| 1. |
- Friman, Tomas, et al.
(författare)
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Increased Fibrosis and Interstitial Fluid Pressure in Two Different Types of Syngeneic Murine Carcinoma Grown in Integrin β3-Subunit Deficient Mice
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:3, s. e34082-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Gustafsson, Renata, et al.
(författare)
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Dermatan sulfate epimerase 1 deficient mice as a model for human abdominal wall defects.
- 2014
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Ingår i: Birth Defects Research. Part A: Clinical and Molecular Teratology. - : Wiley. - 1542-0760 .- 1542-0752. ; 100:9, s. 712-720
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Tidskriftsartikel (refereegranskat)abstract
- Dermatan sulfate (DS) is a highly sulfated polysaccharide with a variety of biological functions in extracellular matrix organization and processes such as tumorigenesis and wound healing. A distinct feature of DS is the presence of iduronic acid, produced by the two enzymes, DS-epimerase 1 and 2, which are encoded by Dse and Dsel, respectively.
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| 3. |
- Kelkka, Tiina, et al.
(författare)
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Mice Lacking NCF1 Exhibit Reduced Growth of Implanted Melanoma and Carcinoma Tumors
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12, s. e84148-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Reyhani, Vahid, et al.
(författare)
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Fibrin binds to collagen and provides a bridge for alpha V beta 3 integrin-dependent contraction of collagen gels
- 2014
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 462, s. 113-123
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 5. |
- Rodriguez, Alejandro, et al.
(författare)
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Phenotypical differences in connective tissue cells emerging from microvascular pericytes in response to over-expression of PDGF-B and TGF-beta in normal skin in vivo
- 2013
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 182:6, s. 2132-2146
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Tidskriftsartikel (refereegranskat)abstract
- Fibrosis is a deleterious consequence of chronic inflammation in a number of human pathological states ultimately leading to, if not perturbed to organ dysfunction and failure. Two key processes in fibrosis are activation of blood vessels and connective tissue cells leading to excess deposition of ECM components; collagen type I being the most abundant. In the present study the effects of two growth factors known to be important in the fibrotic process, namely PDGF-B and TGF-β1, were studied. Adenoviral vectors engineered to express PDGF-B or TGF-β1 were introduced into mouse skin thereby inducing a transient over-expression of either growth factor. After 3, 7 and 14 days post injection, tissues were harvested and morphology and protein expression were examined on plastic embedded 1 µm thick sections and by immunohistochemistry on frozen sections, respectively. Over-expression of both TGF-β1 and PDGF-B lead to a fibrotic response consisting of a marked macrophage influx as well as an expansion of the connective tissue cell population. In both conditions the latter originated from microvascular pericytes. The resulting phenotype of the emerging connective tissue cell population differed between PDGF-B and TGF-β1 treated skin. In tissues over expressing PDGF-B but not TGF-β1 the fibrotic process was partially reversible. Both growth factors were able to initiate, but neither were able to sustain the process of angiogenesis, which lead to vascular regression. PDGF-B but not TGF-β1 was able to stimulate but not maintain a distinct form of angiogenesis i.e. glomeruloid body formation. In conclusion, over-expression of PDGF-B and TGF-β1 in normal skin resulted in the emergence of connective tissue cells differing in their phenotype, originating in both cases from a common cell namely the microvascular pericyte. Therefore the vasculature and the fibrotic process are linked in a previously unrecognized way.
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| 6. |
- Shami, Annelie, et al.
(författare)
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Fibromodulin Deficiency Reduces Low-Density Lipoprotein Accumulation in Atherosclerotic Plaques in Apolipoprotein E-Null Mice.
- 2012
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to analyze how an altered collagen structure affects development of atherosclerotic plaques. METHODS AND RESULTS: Fibromodulin-null mice develop an abnormal collagen fibril structure. In apolipoprotein E (ApoE)-null and ApoE/fibromodulin-null mice, a shear stress-modifying carotid artery cast induced formation of atherosclerotic plaques of different phenotypes; inflammatory in low-shear stress regions and fibrous in oscillatory shear stress regions. Electron microscopy showed that collagen fibrils were thicker and more heterogeneous in oscillatory shear stress lesions from ApoE/fibromodulin-null mice. Low-shear stress lesions were smaller in ApoE/fibromodulin-null mice and contained less lipids. Total plaque burden in aortas stained en face with Oil Red O, as well as lipid accumulation in aortic root lesions, was also decreased in ApoE/fibromodulin-null mice. In addition, lipid accumulation in RAW264.7 macrophages cultured on fibromodulin-deficient extracellular matrix was decreased, whereas levels of interleukin-6 and -10 were increased. Our results show that an abnormal plaque collagen fibril structure can influence atherosclerotic plaque development. CONCLUSIONS: The present findings suggest a more complex role for collagen in plaque stability than previously anticipated, in that it may promote lipid-accumulation and inflammation at the same time as it provides mechanical stability.
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| 7. |
- Thelin, Martin, et al.
(författare)
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Biological Functions of Iduronic Acid in Chondroitin/Dermatan Sulfate.
- 2013
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 280:10, s. 2431-2446
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Forskningsöversikt (refereegranskat)abstract
- The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides, as it generates a more flexible chain with increased binding potentials. Iduronic acid in chondroitin/dermatan sulfate influences multiple cellular properties such as migration, proliferation, differentiation, angiogenesis and regulation of cytokine/growth factor activities. During pathological conditions such as wound healing, inflammation and cancer iduronic acid has diverse regulatory functions. Iduronic acid is formed by the two epimerases DS-epimerase 1 and DS-epimerase 2 which have different tissue distribution and properties. The role of IdoA in chondroitin/dermatan sulfate is underlined by the vast changes of connective tissue features in patients with a new type of Ehler-Danlos syndrome, adducted thumb-clubfoot syndrome. Future direction of research is to understand the roles of the two epimerases and their interplay with sulfotransferases involved in CS/DS biosynthesis. Further, a better definition of chondroitin/dermatan sulfate functions using different knock-out models is needed. In this review, we focus on the two enzymes responsible for iduronic acid formation and the role of iduronic acid in health and disease. © 2013 The Authors Journal compilation © 2013 FEBS.
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