Decorin as a multivalent therapeutic agent against cancer

Neill, Thomas; Schaefer, Liliana; Iozzo, Renato V.

doi:10.1016/j.addr.2015.10.016

Cited by 105 publications

(90 citation statements)

References 189 publications

(253 reference statements)

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“…Decorin (Dcn) is a SLRP that is most closely related to Bgn (6), yet in contrast to what we found for Bgn, Dcn has inhibitory effects on angiogenesis (25,26). It is unclear why Dcn and Bgn have what appears to be opposite effects on angiogenesis, but it is likely that tissue context is involved (27).…”

Section: Discussioncontrasting

confidence: 93%

Biglycan potentially regulates angiogenesis during fracture repair by altering expression and function of endostatin

et al. 2016

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The small proteoglycan biglycan (Bgn) is highly expressed in the organic matrix of bone and plays a role in bone formation. Previous work implicated Bgn in vessel growth during bone healing (1). By infusing barium sulfate (BaSO4) into WT and Bgn-deficient mice we discovered the positive effect of Bgn in modulating angiogenesis during fracture healing. Using micro-computed tomography angiography we found significant differences in the vessel size and volume among other parameters. To further understand the mechanistic basis for this, we explored the relationship between Bgn and the anti-angiogenic protein endostatin. Immunohistochemistry (IHC) showed co-localization of Bgn and endostatin in regions of bone formation, with increased endostatin staining in Bgn-KO compared to WT at 14 days post-fracture. To further elucidate the relationship between Bgn and endostatin, an endothelial cell tube formation assay was used. This study showed that endothelial cells treated with endostatin had significantly decreased vessel length and vessel branches compared to untreated cells, while cells treated with endostatin and Bgn at a 1:1 molar ratio had vessel length and vessel branches comparable to untreated cells. This indicated that Bgn was able to mitigate the inhibitory effect of endostatin on endothelial cell growth. In summary, these results suggest that Bgn is needed for proper blood vessel formation during fracture healing, and one mechanism by which Bgn impacts angiogenesis is through inhibition of endostatin.

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Section: Discussioncontrasting

confidence: 93%

Biglycan potentially regulates angiogenesis during fracture repair by altering expression and function of endostatin

et al. 2016

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“…Decorin controls also the bioavailability of TGF-β whose release depends on the activity of different proteases involved in angiogenesis [166,167]. Furthermore, soluble decorin is a high affinity antagonistic ligand for several key receptors tyrosine kinases including Epithelial Growth Factor Receptor (EGFR), HGF Receptor, IGF-1 Receptor and VEGFR2 [168]. The engagement of decorin with cell surface receptors can either activate or inhibit the function of the receptor, depending on the physiological state of the tissue [169].…”

Section: Proteoglycans: Complex Functions From the Protein Core Anmentioning

confidence: 99%

Extracellular Matrix, a Hard Player in Angiogenesis

Mongiat

Andreuzzi

Tarticchio

et al. 2016

IJMS

158

133

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The extracellular matrix (ECM) is a complex network of proteins, glycoproteins, proteoglycans, and polysaccharides. Through multiple interactions with each other and the cell surface receptors, not only the ECM determines the physical and mechanical properties of the tissues, but also profoundly influences cell behavior and many physiological and pathological processes. One of the functions that have been extensively explored is its impingement on angiogenesis. The strong impact of the ECM in this context is both direct and indirect by virtue of its ability to interact and/or store several growth factors and cytokines. The aim of this review is to provide some examples of the complex molecular mechanisms that are elicited by these molecules in promoting or weakening the angiogenic processes. The scenario is intricate, since matrix remodeling often generates fragments displaying opposite effects compared to those exerted by the whole molecules. Thus, the balance will tilt towards angiogenesis or angiostasis depending on the relative expression of pro- or anti-angiogenetic molecules/fragments composing the matrix of a given tissue. One of the vital aspects of this field of research is that, for its endogenous nature, the ECM can be viewed as a reservoir to draw from for the development of new more efficacious therapies to treat angiogenesis-dependent pathologies.

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“…Decorin, a component of connective tissue, binds to collagen and plays an important role in matrix assembly. Furthermore, decorin, like elastin, is capable of suppressing the growth of various tumor cell lines [73, 74]. Interestingly, with the reduction of versican expression, a number of sulfo-, acetylgalactosaminyl-, and xylotransferases associated with the biosynthesis of versican and other proteoglycans were elevated, while others were reduced.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of versican expression by siRNA facilitates tropoelastin synthesis and elastic fiber formation by human SK-LMS-1 leiomyosarcoma smooth muscle cells in vitro and in vivo

et al. 2016

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Versican is an extracellular matrix (ECM) molecule that interacts with other ECM components to influence ECM organization, stability, composition, and cell behavior. Versican is known to increase in a number of cancers, but little is known about how versican influences the amount and organization of the ECM components in the tumor microenvironment. In the present study, we modulated versican expression using siRNAs in the human leiomyosarcoma (LMS) smooth muscle cell line SK-LMS-1, and observed the formation of elastin and elastic fibers in vitro and also in vivo in a nude mouse tumor model. Constitutive siRNA-directed knockdown of versican in LMS cells resulted in increased levels of elastin, as shown by immunohistochemical staining of the cells in vitro, and by mRNA and protein analyses. Moreover, versican siRNA LMS cells, when injected into nude mice, generated smaller tumors that had significantly greater immunohistochemical and histochemical staining for elastin when compared to control tumors. Additionally, microarray analyses were used to determine the influence of versican isoform modulation on gene expression profiles, and to identify genes that influence and relate to the process of elastogenesis. cDNA microarray analysis and TaqMan low density array validation identified previously unreported genes associated with downregulation of versican and increased elastogenesis. These results highlight an important role for the proteoglycan versican in regulating the expression and assembly of elastin and the phenotype of LMS cells.

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Decorin as a multivalent therapeutic agent against cancer

Cited by 105 publications

References 189 publications

Biglycan potentially regulates angiogenesis during fracture repair by altering expression and function of endostatin

Biglycan potentially regulates angiogenesis during fracture repair by altering expression and function of endostatin

Extracellular Matrix, a Hard Player in Angiogenesis

Inhibition of versican expression by siRNA facilitates tropoelastin synthesis and elastic fiber formation by human SK-LMS-1 leiomyosarcoma smooth muscle cells in vitro and in vivo

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