Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation.The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.Certain solid tumors, such as breast and prostate cancer, have a propensity to metastasize to bone and cause osteolysis and abnormal new bone formation (1, 2). The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. In fact, bone metastases are heterogeneous: data gleaned from a rapid autopsy program indicate that the same prostate cancer patient often has evidence of osteolytic and osteoblastic disease as shown by histologic examination (3). The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone, illustrated in Fig. 1. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases. Breast Cancer: The Prototypic OsteolyticTumorBreast cancer commonly metastasizes to and destroys bone, causing pain and fracture. Tumors produce many factors that stimulate osteolysis: parathyroid hormone-related protein (PTHrP), interleukin (IL)-11, IL-8, IL-6, and receptor activator of nuclear factor-nB ligand (RANKL;. Substantial data support a role for bone-derived transforming growth factor-h (TGF-h) and tumor-derived osteolytic factors, such as PTHrP, in a vicious cycle of local bone destruction in osteolytic metastases. Bone matrix stores several immobilized growth factors, particularly TGF-h, which is released in active form during osteoclastic resorption (10) and stimulates PTHrP production by tumor cells. PTHrP in turn mediates bone destruction by stimulating osteoclasts. A dominant-negative mutant of the type II TGF-h receptor inhibited TGF-h-induced PTHrP secretion in vitro and development of bone metastases in an MDA-MB-231 experimental metastasis model (5, 6). In addition, TGF-h regulates several genes that are responsible for enhanced bone metastases in MDA-MB-231: IL-11 and connective tissue growth factor (CTGF; refs. 8, 9). Collectively, these studies provided proof of principle to support a role for TGF-h blockade in the treatment of breast cancer bone metastases.SD-20...

Breast cancer frequently metastasizes to bone, in which tumor cells receive signals from the bone marrow microenvironment. One relevant factor is TGF-b, which upregulates expression of the Hedgehog (Hh) signaling molecule, Gli2, which in turn increases secretion of important osteolytic factors such as parathyroid hormonerelated protein (PTHrP). PTHrP inhibition can prevent tumor-induced bone destruction, whereas Gli2 overexpression in tumor cells can promote osteolysis. In this study, we tested the hypothesis that Hh inhibition in bone metastatic breast cancer would decrease PTHrP expression and therefore osteolytic bone destruction. However, when mice engrafted with human MDA-MB-231 breast cancer cells were treated with the Hh receptor antagonist cyclopamine, we observed no effect on tumor burden or bone destruction. In vitro analyses revealed that osteolytic tumor cells lack expression of the Hh receptor, Smoothened, suggesting an Hh-independent mechanism of Gli2 regulation. Blocking Gli signaling in metastatic breast cancer cells with a Gli2-repressor gene (Gli2-rep) reduced endogenous and TGF-b-stimulated PTHrP mRNA expression, but did not alter tumor cell proliferation. Furthermore, mice inoculated with Gli2-Rep-expressing cells exhibited a decrease in osteolysis, suggesting that Gli2 inhibition may block TGF-b propagation of a vicious osteolytic cycle in this MDA-MB-231 model of bone metastasis. Accordingly, in the absence of TGF-b signaling, Gli2 expression was downregulated in cells, whereas enforced overexpression of Gli2 restored PTHrP activity. Taken together, our findings suggest that Gli2 is required for TGF-b to stimulate PTHrP expression and that blocking Hh-independent Gli2 activity will inhibit tumor-induced bone destruction. Cancer Res; 71(3); 822-31. Ó2010 AACR.

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