Endothelin-1 from prostate cancer cells is enhanced by bone contact which blocks osteoclastic bone resorption

Abstract

The causes for the propensity of metastasized prostate cancer cells to grow in bone and to induce osteoblastic lesions remain unresolved. Co-culture of human prostate cancer cell lines with bone slices was determined to increase the level of endothelin-1 (ET-1) mRNA and its production. ET-1 is an ejaculate protein that also stimulates osteoblasts. Osteoclastic bone resorption was significantly blocked by the presence of androgen-independent prostate cancer cells in a dose-dependent manner as that of synthetic ET-1. The inhibition could be neutralized by specific ET-1 antibody, indicating the association of prostate cancer-derived ET-1 with inhibition of bone resorption. The combined ET-1 activity on osteoclasts and osteoblasts disrupts bone remodelling. ET-1 production is also elevated in the presence of prostate-specific antigen (PSA). ET-1 in turn enhances DNA synthesis of prostate cancer cells. Interactions among cancer cells, bone, ET-1 and PSA may be critical in cancer growth and lesions in bone. © 2000 Cancer Research Campaign

Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

“…In addition, growth factors synthesized by the increased numbers of osteoblasts become sequestered in the newly synthesized bone matrix and also become rich in the local microenvironment which promotes further tumor growth and survival. The osteoblastic nature of the metastases is further supported by inhibition of osteoclastic bone resorption by ET-1 [73].…”

Mechanisms of cancer metastasis to the bone

“…Indeed exogenous ET-1 increases prostate cancer cell proliferation and enhances the mitogenic effect of other growth factors including, IGF-1, PDGF and EGF [33]. The bone microenvironment may enhance ET-1 expression by cancer cells [34]. One mechanistic definition of ET-1 action includes the finding that ET-1 drives net bone formation by inhibiting osteoclast bone resorption and osteoclast motility [35].…”

Molecular mechanisms of metastasis in prostate cancer

“…PECs produce ET-1, and its receptor, ETa, is present throughout the prostate gland [73][74][75]. ET-1 is also produced by PCa cells in a bone environment [76]. Experiments using an osteoblast mouse model [72] showed that tumours producing ET-1 (e.g., PCa) act via ETa receptors on osteoblasts to stimulate accelerated bone formation.…”