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Inhibition of angiopoietin‐2 in LuCaP 23.1 prostate cancer tumors decreases tumor growth and viability
Author(s) -
Morrissey Colm,
Dowell Alex,
Koreckij Theodore D.,
Nguyen Holly,
Lakely Bryce,
Fanslow William C.,
True Lawrence D.,
Corey Eva,
Vessella Robert L.
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21216
Subject(s) - angiogenesis , medicine , prostate cancer , prostate , angiopoietin receptor , cancer research , neovascularization , in vivo , cancer , pathology , biology , microbiology and biotechnology
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. Prostate 70: 1799–1808, 2010. © 2010 Wiley‐Liss, Inc.