Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma.
OBJECTIVE
The blood vessel-destabilizing Tie2 ligand angiopoietin-2 (Ang-2) acts in concert with the vascular endothelial growth factor/vascular endothelial growth factor receptor system to control vessel assembly during tumor progression. We hypothesized that circulating soluble Ang-2 (sAng-2) may be involved in melanoma progression.


METHODS
Serum samples (n=98) from melanoma patients (American Joint Committee on Cancer stages I-IV), biopsies of corresponding patients, and human melanoma cell lines were analyzed for expression of Ang-2 and S100beta. Multiple sera of a subcohort of 33 patients were tested during progression from stage III to IV. Small interfering RNA-based loss-of-function experiments were done to assess effects of Ang-2 on melanoma cells.


RESULTS
Circulating levels of sAng-2 correlate with tumor progression in melanoma patients (P<0.0001) and patient survival (P=0.007). Analysis of serum samples during the transition from stage III to IV identified an increase of sAng-2 up to 400%. Comparative analyses revealed a 56% superiority of sAng-2 as predictive marker over the established marker S100beta. Immunohistochemistry and reverse transcription-PCR confirmed the prominent expression of Ang-2 by tumor-associated endothelial cells but identified Ang-2 also as a secreted product of melanoma cells themselves. Corresponding cellular experiments revealed that human melanoma-isolated tumor cells were Tie2 positive and that Ang-2 acted as an autocrine regulator of melanoma cell migration and invasion.


CONCLUSIONS
The experiments establish sAng-2 as a biomarker of melanoma progression and metastasis correlating with tumor load and overall survival. The identification of an autocrine angiopoietin/Tie loop controlling melanoma migration and invasion warrants further functional experiments and validate the angiopoietin/Tie system as a promising therapeutic target for human melanomas.
Helfrich
Iris
I
Joint Research Division of Vascular Biology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. iris.helfrich@uk-essen.de
Edler
Lutz
L
Sucker
Antje
A
Thomas
Markus
M
Christian
Sven
S
Schadendorf
Dirk
D
Augustin
Hellmut G
HG
D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood; D002478:Cells, Cultured; D018450:Disease Progression; D042783:Endothelial Cells / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000401:mortality / Q000473:pathology / Q000556:secondary; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000097:blood; D042787:Receptor, TIE-2 / Q000032:analysis / Q000502:physiology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D012878:Skin Neoplasms / Q000097:blood* / Q000401:mortality / Q000473:pathology
D042702:Angiopoietin-2; D014408:Biomarkers, Tumor; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D042787:Receptor, TIE-2