergen, Dept Biomed, Bergen, Norway.
    Guss, Bengt
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden.
    Reed, Rolf K.
    Univ Bergen, Dept Biomed, Bergen, Norway; Univ Bergen, Ctr Canc Biomarkers CCBIO, Bergen, Norway.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Lund Univ, Dept Lab Med, Translat Canc Res, Sweden.
    Integrin αVβ3 can substitute for collagen‐binding β1‐integrins in vivo to maintain a homeostatic interstitial fluid pressure2018In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 103, no 5, p. 629-634Article in journal (Refereed)
    Abstract [en]

    Accumulated data indicate that cell‐mediated contraction of reconstituted collagenous gels in vitro can serve as a model for cell‐mediated control of interstitial fluid pressure (PIF) in vivo. A central role for collagen‐binding β1‐integrins in both processes has been established. Furthermore, integrin αVβ3 takes over the role of collagen‐binding β1‐integrins in mediating contraction after perturbations of collagen‐binding β1‐integrins in vitro. Integrin αVβ3 is also instrumental for normalization of dermal PIF that has been lowered due to mast cell degranulation with compound 48/80 (C48/80) in vivo. Here we demonstrate a role of integrin αVβ3 in maintaining a long term homeostatic dermal PIF in mice lacking the collagen‐binding integrin  α11β1 (α11−/− mice). Measurements of PIF were performed after circulatory arrest. Furthermore, cell‐mediated integrin αVβ3‐directed contraction of collagenous gels in vitro depends on free access to a collagen site known to bind several extracellular matrix (ECM) proteins that form substrates for αVβ3‐directed cell attachment, such as fibronectin and fibrin. A streptococcal collagen‐binding protein, CNE, specifically binds to and blocks this site on the collagen triple helix. Here we show that whereas CNE perturbed αVβ3‐directed and platelet‐derived growth factor BB‐induced normalization of dermal PIF after C48/80, it did not affect αVβ3‐dependent maintenance of a homeostatic dermal PIF. These data imply that dynamic modification of the ECM structure is needed during acute patho‐physiological modulations of PIF but not for long‐term maintenance of a homeostatic PIF. Our data thus show that collagen‐binding β1‐integrins, integrin αVβ3 and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis.

  • 28.
    Lidén, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Ansgar
    Nedrebö, Torbjörn
    Reed, Rolf K.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on beta3 but not beta1 integrins2006In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 98, no 5, p. 635-641Article in journal (Refereed)
    Abstract [en]

    Interstitial fluid pressure (PIF) is one of the determinants of transcapillary fluid flux and thereby interstitial fluid volume. Cell-mediated control of PIF regulates fluid content in the loose interstitial connective tissues that surround the capillary bed. To maintain a normal PIF in dermis, β1 integrins mediate the tensile strength applied by connective tissue cells on the extracellular matrix. Platelet-derived growth factor (PDGF)-BB normalizes anaphylaxis-induced reduction of PIF. Anti–β3 integrin IgG and a cyclic RGD peptide that inhibits the αVβ3 integrin blocked the ability of PDGF-BB to normalize the lowered PIF resulting from mast cell degranulation. PDGF-BB was unable to normalize PIF lowered as a result of mast cell degranulation in β3-negative mice. Monoclonal anti–β3 integrin IgG had no effect on PIF in normal mouse dermis. In contrast, administration of anti–β1 integrin IgM lowered PIF in normal dermis but had no effect on PDGF-BB–induced normalization of PIF after anaphylaxis. Furthermore, collagen gel contraction mediated by wild-type mouse embryonal fibroblasts were only marginally affected by function-blocking anti–β1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by αV-negative mouse embryonic fibroblasts was completely blocked by anti–β1 integrin antibodies, even after stimulation with PDGF-BB. These results show a previously unrecognized in vivo function for the αVβ3 integrin, as a participant in the control of PIF during inflammatory reactions. Furthermore, our data demonstrate that PDGF-BB induces connective tissue cells to generate tensile forces via αVβ3 during such reactions.

