Endothelin-1 and osteoblastic metastasis.

W hen cancer metastasizes to distant sites, it essentially forms an army of occupation. Just as the presence of an army of occupation alters the behavior of the preexisting resident population, the resident host cells react in a variety of ways to the presence of the metastatic cancer cells. In the majority of cases, they increase their resorptive or destructive capacity, and the result is an osteolytic bone lesion. However, in some notable cases, the response is predominantly formative or osteoblastic. This is particularly true for metastatic prostate cancer, although it is also frequent in a variety of hematologic malignancies as well as in patients with breast cancer. The mechanisms responsible, until recently, have been largely unknown and undefined. It is well known and widely lamented that animal models that consistently produce prostate cancer-induced osteoblastic metastases are virtually nonexistent. Recently, however, there have been successful efforts to use breast cancer models to reliably produce these lesions (1, 2). The study by Yin et al. (3) in this issue of PNAS also uses a preclinical model of osteoblastic metastasis caused by human breast cancer cells to show that endothelin-1 is the responsible mediator for these lesions in this case, and that specific antagonists to the endothelin-1 receptor inhibit the osteoblastic response to the presence of tumor in the bone marrow cavity. The model comprises nude mice inoculated with human breast cancer cells in the left cardiac ventricle, after which the cancer cells invade bone marrow and other distant sites to form metastases. The particular human tumors studied by Yin et al. formed osteoblastic metastases, although other human breast tumors form osteolytic or mixed osteolytic–osteoblastic metastases under these circumstances (1, 2, 4). These observations represent a major step forward in our understanding of the potential mechanisms involved in the pathophysiology of osteoblastic metastasis. In the past, many mechanisms for this phenomenon have been proposed, including production by tumor cells of growth regulatory factors such as the fibroblast growth factors and bone morphogenetic proteins, and fragments of plasminogen activator and of PTH-related peptide (PTH-rP) (5–8). However, none of these factors has been proven to be causative in any existing model. What these authors have shown is that the tumor they studied expressed endothelin-1, that conditioned media from the tumor cells stimulated bone formation in vitro through an endothelin-1-mediated mechanism, and that inhibition of endothelin-1 by the use of a specific receptor antagonist reduced the bone lesions in vivo. This is very convincing evidence, similar to that which showed that PTH-rP was responsible for humoral hypercalcemia of malignancy (9), and that local production of PTH-rP was responsible for osteolytic metastasis caused by human breast cancer cells (2).