Altered expression of genes regulating angiogenesis in experimental androgen-independent prostate cancer.
BACKGROUND
The aim of this study was to investigate how the expression of genes regulating angiogenesis is altered when prostate cancer cells progress into androgen-independency.


METHODS
A gene array specific for angiogenesis was used to compare the human prostate cancer cell line LNCaP (androgen-dependent) with its more angiogenic and tumorigenic subline LNCaP-19 (androgen-independent). Results were verified with real-time RT-PCR, and further investigations were focused on the angiogenesis inhibitor a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1). Expression of ADAMTS1 was investigated in vitro as well as in subcutaneous tumors with real-time RT-PCR and Western blotting. Microvessel density (MVD), versican proteolysis and protein levels of TIMP-2 and TIMP-3, known as ADAMTS1 inhibitors, were also analyzed in tumor xenografts.


RESULTS
The gene array revealed decreased expression of ADAMTS1, ephrin-A5, fibronectin 1, and neuropilin 1 in LNCaP-19 compared to LNCaP, while expression of midkine and VEGF were increased. Further studies showed that mRNA and protein levels of ADAMTS1 were significantly lower in LNCaP-19 compared to LNCaP, both in vitro and in subcutaneous tumors. The amount of ADAMTS1 correlated negatively with MVD, but no relation was found between ADAMTS1 and versican proteolysis.


CONCLUSIONS
Expression of several genes associated with angiogenesis was altered during transition into androgen-independency. Among these, a significant decrease was found for ADAMTS1, whose expression inversely correlated with MVD. Its role in progression of prostate cancer needs further investigation, but this inhibitor of angiogenesis could be an interesting candidate for future anti-angiogenic therapy.
Gustavsson
Heléne
H
Department of Urology, Lundberg Laboratory for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
Jennbacken
Karin
K
Welén
Karin
K
Damber
Jan-Erik
JE
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071097:ADAMTS1 Protein; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D053675:Versicans / Q000235:genetics / Q000378:metabolism
D000728:Androgens; D019717:Tissue Inhibitor of Metalloproteinase-3; D053675:Versicans; D019716:Tissue Inhibitor of Metalloproteinase-2; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human