Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44

Fuchs, Katharina; Hippe, Andreas; Schmaus, Anja; Homey, Bernhard; Sleeman, Jonathan; Orian-Rousseau, Véronique

doi:10.1038/cddis.2013.364

Cited by 85 publications

(79 citation statements)

References 48 publications

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“…Previous studies have suggested an interaction between hyaluronan-activated CD44 and CXCL12/CXCR4 signaling in induction of leukemia cell and human umbilical endothelial cell-polarization and subsequent migration [63], [73]. Ligand-induced CXCR4 activation promotes angiogenesis via stimulation of endothelial cell migration and proliferation, as well as VEGF production [43].…”

Section: Discussionmentioning

confidence: 99%

Knock-Down of CD44 Regulates Endothelial Cell Differentiation via NFκB-Mediated Chemokine Production

2014

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A striking feature of microvascular endothelial cells is their capacity to fuse and differentiate into tubular structures when grown in three-dimensional (3D) extracellular matrices, in collagen or Matrigel, mimicking the in vivo blood vessel formation. In this study we demonstrate that human telomerase-immortalised foreskin microvascular endothelial (TIME) cells express high levels of the hyaluronan receptor CD44 and the hyaluronidase HYAL2. Knock-down of CD44 or HYAL2 resulted in an inability of TIME cells to form a tubular network, suggesting a key regulatory role of hyaluronan in controlling TIME cell tubulogenesis in 3D matrices. Knock-down of CD44 resulted in an upregulation of mRNA expression of the chemokines CXCL9 and CXCL12, as well as their receptors CXCR3 and CXCR4. This was accompanied by a defect maturation of the tubular structure network and increased phosphorylation of the inhibitor of NFκB kinase (IKK) complex and thus translocation of NFκB into the nucleus and activation of chemokine targed genes. Furthermore, the interaction between CD44 and hyaluronan determines the adhesion of breast cancer cells. In summary, our observations support the notion that the interaction between CD44 and hyaluronan regulates microvascular endothelial cell tubulogenesis by affecting the expression of cytokines and their receptors, as well as breast cancer dissemination.

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Section: Discussionmentioning

confidence: 99%

Knock-Down of CD44 Regulates Endothelial Cell Differentiation via NFκB-Mediated Chemokine Production

2014

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“…In contrast, high molecular weight HA (HMW-HA) was reported to be anti-angiogenic [207,208] and immunosuppressive [209]. Despite these evidences, their role in angiogenesis is controversial since LMW-HA was also shown to inhibit angiogenesis impairing the CXC ligand 12 (CXCL12)/CXC Receptor 4 (CXCR4) pathway, as opposed to what observed with HMW-HA [210]. In addition, HMW-HA seems to stimulate angiogenesis cooperating with versican and inducing FGF-2 expression [211].…”

Section: Hyaluronan: Not Only a Mere Gluementioning

confidence: 99%

Extracellular Matrix, a Hard Player in Angiogenesis

Mongiat

Andreuzzi

Tarticchio

et al. 2016

IJMS

162

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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“…11 The key function of CD44 in growth control and in transformation prompted us to test its potential role as a regulator of the Wnt pathway. CD44 is a major Wnt target in the intestine.…”

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confidence: 99%

CD44 functions in Wnt signaling by regulating LRP6 localization and activation

et al. 2014

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Wnt reception at the membrane is complex and not fully understood. CD44 is a major Wnt target gene in the intestine and is essential for Wnt-induced tumor progression in colorectal cancer. Here we show that CD44 acts as a positive regulator of the Wnt receptor complex. Downregulation of CD44 expression decreases, whereas CD44 overexpression increases Wnt activity in a concentration-dependent manner. Epistasis experiments place CD44 function at the level of the Wnt receptor LRP6. Mechanistically, CD44 physically associates with LRP6 upon Wnt treatment and modulates LRP6 membrane localization. Moreover, CD44 regulates Wnt signaling in the developing brain of Xenopus laevis embryos as shown by a decreased expression of Wnt targets tcf-4 and en-2 in CD44 morphants.

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Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44

Cited by 85 publications

References 48 publications

Knock-Down of CD44 Regulates Endothelial Cell Differentiation via NFκB-Mediated Chemokine Production

Knock-Down of CD44 Regulates Endothelial Cell Differentiation via NFκB-Mediated Chemokine Production

Extracellular Matrix, a Hard Player in Angiogenesis

CD44 functions in Wnt signaling by regulating LRP6 localization and activation

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