Angiotensin‐(1‐7) attenuates metastatic prostate cancer and reduces osteoclastogenesis

Abstract

BACKGROUIND Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone with anti-proliferative and anti-angiogenic properties. The primary objective of this study was to determine whether Ang-(1-7) effectively reduces prostate cancer metastasis in mouse xenografts. METHODS Human PC3 prostate cancer cells were injected into the aortic arch via the carotid artery of SCID mice pretreated with Ang-(1-7) or injected into the tibia of athymic mice, administered Ang-(1-7) for 5 weeks beginning 2 weeks post-injection. Tumor growth and volume were determined by bioluminescent and magnetic resonance imaging. The presence of tumors was confirmed by hematoxylin and eosin staining; TRAP histochemistry was used to identify osteolytic lesions. The effect of Ang-(1-7) on osteoclastogenesis was assessed in differentiated bone marrow cells. RESULTS Pre-treatment with Ang-(1-7) prevented metastatic tumor formation following intra-aortic injection of PC3 cells, while 83% of untreated mice developed tumors in metastatic sites. Circulating VEGF was significantly higher in control mice compared to mice administered Ang-(1-7). A five-week regimen of the heptapeptide hormone attenuated intra-tibial tumor growth; Ang-(1-7) was significantly higher in the tibia of treated mice than in control animals. Osteoclastogenesis was reduced by 50% in bone marrow cells differentiated in the presence of Ang-(1-7), suggesting that the heptapeptide hormone prevents the formation of osteolytic lesions to reduce tumor survival in the bone microenvironment. CONCLUSIONS These findings suggest that Ang-(1-7) may serve as an anti-angiogenic and anti-metastatic agent for advanced prostate cancer. By extension, the heptapeptide hormone may provide effective therapy for bone metastasis produced from primary tumors of the lung and breast.

Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts

“…We also observed significant VEGF reduction in NPC cell lines treated with Lenti-Ang-(1-7). These results are in agreement with previous studies showing decreased VEGF mRNA levels in lung cancer and prostate cancer cell lines treated with the heptapeptide (12,15,16). However, the molecular mechanisms for the Ang-(1-7)-mediated decrease in VEGF are not completely established.…”

“…S1) of cultured nasopharyngeal cancer cells. These results are in agreement with findings observed in lung, breast or prostate cancers, in which Ang-(1-7) suppressed cell proliferation and tumor xenografts (11,13,15,16). However, Ang-(1-7) had no effect on cell growth in human colon adenocarcinoma (36).…”

“…A phase I clinical trial demonstrated that Ang-(1-7) is a first-in-class antiangiogenic drug with activity for treating cancer that is linked to reduction of plasma placental growth factor (PlGF) levels (14). Recent studies showed that Ang-(1-7) attenuates metastatic prostate cancer and reduces osteoclastogenesis (15), and also reduces proliferation and angiogenesis of human prostate cancer xenografts with a decrease in angiogenic factors and an increase in sFlt-1 (16). These findings suggest that Ang-(1-7) reduces tumor size by attenuating proliferation and angiogenesis.…”

The renin-angiotensin system meets the hallmarks of cancer

“…They found in pre-treated mice with Ang(1-7) a prevention in metastatic tumour formation while the untreated mice developed tumours in metastatic sites. 34 In a retrospective study, Keizman et al evaluated the concomitant use of angiotensin system inhibitors with sunitinib treatment in metastatic renal cell carcinoma. The patients who received angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers, before or within one month of sunitinib treatment, presented a significant (hazard ratio (HR) 0.537, p = 0.0055) seven-month increase of progression-free survival.…”

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

“…47 Heptapeptide hormone angiotensin-(1-7) (Ang- (1-7)) decreases the secretion of vascular endothelial growth factor (VEGF) and PIGF from PC3 and DU145 prostate cancer cells, and it prevents cancer cell proliferation and migration, inhibiting bone metastasis and osteoclastogenesis. 48 Although some recent studies caution against the paradigm of a purely hypoxic niche, 10,19 bone marrow has long been thought to be a hypoxic environment. When treated with TGF-b under hypoxic conditions, the breast cancer cell line MDA-MB-231 increases the expression of angiogenesis factor VEGF and homing receptor CXCR4 through hypoxia-inducible factor (HIF)-1a.…”