A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

Abstract

O steoblastic metastases occur in advanced cases of prostate cancer and frequently in breast cancer (1). Many factors have been proposed to cause disorganized new bone formation at sites of metastases, including insulin-like growth factors 1 and 2, transforming growth factor (TGF)-␤, prostate-specific antigen, urokinase-type plasminogen activator, fibroblast growth factors (FGF)-1 and -2, bone morphogenic proteins (BMPs), and, in particular, endothelin-1 (ET-1) (2-7).ET-1 is a potent vasoconstrictor that binds to ET A and ET B receptors with the latter functioning in ligand clearance (8,9). ET-1 is produced by and affects bone cells (10-12). It stimulates mitogenesis in osteoblasts, which express both ET A and ET B receptors (13-15). ET-1 can decrease osteoclast activity and motility (16).The prostate expresses ET-1 ligand and receptors (5-7). Primary and metastatic prostate cancers make 6,17,18), which can stimulate autocrine proliferation and potentiate effects of insulin-like growth factors, platelet-derived growth factor, epidermal growth factor, and FGF-2 (5). ET B receptor expression is decreased in prostate cancer (5). Nelson et al. (6) found that plasma ET-1 concentrations were higher in men with advanced prostate cancer with bone metastases compared with men with organ-confined disease (6). ET-1 concentrations did not correlate to tumor burden in bone. Five human prostate cancer cell lines expressed ET-1 messenger RNA, and ET-1 increased BMP-initiated bone formation (6).Breast cancers also express ET-1 and are the next most common cause of osteoblastic metastases. Breast cancer cells can convert preproET-1 to 20). Thus, substantial data implicate ET-1 in the pathogenesis of osteoblastic metastases, but a causal role for ET-1 in bone metastasis has not been directly tested. Questions remain about the importance of ET-1 on bone formation in vivo and whether ET-1 receptor blockade would decrease osteoblastic metastases.We found three human breast cancer cell lines that produce ET-1 and cause osteoblastic bone metastases. We used nude mice inoculated with ZR-75-1 cells to demonstrate a causal role for ET-1 in osteoblastic metastasis. Endothelin A receptor blockade in this model dramatically decreased metastases and tumor burden in bone. Materials and MethodsCells. ZR-75-1 and T47D were from American Type Culture Collection. C. Kent Osborne (San Antonio, TX) provided MCF-7 and MDA-MB-231. ZR-75-1 and T47D cells were grown in RPMI medium 1640; MDA-MB-231 in DMEM; MCF-7 in Iscove's modified Eagle's medium (IMEM); and BT483, BT549, MDA-MB435s, HS578T, MDA-MB-436, MDA-MB-361 PC-3, DU145, LNCaP, and TSU-Pr1 in 1:1 mixture of F12͞DMEM. All media contained 10% FCS, 1% penicillin͞streptomycin, and 1% nonessential amino acids in a 37°C atmosphere of 5% CO 2 ͞95% air. T47D and MCF-7 culture media were supplemented with insulin. At 80% confluence, 250 l of serum-free media was conditioned in 48-well plates for 48 h, and cells were counted. ET-1 and BQ-123 were from American Peptide (Sunnyvale, CA). New Bone Formation ...

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

“…(16) Tumor-produced ET-1 may also have a major role in the establishment of osteoblastic bone metastases in prostate and breast cancer. (46,47) In the present study, the number of metastatic lung nodules in the mice treated with ABT-627 was significantly lower than that in the control mice in the experimental lung metastasis model (P = 0.001). ABT-627 clearly inhibits experimental lung metastasis in nude mice.…”

Mechanisms of cancer metastasis to the bone

“…ET-1 mediates its effects on bone formation through the Endothelin A (ET A ) receptor. In a xenograft breast cancer model of osteoblastic bone metastasis, treatment with endothelin-1A-receptor antagonist reduced both osteoblastic bone metastases and tumor burden [32]. Osteoblastic prostate and breast cancers express ET-1 and ET A receptor, suggesting that tumor produced ET-1 may have paracrine and autocrine effects.…”

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

“…Animal models of breast cancer bone metastases show survival increases with agents that target bone responses to tumor, such as increased osteoclastic bone resorption with bisphosphonates (Daubiné et al 2007;Coleman 2009) or increased osteoblastic activity with endothelin receptor antagonists (Yin et al 2003;James et al 2009), rather than directly inhibiting tumor cells. Recent clinical trials have shown improved survival in breast (Coleman 2009) and prostate (James et al 2009) cancer patients, respectively, treated with these agents.…”