Angiopoietin Growth Factor Research Articles

Intron retention as an alternative splice variant of the cattle ANGPTL6 gene

Angiopoietin-like protein 6, which is encoded by ANGPTL6 gene (also known as angiopoietin growth factor, AGF), has been extensively characterized with regard to its proposed functions as angiogenesis and energy metabolism. The present results showed the occurrence of alternative splicing by intron retention (IR) event in the bovine ANGPTL6 gene (bANGPTL6). By means of RT-PCR, TA clone and sequencing, we have shown that the bANGPTL6 gene has a splice variant generated by the retention of its partial intron 3. The computational analysis of the bANGPTL6 genomic sequence showed that its intron 3 has a high percentage of GC (62.31%) and a length of 199 nt, characteristics that have been associated with an IR event. The IR event does not interfere with the coding region as the bANGPTL6 prepropeptide is entirely coded in the third exon. Additionally, both the intronless (namely, bANGPTL6α) and intron-retaining (namely, bANGPTL6β) ANGPTL6 transcripts are constitutively co-expressed in the bovine liver. Further, the relative expression level of different variants in liver was tested by both semi-RT-PCR and RT-qPCR methods. The results suggested bANGPTL6β are significantly higher than bANGPTL6α. Overall, our findings will be helpful for studies on the molecular mechanism of IR events and the functions of ANGPTL6 gene. Specially, bANGPTL6β gene probably contributes to a new target for treatment of obesity and obesity-related diseases.

Abstract IA16: Combinatorial targeting of angiogenic growth factor pathways

Abstract Solid tumors require blood vessels for growth and dissemination, and use lymphatic vessels as additional conduits for metastatic spread. Most of the current anti-angiogenic therapies are targeted against the vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. However, in many cases resistance to the therapy occurs, and thus far the clinical therapeutic benefit has been limited to only modest improvements in overall survival. Therefore, novel treatment modalities are required. The major angiogenic pathways include a family of five VEGFs and their three receptors. I will discuss the other members of the VEGF-VEGFR family, as well as two of the three angiopoietin growth factors and their receptors Tie1 and Tie2 as targets for the inhibition of tumor angiogenesis and metastasis. Biochemical, cell biological and genetic experiments have revealed the crosstalk between the pathways, their activation mechanisms and their essential functions in tissues. These studies have shown that even the Tie1 receptor, which does directly not bind angiopoietins, but is part of the angiopoietin-receptor complex, is crucial for tumor angiogenesis and growth. Some of the angiopoietin signals also regulate vessel stability and the delivery of therapeutics to the tumor. Furthermore, recent results have indicated that integrin-mediated angiopoietin-2 signals can induce vessel destabilization. Combinatorial blocking of multiple angiogenic growth factor pathways shows promise in improving the efficacy of anti-angiogenic therapy without significantly increasing its side-effects. Citation Format: Kari K. Alitalo. Combinatorial targeting of angiogenic growth factor pathways. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA16.

Abstract IA03: Combinatorial targeting of endothelial growth factor pathways

Abstract Solid tumors require blood vessels for growth and dissemination, and use lymphatic vessels as additional conduits for metastatic spread. The identification of growth factor receptor pathways regulating angiogenesis has led to clinical approval of the first anti-angiogenic molecules targeted against the vascular endothelial growth factor (VEGF)-VEGFR-2 pathway. However, in many cases resistance to anti-VEGF-VEGFR therapy occurs, and thus far the clinical benefit has been limited to only modest improvements in overall survival. Therefore, novel treatment modalities are required. I will discuss the other members of the VEGF-VEGFR family, as well as the angiopoietin growth factors and their Tie2 receptor as targets for the inhibition of tumor angiogenesis, lymphangiogenesis and metastasis. Our recent studies reveal that also the orphan receptor Tie1 is crucial for tumor angiogenesis and growth, but not for steady-state function of the vasculature. Combinatorial targeting of multiple vascular growth factor pathways shows promise for improving the efficacy of anti-angiogenic tumor therapy. Citation Format: Kari K. Alitalo. Combinatorial targeting of endothelial growth factor pathways. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA03. doi:10.1158/1538-7445.CHTME14-IA03

Angiopoietin growth factors and Tie receptor tyrosine kinases in renal vascular development.

Angiopoietin-1 (Ang-1) is a secreted growth factor which binds to and activates the Tie-2 receptor tyrosine kinase. The factor enhances endothelial cell survival and capillary morphogenesis, and also limits capillary permeability. Ang-2 binds the same receptor but fails to activate it: hence, it is a natural inhibitor of Ang-1. Ang-2 destabilises capillary integrity, facilitating sprouting when ambient vascular endothelial growth factor (VEGF) levels are high, but causing vessel regression when VEGF levels are low. Tie-1 is a Tie-2 homologue but its ligands are unknown. Angiopoietin and Tie genes are expressed in the mammalian metanephros, the precursor of the adult kidney, where they may play a role in endothelial precursor growth. Tie-1-expressing cells can be detected in the metanephros when it first forms and, based on transplantation experiments, these precursors contribute to the generation of glomerular capillaries. During glomerular maturation, podocyte-derived Ang-1 and mesangial-cell-derived Ang-2 may affect growth of nascent capillaries. After birth, vasa rectae acquire their mature configuration and Ang-2 expressed by descending limbs of loops of Henle would be well placed to affect the growth of this medullary microcirculation. Finally, preliminary data implicate angiopoietins in deregulated vessel growth in Wilms' kidney tumours and in vascular remodelling after nephrotoxicity.