Abstract 550: Angiotensin-(1-7) inhibits prostate cancer angiogenesis and metastasis to bone

Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. We previously showed that angiotensin-(1-7) [Ang-(1-7)], a seven amino acid peptide hormone, significantly inhibited the growth of human lung cancer cells and tumors, with an associated reduction in angiogenesis. Since previous epidemiological studies suggest that administration of anti-hypertensive drugs which increase Ang-(1-7) reduces the risk of sex-specific cancers, we investigated the effects of the heptapeptide on prostate cancer. Ang-(1-7) markedly reduced human LNCaP prostate tumor xenograft size by 72% in association with a decrease in Ki67 and CD34, markers of tumor proliferation and angiogenesis, respectively. Ang-(1-7) significantly decreased both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) with a concomitant 12-fold increase in the soluble fraction of VEGF receptor 1 (sFlt-1); sFlt-1 is a decoy receptor that traps PlGF and VEGF, rendering the ligands unavailable to membrane-associated VEGF receptors. Ang-(1-7) also inhibits metastasis of prostate cancer to bone, which is the primary cause of mortality in prostate cancer patients. Human prostate cancer cells were injected into the circulation of SCID mice pretreated with Ang-(1-7), to determine the effect of the heptapeptide on the migration of cells to the metastatic environment. Six weeks following the injection of stably transfected luciferase tagged PC3 (PC3Luc) cells, 5 of the 6 untreated mice developed metastatic bone tumors, measured by bioluminescence and MRI imaging; in contrast, no detectable tumors were observed in mice administered Ang-(1-7). Circulating VEGF was significantly higher in untreated mice compared to mice treated with the heptapeptide. Ang-(1-7) also significantly reduced metastatic tumor formation in athymic mice injected with PC3Luc cells in the tibia as determined by bioluminescence, MRI imaging and immunohistochemistry. Osteolytic lesions as assessed by tartrate resistant acid phosphatase (TRAP) staining were observed surrounding the tibial tumors in control animals. A 50% reduction in osteoclastogenesis was observed when bone marrow cells were differentiated with RANK ligand and colony-stimulating factor in the presence of Ang-(1-7) [from 78.6 ± 8.0 TRAP+-multinucleated cells/field to 33.6 ± 4], suggesting that Ang-(1-7) hinders tumor survival in the bone microenvironment and prevents the formation of osteolytic lesions. Since VEGF is known to facilitate tumor growth and osteolytic disease by enhancing osteoclast survival, the inhibition of VEGF coupled with the reduction in osteoclastogenesis may mediate the inhibition of metastatic skeletal tumor formation. These results suggest that Ang-(1-7) may serve as an anti-proliferative, anti-angiogenic, and anti-metastatic agent for the treatment of prostate cancer that targets the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 550. doi:10.1158/1538-7445.AM2011-550