We describe that galectin-1 (gal-1) is a receptor for the angiogenesis inhibitor anginex, and that the protein is crucial for tumor angiogenesis. gal-1 is overexpressed in endothelial cells of different human tumors. Expression knockdown in cultured endothelial cells inhibits cell proliferation and migration. The importance of gal-1 in angiogenesis is illustrated in the zebrafish model, where expression knockdown results in impaired vascular guidance and growth of dysfunctional vessels. The role of gal-1 in tumor angiogenesis is demonstrated in gal-1-null mice, in which tumor growth is markedly impaired because of insufficient tumor angiogenesis. Furthermore, tumor growth in gal-1-null mice no longer responds to antiangiogenesis treatment by anginex. Thus, gal-1 regulates tumor angiogenesis and is a target for angiostatic cancer therapy.angiostatic therapy ͉ endothelial cell ͉ galectin ͉ tumor models ͉ anginex A n adequate vasculature is a prerequisite for tumors to grow, and the need for neovessel formation (or angiogenesis) provides a target for treatment of cancer (1). Endothelial cells (EC) that line the tumor vasculature are particularly suitable target cells for therapeutic approaches, because they are easily accessible to agents delivered by the blood (2). However, to affect only tumor vasculature, specific targets on angiogenically active EC are essential. To date, only a few targets of tumor vasculature have been identified (3).We recently developed the specific angiostatic peptide anginex, which inhibits tumor growth through specific inhibition of angiogenesis (4-6). Although a broad profile of activities of anginex is known, such as prevention of EC adhesion and induction of apoptosis, the molecular target on tumor EC was never identified. In a receptor-finding study using a yeast twohybrid screening approach, we identified galectin-1 (gal-1) as a target protein of anginex.gal-1 belongs to a family of carbohydrate-binding proteins that share a conserved carbohydrate recognition domain of Ϸ130 aa (7-9). Over a dozen mammalian galectins have been described (10, 11), and members of this family are expressed in a wide range of species, suggesting an important role for galectins in basic cellular mechanisms. Galectins can be secreted and, depending on the cell type or state of differentiation, they have been found in the nucleus, cytoplasm, or extracellular matrix. It has been proposed that gal-1 mediates cell adhesion and migration (12) and is involved in several processes, including proliferation (13), apoptosis (14), and even mRNA splicing (15). The role of gal-1 in EC function or vascular biology has not been extensively studied.Here, we describe the function of gal-1 in angiogenesis. We provide direct functional evidence that gal-1 is required for tumor angiogenesis and outgrowth of tumors. Furthermore, we show that gal-1 is the target for the potent angiogenesis inhibitor anginex, thus establishing gal-1 as an important target for anticancer therapy.Results gal-1 Binds the Angiostatic Peptide Anginex...
Netherlands Trial Registry Identifier: NTR2249.
Paternal exposure to high levels of radioactivity causes heritable germline minisatellite mutations. However, the effect of more general paternal exposures, such as cigarette smoking, on germline mutations remains unexplored. We analyzed two of the most commonly used minisatellite loci (CEB1 and B6.7) to identify germline mutations in blood samples of complete mother-father-child triads from the Norwegian Mother and Child Cohort Study (MoBa). The presence of mutations was subsequently related to general lifestyle factors, including paternal smoking before the partner became pregnant. Paternally derived mutations at the B6.7 locus (mutation frequency 0.07) were not affected by lifestyle. In contrast, high gross yearly income as a general measure of a healthy lifestyle coincided with low-mutation frequencies at the CEB1 locus (P=0.047). Income was inversely related to smoking behavior, and paternally derived CEB1 mutations were dose dependently increased when the father smoked in the 6 mo before pregnancy, 0.21 vs. 0.05 in smoking and nonsmoking fathers, respectively (P=0.061). These results suggest that paternal lifestyle can affect the chance of heritable mutations in unstable repetitive DNA sequences. To our knowledge, this is the first study reporting an effect of lifestyle on germline minisatellite mutation frequencies in a human population with moderate paternal exposures.
Three months of SET for IC leads to more patients meeting the ACSM/AHA public health minimum recommendations for PA. Assessment of PA could be incorporated as an outcome parameter in future research comparing different treatment modalities for peripheral arterial disease.
Benzo(a)pyrene (B[a]P) can induce somatic mutations, whereas its potential to induce germ cell mutations is unclear. There is circumstantial evidence that paternal exposure to B[a]P can result in germ cell mutations. Since DNA adducts are thought to be a prerequisite for B[a]P induced mutations, we studied DNA adduct kinetics by 32 P-postlabeling in sperm, testes and lung tissues of male mice after a single exposure to B[a]P (13 mg/kg bw, by gavage). To investigate DNA adduct formation at different stages of spermatogenesis, mice were sacrificed at Day 1, 4, 7, 10, 14, 21, 32, and 42 after exposure. In addition, DNA repair deficient (Xpc 2/2 ) mice were used to study the contribution of nucleotide excision repair in DNA damage removal. DNA adducts were detectable with highest levels in lung followed by sperm and testis. Maximum adduct levels in the lung and testis were observed at Day 1 after exposure, while adduct levels in sperm reached maximum levels at 1 week after exposure. Lung tissue and testis of Xpc 2/2 mice contained significantly higher DNA adduct levels compared to wild type (Wt) mice over the entire 42 day observation period (P < 0.05). Differences in adduct half-life between Xpc 2/2 and Wt mice were only observed in testis. In sperm, DNA adduct levels were significantly higher in Xpc 2/2 mice than in Wt mice only at Day 42 after exposure (P 5 0.01). These results indicate that spermatogonia and testes are susceptible for the induction of DNA damage and rely on nucleotide excision repair for maintaining their genetic integrity. Environ. Mol. Mutagen. 51:123-129, 2010. V V C 2009 Wiley-Liss, Inc.
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