ZFIN ID: ZDB-PUB-091101-30
Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumor growth in mice
Xiang, W., Ke, Z., Zhang, Y., Cheng, G.H., Irwan, I.D., Sulochana, K.N., Potturi, P., Wang, Z., Yang, H., Wang, J., Zhuo, L., Kini, R.M., and Ge, R.
Date: 2011
Source: Journal of Cellular and Molecular Medicine   15(2): 359-74 (Journal)
Registered Authors: Ke, Zhiyuan
Keywords: isthmin, angiogenesis, antiangiogenesis, cancer
MeSH Terms:
  • Amino Acid Sequence
  • Angiogenesis Inhibitors/metabolism
  • Angiogenesis Inhibitors/pharmacology
  • Animals
  • Apoptosis
  • Cell Adhesion
  • Cell Movement/drug effects
  • Cell Proliferation
  • Cloning, Molecular
  • Fibroblast Growth Factor 2/antagonists & inhibitors
  • Humans
  • Integrins/metabolism
  • Melanoma, Experimental/blood supply
  • Melanoma, Experimental/metabolism
  • Melanoma, Experimental/pathology*
  • Mice
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Neovascularization, Pathologic*
  • Neovascularization, Physiologic*
  • Proteins/chemistry
  • Proteins/genetics
  • Proteins/metabolism*
  • Proteins/pharmacology
  • Recombinant Proteins/metabolism
  • Sequence Alignment
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A/antagonists & inhibitors
  • Zebrafish
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Zebrafish Proteins/pharmacology
PubMed: 19874420 Full text @ J. Cell. Mol. Med.
Antiangiogenesis represents a promising therapeutic strategy for the treatment of various malignances. Isthmin is a gene highly expressed in the isthmus of the midbrain-hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kDa protein containing a Thrombospondin Type 1 Repeat (TSR) domain in the central region and an Adhesion-associated domain in MUC4 and Other Proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that isthmin is a novel angiogenesis inhibitor. Recombinant mouse isthmin inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed VEGF-bFGF induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, isthmin induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. Isthmin binds to alphavbeta5 integrin on EC surface and support EC adhesion. Overexpression of isthmin significantly suppressed mouse B16 melanoma tumor growth through inhibition of tumor angiogenesis without affecting tumor cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmental vessels in the trunk. Our results demonstrate that isthmin is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis.