Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells

Thomas, Jean‐Léon; Baker, Kasey L.; Han, Joungho; Calvo, Charles‐Félix; Nurmi, Harri; Eichmann, Anne; Alitalo, Kari

doi:10.1007/s00018-013-1312-6

Cited by 63 publications

(51 citation statements)

References 129 publications

(141 reference statements)

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“…remodeling of the extracellular matrix (metalloproteases and their tissue inhibitors); IV. Notch pathway activation (ligands, receptors, regulators and effectors), which is indispensable for well-oriented vascular growth characterized by vessels without functional lumens and the absence of excessive sprouting; and finally, V. the maturation and stabilization of the new vessels through the recruitment of pericytes (PDGF pathway, NOTCH3 and angiopoietin 1) (Mitchell & Parangi 2005, Carmeliet et al 2009, Phng & Gerhardt 2009, Raza et al 2010, Sakurai & Kudo 2011, Garcia & Kandel 2012, Thomas et al 2013. Almost all the proangiogenic genes we analyzed displayed significantly higher mRNA levels in the RETmut tumors than in those with wild-type RET, and the involvement of RET activation in this upregulation was confirmed by the results observed when the gene was silenced with siRNA in MTC cell lines.…”

Section: Discussionmentioning

confidence: 99%

RET mutation and increased angiogenesis in medullary thyroid carcinomas

Verrienti¹,

Tallini²,

Colato³

et al. 2016

Endocrine-Related Cancer

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Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wildtype RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors. 23:8Research A Verrienti et al.Increased angiogenesis in RET-mutated MTCs RET mutation and increased angiogenesis in medullary thyroid carcinomas

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Section: Discussionmentioning

confidence: 99%

RET mutation and increased angiogenesis in medullary thyroid carcinomas

Verrienti¹,

Tallini²,

Colato³

et al. 2016

Endocrine-Related Cancer

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“…EC migration is triggered by a multitude of signaling pathways that can act in a particular manner on different blood vessels, and this selectivity is thought to be important for coordinating the simultaneous formation of separate blood vessels (Vanhollebeke et al, 2015;Wiley et al, 2011;Ulrich et al, 2016). In addition to activating signals, angiogenic sprouts encounter numerous guidance cues that ensure proper pathway finding (reviewed by Carmeliet and Tessier-Lavigne, 2005 invades all organs, it will be essential to dissect the relevant migratory cues in each case individually and identify attractive as well as repulsive cues in order to get a coherent and comprehensive picture of the mechanisms that regulate EC migration during angiogenesis (for examples, see Cha et al, 2012;Harrison et al, 2015;Tata et al, 2015;Thomas et al, 2013;Xu et al, 2014).…”

Section: Endothelial Cell Migrationmentioning

confidence: 99%

Cell behaviors and dynamics during angiogenesis

et al. 2016

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Vascular networks are formed and maintained through a multitude of angiogenic processes, such as sprouting, anastomosis and pruning. Only recently has it become possible to study the behavior of the endothelial cells that contribute to these networks at a single-cell level in vivo. This Review summarizes what is known about endothelial cell behavior during developmental angiogenesis, focusing on the morphogenetic changes that these cells undergo.

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“…For example, VEGF-induced motility in tip cells versus proliferation in stalk cells is mediated by lateral inhibition upon Notch1 receptor activation by delta-like 4 (Dll4) ligand. VEGF migration versus proliferation in Notch-expressing stalk cells is further modulated by Jagged-1 ligand, which antagonizes Dll4 by competing for Notch receptor (Reviewed in [56]). In this study, we found that EphA2 regulation of Slit2 also regulates endothelial cell response to VEGF.…”

Section: Discussionmentioning

confidence: 99%

Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium

Youngblood

Wang

Song

et al. 2015

Molecular Cancer Research

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Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate pro-angiogenic molecules while simultaneously suppressing angiostatic pathways in order to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit pro- and anti-angiogenic signals is a key step in developing new, molecularly targeted anti-angiogenic therapies. While EphA2, a receptor tyrosine kinase (RTK), is required for vascular endothelial growth factor (VEGF)-induced angiogenesis, the mechanism through which these pathways intersect remains unclear. Slit2 expression is elevated in EphA2-deficient endothelium, and here it is reported that inhibiting Slit activity rescues VEGF-induced angiogenesis in cell culture and in vivo, as well as VEGF-dependent tumor angiogenesis, in EphA2-deficient endothelial cells and animals. Moreover, blocking Slit activity or Slit2 expression in EphA2-deficient endothelial cells restores VEGF-induced activation of Src and Rac, both of which are required for VEGF-mediated angiogenesis. These data suggest that EphA2 suppression of Slit2 expression and Slit angiostatic activity enables VEGF-induced angiogenesis in vitro and in vivo, providing a plausible mechanism for impaired endothelial responses to VEGF in the absence of EphA2 function.

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Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells

Cited by 63 publications

References 129 publications

RET mutation and increased angiogenesis in medullary thyroid carcinomas

RET mutation and increased angiogenesis in medullary thyroid carcinomas

Cell behaviors and dynamics during angiogenesis

Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium

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