  • 29.
    Lidén, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Karlström, Åsa
    Lannergård, Jonas
    Kalamajski, Sebastian
    Guss, Bengt
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rydén, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A fibronectin-binding protein from Streptococcus equi binds collagen and modulates cell-mediated collagen gel contraction2006In: Biochemical and Biophysical Research Communications, Vol. 340, p. 604-610Article in journal (Refereed)
  • 30.
    Lidén, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Karlström, Åsa
    Lannergård, Jonas
    Kalamajski, Sebastian
    Guss, Bengt
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rydén, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A fibronectin-binding protein from Streptococcus equi binds collagen and modulates cell-mediated collagen gel contraction2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 340, no 2, p. 604-610Article in journal (Refereed)
    Abstract [en]

    The N-terminal fragment (FNZN) of the fibronectin-binding protein FNZ from Streptococcus equi subspecies zooepidemicus was investigated as to effects on murine cell interactions with extracellular matrix proteins. FNZN bound to immobilized fibronectin (FN) and native, but not denatured, collagen type I. FNZN had no effect on primary adhesion of cells from the murine myoblastic C2C12 cell line to immobilized fibronectin. C2C12 cells adhered to immobilized FNZN, a process that was not inhibited by anti-human FN IgG or by an inhibitor of integrin alphaVbeta3. C2C12 cells lack collagen-binding beta1 integrins and neither adhere to native collagen nor mediate contraction of three-dimensional collagen gels. FNZN stimulated collagen gel contraction by C2C12 cells but not adhesion of C2C12 cells to collagen. Experiments with an alphaVbeta3-inhibitor suggested that FNZN promoted contraction by a process requiring alphaVbeta3. Our data suggest that FNZN by binding to cells, collagen, and FN modulate complex adhesive processes mediated by the alphaVbeta3 integrin. Since alphaVbeta3-mediated contractile events function to counteract edema formation during inflammation, it is possible that FNZN and its secreted homologue FNE modulate edema responses in infected tissues.

  • 31.
    Lidén, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van Wieringen, Tijs
    Lannergård, Jonas
    Karlström, Åsa
    Guss, Bengt
    Rubin, Kristofer
    Effects of streptococcal extracellular matrix-binding proteins on αVβ3-directed collagen gel contractionManuscript (Other academic)
  • 32.
    Lidén, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van Wieringen, Tijs
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lannergård, Jonas
    Kassner, Anja
    Heinegård, Dick
    Reed, Rolf K.
    Guss, Bengt
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A secreted collagen- and fibronectin-binding streptococcal protein modulates cell-mediated collagen gel contraction and interstitial fluid pressure2008In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 3, p. 1234-1242Article in journal (Refereed)
    Abstract [en]

    Fibroblast-mediated collagen gel contraction depends on collagen-binding beta1 integrins. Perturbation of these integrins reveals an alternative contraction process that is integrin alphaVbeta3-dependent and platelet-derived growth factor (PDGF) BB-stimulated. Connective tissue cells actively control interstitial fluid pressure (IFP), and inflammation-induced lowering of IFP provides a driving force for edema formation. PDGF-BB normalizes a lowered IFP by an alphaVbeta3-dependent process. A potential modulation of IFP by extracellular matrix-binding bacterial proteins has previously not been addressed. The fibronectin (FN)-binding protein FNE is specifically secreted by the highly virulent Streptococcus equi subspecies equi. FNE bound FN and native collagen type I with K(d) values of approximately 20 and approximately 50 nm determined by solid-phase binding assays. Rotary shadowing revealed a single FNE binding site located at on average 122 nm from the C terminus of procollagen type I. FNE induced alphaVbeta3-mediated contraction by C2C12 cells in a concentration-dependent manner having a maximal effect at approximately 100 nm. This activity of FNE required cellular FN, and FNE acted synergistically to added plasma FN or PDGF-BB. FNE enhanced binding of soluble FN to immobilized collagen, and conversely the binding of collagen to immobilized FN. Marked bell-shaped concentration dependences for these interactions suggest that FNE forms a bridge between FN and collagen. Finally, FNE normalized dermal IFP lowered by anaphylaxis. Our data suggest that secreted FNE normalized lowering of IFP by stimulating connective tissue cell contraction.

