Osteoprotegerin (OPG)--a potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis?
The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n=512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n=178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours.
Cross
Simon S
SS
Academic Units of Clinical Oncology, Pathology and Surgical Oncology, School of Medicine and Biomedical Sciences,University of Sheffield, Sheffield, UK.
Yang
Zhiyong
Z
Brown
Nicola J
NJ
Balasubramanian
Sabapathy P
SP
Evans
Clair A
CA
Woodward
Julia K
JK
Neville-Webbe
Helen L
HL
Lippitt
Jenny M
JM
Reed
Malcolm W R
MW
Coleman
Robert E
RE
Holen
Ingunn
I
D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics*; D002470:Cell Survival; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic; D053244:Osteoprotegerin; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human