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Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells.

ABSTRACT: Fibronectin is a major extracellular matrix glycoprotein with several alternatively spliced variants, including extra domain A (EDA), which was demonstrated to promote tumorigenesis via stimulating angiogenesis and lymphangiogenesis. Given that CD133(+)/CD44(+) cancer cells are critical in tumorigenesis of colorectal cancer (CRC), we hypothesize that fibronectin EDA may promote tumorigenesis by sustaining the properties of CD133(+)/CD44(+) colon cancer cells. We found that tumor tissue and serum EDA levels are substantially higher in advanced versus early stage human CRC. Additionally we showed that tumor tissue EDA levels are positively correlated with differentiation status and chemoresistance, and correlated with a poor prognosis of CRC patients. We also showed that in colon cancer cells SW480, CD133(+)/CD44(+) versus CD133(-)/CD44(-) cells express significantly elevated EDA receptor integrin ?9?1. Silencing EDA in SW480 cells reduces spheroid formation and cells positive for CD133 or CD44, which is associated with reduced expressions of embryonic stem cell markers and increased expressions of differentiation markers. Blocking integrin ?9?1 function strongly reversed the effect of EDA overexpression. We also provided evidence suggesting that EDA sustains Wnt/?-catenin signaling activity via activating integrin/FAK/ERK pathway. In xenograft models, EDA-silenced SW480 cells exhibit reduced tumorigenic and metastatic capacity. In conclusion, EDA is essential for the maintenance of the properties of CD133(+)/CD44(+) colon cancer cells.

SUBMITTER: Ou J

PROVIDER: S-EPMC3917514 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells.

Ou Juanjuan J Deng Jia J Wei Xing X Xie Ganfeng G Zhou Rongbin R Yu Liqing L Liang Houjie H

Stem cell research 20130604 2

Fibronectin is a major extracellular matrix glycoprotein with several alternatively spliced variants, including extra domain A (EDA), which was demonstrated to promote tumorigenesis via stimulating angiogenesis and lymphangiogenesis. Given that CD133(+)/CD44(+) cancer cells are critical in tumorigenesis of colorectal cancer (CRC), we hypothesize that fibronectin EDA may promote tumorigenesis by sustaining the properties of CD133(+)/CD44(+) colon cancer cells. We found that tumor tissue and serum ...[more]

PMID: 23811539

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Project description:BackgroundElevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma and is due to trabecular meshwork (TM) damage. Here, we investigate the role of an endogenous Toll-like receptor 4 (TLR4) ligand, FN-EDA, in the development of glaucoma utilizing a transgenic mouse strain (B6.EDA+/+) that constitutively expresses only FN containing the EDA isoform.MethodsEyes from C57BL6/J (wild-type), B6.EDA+/+ (constitutively active EDA), B6.EDA-/- (EDA null) mice were processed for electron microscopy and consecutive images of the entire length of the TM and Schlemm's canal (SC) from anterior to posterior were collected and montaged into a single image. ECM accumulation, basement membrane length, and size and number of giant vacuoles were quantified by ImageJ analysis. Tlr4 and Iba1 expression in the TM and ONH cells was conducted using RNAscope in situ hybridization and immunohistochemistry protocols. IOP was measured using a rebound tonometer, ON damage assessed by PPD stain, and RGC loss quantified in RBPMS labeled retina flat mounts.ResultsUltrastructure analyses show the TM of B6.EDA+/+ mice have significantly increased accumulation of ECM between TM beams with few empty spaces compared to C57BL/6 J mice (p < 0.05). SC basement membrane is thicker and more continuous in B6.EDA+/+ mice compared to C57BL/6 J. No significant structural differences are detected in the TM of EDA null mice. Tlr4 and Iba1 expression is increased in the TM of B6.EDA+/+ mice compared to C57BL/6 J eyes (p < 0.05). IOP is significantly higher in B6.EDA+/+ mice compared to C57BL/6 J eyes (p < 0.001), and significant ON damage (p < 0.001) and RGC loss (p < 0.05) detected at 1 year of age. Tlr4 mRNA is expressed in mouse ONH cells, and is present in ganglion cell axons, microglia, and astrocytes. There is a significant increase in the area occupied by Iba-1 positive microglia cells in the ONH of B6.EDA+/+ mice compared to C57BL/6 J control eyes (p < 0.01).ConclusionsB6.EDA+/+ mice have increased ECM accumulation in the TM, elevated IOP, enhanced proinflammatory changes in the ONH, loss of RGCs, and ONH damage. These data suggest B6.EDA+/+ mice recapitulate many aspects of glaucomatous damage.

Project description:Background and Purpose- Cellular Fn-EDA (fibronectin containing extra domain A) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. Although global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods- We generated novel plasma Fn-EDA-/- ( Fn-EDA fl/fl Alb Cre) and endothelial Fn-EDA-/- ( Fn-EDA fl/fl Tie2 Cre) strains on hyperlipidemic apolipoprotein E-deficient ( ApoE-/-) background. By following the Stroke Therapy Academic Industry Roundtable guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in 2 different models of stroke: intraluminal monofilament and embolic model on days 1, 3, and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by magnetic resonance imaging), cerebral blood flow (by laser speckle imaging), neurological and sensory-motor outcome, and postischemic thrombo-inflammation (platelet thrombi, fibrin, neutrophil, phospho-NFκB [nuclear factor κB], TNFα [tumor necrosis factor α], and IL1β [interleukin 1β]). Results- Stroke outcome was comparable in ApoE-/- Fn-EDA fl/fl Tie2 Cre and control ApoE-/- Fn-EDA fl/fl mice suggesting endothelial Fn-EDA does not contribute to stroke. ApoE-/- Fn-EDA fl/fl Alb Cre mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3, and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased postischemic thrombo-inflammatory response ( P<0.05 versus ApoE-/- Fn-EDA fl/fl). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional cerebral blood flow at 1 hour in ApoE-/- Fn-EDA fl/fl Alb Cre mice suggesting plasma Fn-EDA promotes postischemic secondary thrombosis. Coinfusion of anti-Fn-EDA antibody with r-tPA (recombinant tissue-type plasminogen activator) in ApoE-/- mice, 1 hour after embolization, improved stroke outcome with enhanced survival, and improved neurological outcome ( P<0.05 versus r-tPA). Conclusions- Genetic evidence suggests that plasma Fn-EDA exacerbates stroke outcome by promoting postischemic thrombo-inflammation. Interventions targeting plasma Fn-EDA may reduce brain damage after reperfusion.

Dataset Information

Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells.

Publications

Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells.

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