  • 33.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Golla, Sanjeep S. V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    O-15-Water PET Study of the Effect of Imatinib, a Selective Platelet-Derived Growth Factor Receptor Inhibitor, Versus Anakinra, an IL-1R Antagonist, on Water-Perfusable Tissue Fraction in Colorectal Cancer Metastases2015In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, no 8, p. 1144-1149Article in journal (Refereed)
    Abstract [en]

    High interstitial fluid pressure (IFP) in colorectal cancer metastases may decrease the uptake and, thus, the effects of antitumor drugs. Imatinib, a selective inhibitor of platelet-derived growth factor receptors, and anakinra, an interleukin-1 receptor antagonist, respectively, increase drug uptake or decrease IFP in preclinical models of carcinoma. Drug-induced decrease in IFP in human metastases has not been objectively shown but should be reflected by an increase in water-perfusable tissue fraction (PTF) or tumor blood flow (TBF) using O-15-water PET/CT and kinetic modeling. Hence, the aim of this study was to assess the effects of imatinib and anakinra on PTF and TBF in colorectal cancer metastases in patients. Methods: Nine patients with documented progressive disease despite all established therapy underwent O-15-water PET/CT at baseline and at 2 d and 6-7 d after the start of oral administration of imatinib (400 mg/d). After a washout period of 1 wk, the protocol was repeated with anakinra (100 mg/d) subcutaneously. Six patients underwent a second baseline scan on the same day to assess reproducibility of PTF and TBF measurements. Volumes of interest were drawn over liver metastases and aorta. PTF and TBF were calculated using the standard single-tissue-compartment model. Results: Imatinib administration during 6-7 d increased PTF from 0.62 +/- 0.12 to 0.69 +/- 0.13, compared with baseline and day 2 (P = 0.02, Wilcoxon test). No significant changes were found in TBF. PTF values were no longer significantly different from baseline 1 wk after the last imatinib dosage. Anakinra induced no significant change in PTF or TBF. The repeatability coefficients of PTF and TBF in liver lesions were 22% and 28%, respectively. Conclusion: Imatinib increases PTF of colorectal cancer metastases in patients and hence may increase the delivery of antitumor drugs. O-15-water PET/CT and kinetic modeling provide insights into the microenvironment of human cancers.

  • 34. Martin, M
    et al.
    Åhlén, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimanche-Boitrel, M-T
    Mendrick, D L
    Turner, D C
    Rubin, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Martin, F
    Colon-cancer cell variants producing regressive tumors in syngeneic rats, unlike variants yielding progressive tumors, attach to interstitial collagens through integrin alpha2beta11996In: Int J Cancer, Vol. 65, p. 796-804Article in journal (Refereed)
  • 35.
    Nowinski, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Kiwanuka, Elizabeth
    Koskela, Anita
    Rubin, Kristofer
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Ivarsson, Mikael
    Expression of connective tissue growth factor in burn-wounds and during re-epithelialization-interleukin-1α downregulates dermal expression of connective tissue growth factorManuscript (Other academic)
  • 36.
    Nowinski, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Höijer, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Engstrand, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ivarsson, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Keratinocytes inhibit expression of connective tissue growth factor in fibroblasts in vitro by an interleukin-1alpha dependent mecanism2002In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 119, no 2, p. 449-455Article in journal (Refereed)
    Abstract [en]

    The wound healing process concludes with downregulation of fibroblast activity. Clinical observations suggest that the regenerating epidermis suppresses this activity. An important regulator of fibroblast activity is the fibrogenic cytokine connective tissue growth factor. We hypothesized that epidermal keratinocytes may affect fibroblast activity via this cytokine. We demonstrate keratinocyte-mediated suppression of connective tissue growth factor at both the mRNA and protein levels by around 50% or more when fibroblasts were cultured in multiwell plates with keratinocyte cultures in accompanying semipermeable cell culture inserts, or stimulated by keratinocyte-conditioned media. Both basal and transforming-growth-factor-beta1-stimulated levels of connective tissue growth factor were inhibited. A 3 h coculture period with keratinocytes was sufficient to suppress connective tissue growth factor expression by fibroblasts, but the inhibition developed over a time period of around 16 h. The putative keratinocyte-derived factor(s) responsible for these effects was found to be soluble and stable. By analyzing cytokines secreted by keratinocytes we identified interleukin-1alpha as a potent inhibitor of connective tissue growth factor mRNA expression in fibroblasts. Involvement of this cytokine in keratinocyte-mediated connective tissue growth factor suppression was confirmed by using anti-interleukin-1alpha antibodies. Tumor necrosis factor alpha or prostaglandins did not appear to be involved. In conclusion, our results indicate that interleukin-1alpha secretion by keratinocytes provides a mechanism for the downregulation of connective tissue activity during the end-stage of wound healing, when epithelia coverage has developed over the wound area.

