Endothelins in bone cancer metastases.
Most evidence indicates that osteoblastic bone metastases are due to tumor-produced factors that stimulate the osteoblast. This review supports a causal role for ET-1. Based on our results, we propose a model to explain the tumor cell and bone interactions that are responsible for the osteoblastic response (Figure 2). Tumor cells housed in bone produce factors, such as ET-1, stimulate osteoblast activity. This results in the abundant and disorganized new bone formation that is characteristic of osteoblastic metastases. The effects of ET-1 to stimulate bone formation are mediated by ETA receptors on the osteoblast. ETA receptor inhibition successfully blocked osteoblastic bone metastases in a mouse model. These receptor antagonists are currently in clinical trials for advanced prostate cancer and bone metastases (Stephenson, 2001; Carducci et al., 2002; 2003). Therefore, the molecular mechanisms responsible for osteoblastic metastases are complex and involve bi-directional interactions between tumor cells and bone. Elucidation of the interactions at a molecular level can identify therapeutic targets for osteoblastic metastases. Although ET-1 and ETA receptors are potential targets for this devastating complication of cancer (Remuzzi et al., 2003), they are certainly not the only ones. The rapid pace of metastasis research, will not only expand our therapeutic armamentarium against bone metastases, but will also provide insight into achieving the ultimate goal: the prevention of cancer metastases to bone.
Guise
Theresa A
TA
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia 22904, USA.
Mohammad
Khalid S
KS
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D016232:Endothelins / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000473:pathology / Q000502:physiology
D016232:Endothelins