Basic Mechanisms Responsible for Osteolytic and Osteoblastic Bone Metastases

Abstract

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...

RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis

“…35), which may also facilitate earlier steps in skeletal tumor establishment and development (5). Treatment of PC-3 tumor-bearing animals with OPG-Fc had no obvious effects on the production of other host cytokines and factors (data not shown).…”

Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1

“…However, once metastatic disease is detected, the survival rate is greatly reduced (Sabbatini et al, 1999;Loberg et al, 2005). Bone is the predominant site of distant metastasis from prostate cancer (Coleman, 2006;Guise et al, 2006;Vessella and Corey, 2006). Recent studies on inhibition of osteolytic prostate cancer to bone metastasis have given promising results on suppression of the ability and extent of metastases establishment (Saad et al, 2002(Saad et al, , 2004.…”

Homing of Cancer Cells to the Bone

“…Radiographically, osteoblastic lesions appear as dense areas often located to the axial skeleton, particularly in vertebral bodies and the pelvis. Histologically, tumor cells residing in the bone marrow are surrounded by a high number of osteoblasts that form wide trabeculae of woven bone similar to that observed during primary ossifications [13,14].…”

“…Radiographically, osteolytic lesions appear as radiolucent areas, typically located in the skull or in the proximal end of the long bones. Histologically, one can observe tumor cells residing in the bone marrow and surrounded by osteoclasts [13,14]. Osteolytic lesions may completely destroy the bone cortex allowing the tumor cells to infiltrate and move into the surrounding tissues.…”