  • 37.
    Nowinski, Daniel
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Lysheden, Ann-Sofie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Gardner, Humphrey
    Rubin, Kristofer
    Department of Medical Biochemistry and Microbiology.
    Gerdin, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Ivarsson, Mikael
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Analysis of gene expression in fibroblasts in response to keratinocyte-derived factors in vitro: potential implications for the wound healing process.2004In: J Invest Dermatol, ISSN 0022-202X, Vol. 122, no 1, p. 216-21Article in journal (Refereed)
  • 38.
    Nowinski, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lysheden, Ann-Sophie
    Gardner, Humphrey
    Rubin, Kristofer
    Gerdin, Bengt
    Ivarsson, Mikael
    Analysis of gene expression in fibroblasts in response to keratinocyte-derived factors in vitro:potential implications for the wound healing process2004In: Journal of Investigative Dermatology, ISSN 1523-1747, Vol. 122, no January 1, p. 216-21Article in journal (Refereed)
  • 39. Oldberg, Åke
    et al.
    Kalamajski, Sebastian
    Salnikov, Alexei V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stuhr, Linda
    Mörgelin, Matthias
    Reed, Rolf K.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 35, p. 13966-13971Article in journal (Refereed)
    Abstract [en]

    Research on the biology of the tumor stroma has the potential to lead to development of more effective treatment regimes enhancing the efficacy of drug-based treatment of solid malignancies. Tumor stroma is characterized by distorted blood vessels and activated connective tissue cells producing a collagen-rich matrix, which is accompanied by elevated interstitial fluid pressure (IFP), indicating a transport barrier between tumor tissue and blood. Here, we show that the collagen-binding proteoglycan fibromodulin controls stroma structure and fluid balance in experimental carcinoma. Gene ablation or inhibition of expression by anti-inflammatory agents showed that fibromodulin promoted the formation of a dense stroma and an elevated IFP. Fibromodulin-deficiency did not affect vasculature but increased the extracellular fluid volume and lowered IFP. Our data suggest that fibromodulin controls stroma matrix structure that in turn modulates fluid convection inside and out of the stroma. This finding is particularly important in relation to the demonstration that targeted modulations of the fluid balance in carcinoma can increase the response to cancer therapeutic agents.

  • 40.
    Olsson, P. Olof
    et al.
    Lund Univ, Dept Lab Med, Translat Canc Res, Lund, Sweden..
    Gustafsson, Renata
    Lund Univ, Dept Lab Med, Translat Canc Res, Lund, Sweden..
    in 't Zandt, Rene
    Lund Univ, Bioimaging Ctr, Lund, Sweden..
    Friman, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Maccarana, Marco
    Lund Univ, Dept Expt Med Sci, Matrixbiol, Lund, Sweden..
    Tykesson, Emil
    Lund Univ, Dept Expt Med Sci, Matrixbiol, Lund, Sweden..
    Oldberg, Åke
    Lund Univ, Dept Expt Med Sci, Matrixbiol, Lund, Sweden..
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Lund Univ, Dept Lab Med, Translat Canc Res, Lund, Sweden..
    Kalamajski, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma2016In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 15, no 10, p. 2455-2464Article in journal (Refereed)
    Abstract [en]

    A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a well-developed stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents.

