FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?

Fischer, Christian; Mazzone, Massimiliano; Jonckx, Bart; Carmeliet, Peter

doi:10.1038/nrc2524

Cited by 502 publications

(526 citation statements)

References 194 publications

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“…23 The 11q12.2-q13.2 and 19p13.2-p13.11 segments contain several cancer-associated genes such as RIN1, FOSL1, and VEGFB (11q12.2-q13.2) and JUNB and JUND (19p13.2-p13.11) that are duplicated/rearranged and/or overexpressed in various forms of epithelial cancers. [30][31][32] Whether the 11q and 19p gains in mucoepidermoid carcinoma target any of these genes remains, however, to be shown. The most frequent copy number alterations detected in the 28 mucoepidermoid carcinomas were losses of 18q12.2-qter, 9p21.3, 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3, 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2.…”

Section: Discussionmentioning

confidence: 99%

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

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Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1-MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion-positive whereas only 3 of 13 high-grade tumors were fusion-positive. Highresolution array-based comparative genomic hybridization revealed that fusion-positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P ¼ 0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusionnegative tumors lacked copy number alterations. The profiles of fusion-positive and fusion-negative tumors were very similar to those of low-and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; Po0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients.

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Section: Discussionmentioning

confidence: 99%

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

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“…Finally, PlGF is able to induce its own angiogenic signal through FLT1 independently of VEGF. 4,23 Synergy between PlGF and VEGF in pathological angiogenesis in the gut may have important therapeutic implications for either stimulating or inhibiting angiogenesis in patients with IBD.…”

Section: Discussionmentioning

confidence: 99%

Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury

Hindryckx

Waeytens

Laukens

et al. 2010

Laboratory Investigation

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Angiogenesis has recently been described as a component of inflammatory bowel disease. Placental growth factor (PlGF), a vascular endothelial growth factor (VEGF) homologue, establishes its angiogenic capacity under pathophysiological conditions. We investigated the function of PlGF in experimental models of acute colitis. Acute colonic damage was induced in PlGF knock-out (-/-) mice and PlGF wild-type (+/+) mice by dextran sodium sulfate (DSS) and trinitrobenzenesulfonic acid (TNBS). The concentrations of PlGF and VEGF were measured in distal colonic lysates using an enzyme-linked immunosorbent assay. Colonic injury was evaluated by assessing colon length, colonocyte apoptosis (by terminal dUTP nick-end labeling), colonic cytokine production and histological score. Infiltration of polymorphonuclear cells was determined by assaying myeloperoxidase (MPO) activity. In a separate experiment, recombinant PlGF was administered to PlGF -/- mice by adenoviral transfer before DSS administration. Mucosal vascularization was quantified by computerized morphometric analysis of CD31-stained distal colonic sections. Colonic mucosal hypoxia was visualized by pimonidazole staining. Both VEGF and PlGF were upregulated during acute colitis. In addition, compared with PlGF +/+ controls, PlGF -/- mice showed a significant increase in weight loss and colonic shortening during both DSS and TNBS colitis. This correlated with enhanced colonocyte apoptosis, elevated colonic cytokine levels and increased histological damage score, but not with enhanced inflammatory cell infiltration (MPO activity). The increased morbidity of PlGF -/- mice during DSS colitis was preventable by adenovirus (Ad)-mediated overexpression of PlGF. After the administration of DSS, strongly reduced mucosal angiogenesis was observed in PlGF -/- mice compared with PlGF +/+ mice. This was associated with an early increase in intestinal epithelial pimonidazole accumulation in PlGF -/- mice, suggesting a function of enhanced epithelial hypoxia in the observed differences between the two groups. In summary, our data show that the absence of PlGF strongly inhibits mucosal intestinal angiogenesis in acute colitis, which is associated with an early increase in intestinal epithelial hypoxia and aggravation of the course of the disease

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“…It also promotes survival of cortical neurons (Du et al 2010), promotes axon growth cone formation of dorsal root ganglion neurons , and stimulates proliferation and migration of Schwann cells (Chaballe et al 2011a). PlGF enhances growth of tumor cells, both of solid and hematological tumors (Fischer et al 2008;Schmidt et al 2011).…”

Section: Plgf: a Pleiotropic Factormentioning

confidence: 99%