PubMed · 9780690
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M Ono, M Kuwano. 1998-08-10. [Neovascularization and tumor development].. https://pubmed.ncbi.nlm.nih.gov/9780690/
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The generation of an "angiogenic switch" is essential for tumor growth, yet its regulation is poorly understood. In this investigation, we explored the linkage between metastasis and angiogenesis through CXCL12/CXCR4 signaling. We found that CXCR4 regulates the expression and secretion of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 reduced the secretion of vascular endothelial growth factor and interleukin-8 and increased the generation of angiostatin. At metastatic sites, however, high levels of CXCL12 signaling through CXCR4 reduced PGK1 expression, releasing the angiogenic response for metastastic growth. These data suggest that PGK1 is a critical downstream target of the chemokine axis and an important regulator of an "angiogenic switch" that is essential for tumor and metastatic growth.
INTRODUCTION: Angiogenesis is essential for tumor growth or metastasis. A method involving noninvasive detection of angiogenic activity in vivo would provide diagnostic information regarding antiangiogenic therapy targeting vascular endothelial cells as well as important insight into the role of vascular endothelial growth factor (VEGF) and its receptor (flt-1 and KDR) system in tumor biology. We evaluated radioiodinated VEGF(121), which displays high binding affinity for KDR, and VEGF(165), which possesses high binding affinity for flt-1 and low affinity for KDR, as angiogenesis imaging agents using the LS180 tumor xenograft model. METHODS: VEGF(121) and VEGF(165) were labeled with (125)I by the chloramine-T method. Biodistribution was observed in an LS180 human colon cancer xenograft model. Additionally, autoradiographic imaging and immunohistochemical staining of tumors were performed with (125)I-VEGF(121). RESULTS: (125)I-VEGF(121) and (125)I-VEGF(165) exhibited strong, continuous uptake by tumors and the uterus, an organ characterized by angiogenesis. (125)I-VEGF(121) uptake in tumors was twofold higher than that of (125)I-VEGF(165) (9.12+/-98 and 4.79+/-1.08 %ID/g at 2 h, respectively). (125)I-VEGF(121) displayed higher tumor to nontumor (T/N) ratios in most normal organs in comparison with (125)I-VEGF(165). (125)I-VEGF(121) accumulation in tumors decreased with increasing tumor volume. Autoradiographic and immunohistochemical analyses confirmed that the difference in (125)I-VEGF(121) tumor accumulation correlated with degree of tumor vascularity. CONCLUSION: Radioiodinated VEGF(121) is a promising tracer for noninvasive delineation of angiogenesis in vivo.
The crystal structure of the human Pg-derived angiogenesis inhibitor, angiostatin, complexed to VEK-30, a peptide from the group A streptococcal surface protein, PAM, was determined and refined to 2.3 A resolution. This is the first structure of angiostatin bound to a ligand and provides a model of the interaction between Pg and streptococcal-derived pathogenic proteins. VEK-30 contains a "through-space isostere" for C-terminal lysine, wherein Arg and Glu side chains, separated by one helical turn, bind within the bipolar angiostatin kringle 2 (K2) domain lysine-binding site. VEK-30 also makes several contacts with K2 residues that exist outside of the canonical LBS and are not conserved among the other Pg kringles, thus providing a molecular basis for the selectivity of VEK-30 for K2. The structure also shows that Pg kringle domains undergo significant structural rearrangement relative to one another and reveals dimerization between two molecules of angiostatin and VEK-30 related by crystallographic symmetry. This dimerization, which exists only in the crystal structure, is consistent with the parallel coiled-coil full-length PAM dimer expected from sequence similarities and homology modeling.