  • 41.
    Olsson, P Olof
    et al.
    Lund Univ, Dept Lab Med, Translat Canc Res, Lund, Sweden.
    Kalamajski, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maccarana, Marco
    Dept Expt Med, Matrix Biol, Lund, Sweden.
    Oldberg, Åke
    Dept Expt Med, Matrix Biol, Lund, Sweden.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Lab Med, Translat Canc Res, Lund, Sweden.
    Fibromodulin deficiency reduces collagen structural network but not glycosaminoglycan content in a syngeneic model of colon carcinoma.2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0182973Article in journal (Refereed)
    Abstract [en]

    Tumor barrier function in carcinoma represents a major challenge to treatment and is therefore an attractive target for increasing drug delivery. Variables related to tumor barrier include aberrant blood vessels, high interstitial fluid pressure, and the composition and structure of the extracellular matrix. One of the proteins associated with dense extracellular matrices is fibromodulin, a collagen fibrillogenesis modulator expressed in tumor stroma but scarce in normal loose connective tissues. Here, we investigated the effects of fibromodulin on stroma ECM in a syngeneic murine colon carcinoma model. We show that fibromodulin deficiency decreased collagen fibril thickness but glycosaminoglycan content and composition were unchanged. Furthermore, vascular density, pericyte coverage and macrophage amount were unaffected. Fibromodulin can therefore be a unique effector of dense collagen matrix assembly in tumor stroma and, without affecting other major matrix components or the cellular composition, can function as a main agent in tumor barrier function.

  • 42.
    Pietras, Kristian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Buchdunger, Elisabeth
    Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy2002In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 62, no 19, p. 5476-5484Article in journal (Refereed)
    Abstract [en]

    Lowering of tumor interstitial hypertension, which acts as a barrier for tumor transvascular transport, has been proposed as a general strategy to enhance tumor uptake and therapeutic effects of anticancer drugs. The tyrosine kinase platelet-derived growth factor (PDGF) beta-receptor is one mediator of tumor hypertension. The effects of PDGF antagonists on chemotherapy response were investigated in two tumor models that display PDGF receptor expression restricted to the tumor stroma, and in which PDGF antagonists relieve tumor hypertension. Inhibitory PDGF aptamers and the PDGF receptor tyrosine kinase inhibitor STI571 enhanced the antitumor effect of Taxol on s.c. KAT-4 tumors in SCID mice. Treatment with only PDGF antagonists had no effect on tumor growth. Taxol uptake in tumors was increased by treatment with PDGF antagonists. Cotreatment with PDGF antagonists and Taxol was not associated with antiangiogenic effects, and PDGF antagonists did not enhance the Taxol effect on in vitro growth of KAT-4 cells. STI571 also increased the antitumor effects of 5-fluorouracil on s.c. PROb tumors in syngeneic BDIX rats, without increasing the effect of 5-fluorouracil on cultured PROb cells. Expression of PDGF receptors in tumor stroma, as well as tumor hypertension, occurs in most common solid tumors. Therefore, our results have implications for treatment regimens for large patient groups and merit clinical testing. In conclusion, our study identifies inhibition of PDGF signaling in tumor stroma as a novel, possibly general strategy for enhancement of the therapeutic effects chemotherapy.

