Inhibition of angiopoietin-2 in LuCaP 23.1 prostate cancer tumors decreases tumor growth and viability.
BACKGROUND
Angiopoietin-2 is expressed in prostate cancer (PCa) bone, liver, and lymph node metastases, whereas, its competitor angiopoietin-1 has limited expression in these tissues. Therefore, we hypothesized that the inhibition of angiopoietin-2 activity in PCa will impede angiogenesis, tumor growth, and alter bone response in vivo.


METHODS
To test our hypothesis we used L1-10, a peptide-Fc fusion that inhibits interactions between angiopoietin-2 and its receptor tie2. We blocked angiopoietin-2 activity using L1-10 in established subcutaneous and intra-tibial LuCaP 23.1 xenografts. We then determined the effect of L1-10 on survival, tumor growth, serum PSA, proliferation, microvessel density, and angiogenesis-associated gene expression in subcutaneous tumors. We also determined serum PSA, tumor area, and bone response in intra-tibial tumors.


RESULTS
The administration of L1-10 decreased tumor volume and serum PSA, and increased survival in SCID mice bearing subcutaneous LuCaP 23.1 tumors. Histomorphometric analysis, showed a further significant decrease in tumor epithelial area within the L1-10 treated LuCaP 23.1 subcutaneous tumors (P=0.0063). There was also a significant decrease in cell proliferation (P=0.012), microvessel density (P=0.012), and a significant increase in ANGPT-2 and HIF-1α mRNA expression (P≤0.05) associated with L1-10 treatment. Alternatively, in LuCaP 23.1 intra-tibial tumors L1-10 treatment did not significantly change serum PSA, tumor area or bone response.


CONCLUSIONS
Our results demonstrate that inhibiting angiopoietin-2 activity impedes angiogenesis and growth of LuCaP 23.1 PCa xenografts. Based on these data, we hypothesize that angiopoietin-2 inhibition in combination with other therapies may represent a potential therapy for patients with metastatic disease.
Morrissey
Colm
C
Department of Urology, University of Washington, Seattle, WA 98195, USA. cmorriss@u.washington.edu
Dowell
Alex
A
Koreckij
Theodore D
TD
Nguyen
Holly
H
Lakely
Bryce
B
Fanslow
William C
WC
True
Lawrence D
LD
Corey
Eva
E
Vessella
Robert L
RL
D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology; D002455:Cell Division; D002470:Cell Survival; D017931:DNA Primers; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D016133:Polymerase Chain Reaction; D011467:Prostate / Q000098:blood supply; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology*; D011859:Radiography; D042787:Receptor, TIE-2 / Q000235:genetics; D012878:Skin Neoplasms / Q000473:pathology; D013977:Tibia / Q000000981:diagnostic imaging / Q000473:pathology; D014183:Transplantation, Heterologous
D042702:Angiopoietin-2; D017931:DNA Primers; D042787:Receptor, TIE-2; D017430:Prostate-Specific Antigen