Hedgehog Signaling in Tumor Cells Facilitates Osteoblast-Enhanced Osteolytic Metastases (original) (raw)
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Hedgehog Signaling Induced by Breast Cancer Cells Promotes Osteoclastogenesis and Osteolysis
Journal of Biological Chemistry, 2011
Bone integrity is maintained by a dynamic equilibrium between the activities of bone-forming osteoblasts and boneresorbing osteoclasts. Osteolytic lesions are a painful consequence of metastasis of breast cancer cells to bone in an overwhelming majority of breast cancer patients. Factors secreted by breast cancer cells propel a cascade of events that trigger osteoclastogenesis and elevated bone resorption. In the present study, we show that the Hedgehog (Hh) ligands secreted by breast cancer cells promote osteoclast differentiation and potentiate the activity of mature osteoclasts. Paracrine Hh signaling induced by breast cancer cells mediates a detrimental chain of events by the up-regulation of osteopontin (OPN), which in turn enhances osteoclastic activity by up-regulating cathepsin K and MMP9. Hh signaling is essential for osteoclasts because blocking the Hh pathway using the pharmacological Hh inhibitor, cyclopamine, results in an overall decrease in osteoclastogenesis and resorptive activity. Our studies suggest that inhibiting Hh signaling interferes with the ability of pre-osteoclasts to respond to the stimulatory effects of the breast cancer cells, indicating that Hh signaling is vital to osteoclast activity.
The Hedgehog Pathway Conditions the Bone Microenvironment for Osteolytic Metastasis of Breast Cancer
International Journal of Breast Cancer, 2012
The microenvironment at the site of tumor metastasis plays a key role in determining the fate of the metastasizing tumor cells. This ultimately has a direct impact on the progression of cancer. Bone is the preferred site of metastasis of breast cancer. Painful, debilitating osteolytic lesions are formed as a result of crosstalk between breast cancer cells and cells in the bone, predominantly the osteoblasts and osteoclasts. In this paper, we have discussed the temporal and spatial role of hedgehog (Hh) signaling in influencing the fate of metastatic breast cancer cells in bone. By virtue of its secreted ligands, the Hh pathway is capable of homotypic and heterotypic signaling and consequently altering the microenvironment in the bone. We also have put into perspective the therapeutic implications of using Hh inhibitors to prevent and/or treat bone metastases of breast cancer.
Therapeutic targets for bone metastases in breast cancer
Breast Cancer Research, 2011
Once metastatic breast cancer cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts) and hijack signals coming from the bone matrix, thereby disrupting physiological bone remodeling [2,3]. Indeed, there is a 'vicious cycle' whereby metastatic cells residing in the bone marrow secrete factors that stimulate osteoclastmediated bone resorption and growth factors released from resorbed bone stimulate tumor growth [2]. Breast cancer cells may also interact with preosteoclasts, resulting in direct stimulation of osteoclast diff erentiation and maturation [4]. Furthermore, breast cancer cells secrete factors that inhibit osteoblast diff erentiation and activity [2,3]. Th eir interaction with osteoblasts also induces the release of cytokines that promote tumor growth [4]. Taken together, this leads to an imbalance between bone resorption and bone formation, resulting in enhanced skeletal destruction and, as a consequence of osteolysis, occurrence of pathological fractures (Figure 1). Several molecules that are produced by breast cancer cells-for example, parathyroid hormone-related protein, interleukins (IL-6, IL-8, and IL-11), cytokines (macrophage colony stimulating factor (M-CSF)) and prostaglandins-stimulate osteoclast activity through the activa tion of the receptor activator of nuclear factor-kB ligand (RANKL)/RANK pathway, which is the primary mediator of osteoclast-mediated bone resorption [3,5]. Breast cancer cells may also directly stimulate
Proceedings of the National Academy of Sciences of the United States of America, 2018
Bone metastasis involves dynamic interplay between tumor cells and the local stromal environment. In bones, local hypoxia and activation of the hypoxia-inducible factor (HIF)-1α in osteoblasts are essential to maintain skeletal homeostasis. However, the role of osteoblast-specific HIF signaling in cancer metastasis is unknown. Here, we show that osteoprogenitor cells (OPCs) are located in hypoxic niches in the bone marrow and that activation of HIF signaling in these cells increases bone mass and favors breast cancer metastasis to bone locally. Remarkably, HIF signaling in osteoblast-lineage cells also promotes breast cancer growth and dissemination remotely, in the lungs and in other tissues distant from bones. Mechanistically, we found that activation of HIF signaling in OPCs increases blood levels of the chemokine C-X-C motif ligand 12 (CXCL12), which leads to a systemic increase of breast cancer cell proliferation and dissemination through direct activation of the CXCR4 receptor...
The role of osteoclasts in breast cancer bone metastasis
Journal of Bone Oncology, 2016
Breast cancer frequently metastasises to the skeleton, interfering with the normal bone remodelling process and inducing bone degradation. Bone degradation is caused by osteoclasts, the normal boneresorbing cells. Osteoclast-mediated bone degradation subsequently leads to the release of bone-derived factors that promote skeletal tumour growth. Osteoclasts themselves stimulate tumour growth. This Review describes the molecular mechanisms through which osteoclasts and breast cancer cells collaborate with each other, triggering the formation of osteolytic bone metastasis.
Molecular mechanisms of breast cancer metastases to bone
Clinical breast cancer, 2005
Bone metastases lead to hypercalcemia, bone pain, fractures, and nerve compression. They cause increased morbidity and mortality in patients with advanced breast cancer. Animal models reproduce many of the features seen in patients with breast cancer and permit identification of tumor- and bone-derived factors important in skeletal metastasis. These factors provide novel targets for therapeutic interventions. Specific tumor-bone molecular interactions mediated by these factors drive a vicious cycle that perpetuates skeletal metastases. In breast cancer, osteolytic metastases are most common, but mixed and osteoblastic metastases occur in a significant number of patients. Parathyroid hormone-related protein is a common osteolytic factor, and vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1 (ET-1), but there are a variety of other potential osteoblastic factors. Stimulation of osteoblasts...
Cellular Players in Breast Cancer Bone Metastases
Clinical Reviews in Bone and Mineral Metabolism, 2013
The current paradigm for bone metastasis is that there is a mutual interaction between osteoclasts and cancer cells, known as the tumor/bone vicious cycle. This model is based largely on findings in immune compromised animals showing amelioration of bone metastases by targeting the osteoclasts. Thus, osteoclast inhibitors are the standard of care in breast cancer bone metastasis. However, clinical studies demonstrate only a 28 % reduction in skeletal-related events in patients with bone metastases treated with bisphosphonates, and currently, there is limited evidence supporting anti-resorptive therapies in reducing the overall incidence of bone metastasis or extending survival. These data indicate that other cells, in addition to the osteoclasts, control tumor growth in bone. This review will discuss the role of the osteoclast, and then focus on additional cellular players, thus expanding the model of bone metastasis pathophysiology to include immune and stromal components.
Tumor-bone cellular interactions in skeletal metastases
Journal of musculoskeletal & neuronal interactions, 2004
Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulatio...
Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway
PloS one, 2016
The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown. Pre-OBs were generated from healthy donor (HD)-derived bone marro...