  • 43.
    Pietras, Kristian
    et al.
    Ludwiginstitutet för Cancerforskning.
    Sjöblom, Tobias
    Ludwiginstitutet för Cancerforskning.
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Carl-Henrik
    Ludwiginstitutet för Cancerforskning.
    Östman, Arne
    Ludwiginstitutet för Cancerforskning.
    PDGF receptors as cancer drug targets.2003In: Cancer Cell, Vol. 3, p. 439-Article in journal (Refereed)
  • 44.
    Pietras, Kristian
    et al.
    Ludwiginstitutet för Cancerforskning.
    Stumm, Michael
    Hubert, Martine
    Buchdunger, Elisabeth
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Carl-Henrik
    Ludwiginstitutet för Cancerforskning.
    McSheehy, Paul
    Wartmann, Markus
    Östman, Arne
    Ludwiginstitutet för Cancerforskning.
    STI571 enhances the therapeutic index of epothilone B by a tumor-selectiveincrease of drug uptake.2003In: Clin Cancer Res, Vol. 9, p. 3779-Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose is to investigate whether STI571, through platelet-derived growth factor receptor inhibition, enhances the therapeutic response to the chemotherapeutic drug epothilone B (EPO906) and, if so, to analyze the mechanism(s) underlying the effect. EXPERIMENTAL DESIGN: SCID mice with s.c. human anaplastic thyroid carcinomas were treated with different doses of EPO906 alone or in combination with STI571 and with different timing of STI571 and EPO906 administration. Tumor growth, tumor interstitial fluid pressure (IFP), and uptake of EPO906 in tumors and normal organs were monitored. RESULTS: STI571 potentiated the therapeutic effect of EPO906. Tumors subjected to combination treatment were >40% smaller than those subjected to monotreatment with EPO906. The improved efficacy was matched by reduced tumor IFP and a 3-fold increase in the tumor levels of EPO906. No significant increase of EPO906 levels was seen in liver, kidney, or the intestinal tract. Cotreatment did not reduce the tolerability of EPO906, as determined by measuring body weight throughout treatment. STI571-induced reduction in tumor IFP and increase in tumor uptake required a minimum of three daily doses of STI571 and was not observed 3 days after last treatment with STI571. The enhancement of EPO906 therapeutic efficacy was only observed when STI571 was scheduled in a manner associated with reduced tumor IFP and increased tumor uptake of EPO906. CONCLUSIONS: We conclude that STI571 increases the therapeutic index of EPO906 by selectively increasing the EPO906 uptake in tumors. The correlations between STI571 effects on tumor IFP and tumor drug uptake of EPO906 suggest a causal relationship between these phenomena. The study thus validates STI571 for combination treatment to enhance the therapeutic index of EPO906 in particular and, possibly, of chemotherapeutics in general.

  • 45.
    Pietras, Kristian
    et al.
    Ludwiginstitutet för Cancerforskning.
    Östman, Arne
    Ludwiginstitutet för Cancerforskning.
    Sjöquist, Mats
    Uppsala University, Department of Comparative Medicine. Uppsala University, Department of Comparative Medicine.
    Buchdunger, Elisabeth
    Reed, Rolf K.
    Heldin, Carl-Henrik
    Ludwiginstitutet för Cancerforskning.
    Rubin, Kristofer
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors.2001In: Cancer Res, Vol. 61, p. 2929-Article in journal (Refereed)
    Abstract [en]

    Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGFbeta receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to-interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFbeta receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.

  • 46.
    Pietras, Kristian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Buchdunger, Elisabeth
    Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland.
    Reed, Rolf K
    Department of Physiology, University of Bergen, N-5009 Bergen, Norway .
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors.2001In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 61, no 7, p. 2929-2934Article in journal (Refereed)
    Abstract [en]

    Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGFbeta receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to-interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFbeta receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.

  • 47. Reed, Rolf K.
    et al.
    Lidén, Åsa
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Edema and fluid dynamics in connective tissue remodelling2010In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 48, no 3, p. 518-523Article, review/survey (Refereed)
    Abstract [en]

    The review describes the role of loose connective tissues with focus on transcapillary exchange and edema formation with relevance for inflammation, fibrosis and tumors. Based on studies in these tissues, comparisons are made to the fibrotic processes in the heart.

  • 48. Reed, Rolf K.
    et al.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Transcapillary exchange: role and importance of the interstitial fluid pressure and the extracellular matrix2010In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, ISSN 20472565, Vol. 87, no 2, p. 211-217Article, review/survey (Refereed)
    Abstract [en]

    This review will summarize current knowledge on the role of the extracellular matrix (ECM) in general and on the interstitial fluid pressure (P-if) in particular with regard to their importance in transcapillary exchange. The fluid volume in the interstitial space is normally regulated within narrow limits by automatic re-adjustment of the interstitial hydrostatic and colloid osmotic pressures in response to perturbations in capillary filtration and by the lymphatics. Contrary to this commonly accepted view, P-if can become an active force and create a fluid flux across the capillaries in several inflammatory reactions and trauma situations rather than limit the changes occurring. The molecular mechanisms involved in the lowering of P-if include the release of cellular tension exerted on the collagen and microfibril networks in the connective tissue via the collagen-binding beta(1)-integrins, thereby allowing the glycosaminoglycan ground substance, which is normally underhydrated, to expand and take up fluid. Several growth factors and cytokines, including the platelet-derived growth factor BB, are able to reverse a lowering of P-if and restore the normal compaction of the ECM. The magnitude of the lowering of P-if varies with the inflammatory response. In several inflammatory reactions, a lowering of P-if to -5 to -10 mmHg is seen, which will increase capillary filtration by 10-20 times since the normal capillary filtration pressure is usually 0.5-1 mmHg (skin and skeletal muscle). Unless this lowering of P-if is taken into account, the enhanced solute flux resulting from an inflammatory response will be ascribed to an increased capillary permeability.

  • 49.
    Reuterdahl, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Sundberg, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Funa, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Gerdin, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Tissue localization of beta receptors for platelet-derived growth factor and platelet-derived growth factor B chain during wound repair in humans1993In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 91, no 5, p. 2065-2075Article in journal (Refereed)
    Abstract [en]

    The expression and localization of PDGF beta receptors and PDGF-AB/BB in human healing wounds was evaluated by immunohistochemical techniques and in situ hybridization. Expression of PDGF beta receptor protein and PDGF-AB/BB were analyzed in wound margin biopsies using the PDGFR-B2 and PDGF 007 antibodies. PDGF beta receptor expression was minor in normal skin. An increased expression of PDGF beta receptor protein was prominent in vessels in the proliferating tissue zone in wounds as early as 1 d after surgery and was apparent < or = 4 wk after surgery. There was also a concordant increase in PDGF beta receptor mRNA detected by in situ hybridization. PDGF-AB/BB was present in healing wounds as well as in normal skin. In normal skin, expression of PDGF-AB/BB was confined to peripheral nerve fibers and to solitary cells of the epidermis and of the superficial dermis. In wounds, infiltrating mononuclear cells also stained for PDGF-AB/BB. To identify cell types expressing PDGF AB/BB and PDGF beta receptors, respectively, we performed double immunofluorescence stainings. PDGF beta receptors were expressed by vascular smooth muscle cells and cells in capillary walls; the receptor protein could not be detected in neurofilament containing structures, T lymphocytes, or CD68 expressing macrophages. PDGF-AB/BB colocalized with neurofilaments, it was present in Langerhans cells of the epidermis and in HLA-DR positive cells located in the epidermal/dermal junction area. Of the macrophages infiltrating the wound, 43 +/- 18% stained positively for PDGF AB/BB. Since PDGF-AB/BB and PDGF beta receptors are expressed in the healing wound, two essential prerequisites for a role of PDGF in wound healing are fulfilled.

  • 50.
    Reyhani, Vahid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Seddigh, Pegah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Guss, Bengt
    Gustafsson, Renata
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fibrin binds to collagen and provides a bridge for alpha V beta 3 integrin-dependent contraction of collagen gels2014In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 462, no P1, p. 113-123Article in journal (Refereed)
    Abstract [en]

    The functional significance of fibrin deposits typically seen in inflammatory lesions, carcinomas and in healing wounds is not fully understood. In the present study, we demonstrate that fibrinogen/fibrin specifically bound to native Col I (collagen type I) and used the Col I fibre network as a base to provide a functional interface matrix that connects cells to the Col I fibres through alpha V beta 3 integrins. This allowed murine myoblast C2C12 cells to contract the collagenous composite gel via alpha V beta 3 integrin. We show that fibrinogen specifically bound to immobilized native Col I at the site known to bind matrix metalloproteinase-1, discoidin domain receptor-2 and fibronectin, and that binding had no effect on Col I fibrillation. A specific competitive inhibitor blocking the Col-I-binding site for fibrinogen abolished the organization of fibrin into discernable fibrils, as well as the C2C12-mediated contraction of Col I gels. Our data show that fibrin can function as a linkage protein between Col I fibres and cells, and suggest that fibrin at inflammatory sites indirectly connects alpha V beta 3 integrins to Col I fibres and thereby promotes cell-mediated contraction of collagenous tissue structures.

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