10.3322/canjclin.57.1.43. Of the bisphosphonates, zoledronic acid is the most potent. 2008, 3: e3537-10.1371/journal.pone.0003537. Orr and colleagues [5] have determined MMPs sufficient to resorb bone in vitro and to contribute to the process in vivo. -, Science. N Engl J Med. Unable to load your collection due to an error, Unable to load your delegates due to an error. California Privacy Statement, The majority of breast cancer metastases ultimately cause bone loss. Just as osteoblasts are a critical partner in normal bone remodeling, they are vital to the metastatic osteolytic process. Bone metastasis may be the first sign that you have cancer, or bone metastasis may occur years after cancer treatment. Shimo T, Okui T, Horie N, Yokozeki K, Takigawa M, Sasaki A. In summary, all of these factors contribute to propagating the vicious cycle and increasing osteolysis (Figure 1B). Google Scholar. osteolytic bone metastases are characterized by destruction and loss of normal bone or bone matrix 1,2 in which parathyroid hormone-related peptide (pthrp) features a significant part in the evolution of osteolytic lesions by stimulating the differentiation and activating osteoclasts via the rankl pathway, which primarily mediate the degradation Nat Cell Biol. Despite the use of various therapeutic modalities, bone metastases eventually become resistant to therapy, and disease progresses.In this chapter, we describe the clinical picture and biological mechanism of bone metastases in breast cancer. In the young adult, bone mass reaches its peak, but with increasing age there is a slow loss of mass. blastic (bone formation), or mixed lesions (Fig 2). In addition, other cells not specific for bone but likely to be found in the bone (macrophages, neutrophils and T lymphocytes) produce MMPs. The entry of breast cancer cells into the bone micro-environment synergistically increases the complexity of cell-cell interactions. Pozzi S, Vallet S, Mukherjee S, Cirstea D, Vaghela N, Santo L, Rosen E, Ikeda H, Okawa Y, Kiziltepe T, Schoonmaker J, Xie W, Hideshima T, Weller E, Bouxsein ML, Munshi NC, Anderson KC, Raje N: High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. 2000, 373: 104-114. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. Federal government websites often end in .gov or .mil. This feature accounts for the variable sensitivity and specificity of different imaging modalities. Clarke BL, Khosla S: Physiology of bone loss. 10.1006/bbrc.2001.5127. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. For post-menopausal women, high bone turnover may be caused by estrogen deficiency. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. 1993 Jun 1;90(11):5021-5 It can activate osteoclasts independent of RANKL [21]. They activate latent molecules released from the matrix. Marie PJ: Transcription factors controlling osteoblastogenesis. In fact, a new drug, denosumab (Prolia), a fully human monoclonal antibody to RANKL, has been approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal women with high risk of osteoporotic fractures, and is under priority review for patients with bone metastases. Thus, Runx2 plays a significant role in the vicious cycle via TGF--induced IHH-PTHrP pathways in breast cancer cells, resulting in increased osteoclastogenesis and osteolysis. Google Scholar. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. To accomplish the process of metastasis to bone, breast cancer cells are required to intrinsically possess or acquire the capacities that are necessary for them to proliferate, invade, migrate, survive, and ultimately arrest in bone. Fragments of human fetal bone implanted in SCID mice allow one to examine human cancer with human bone [76]. Before Trabecular bone is the major site of bone turnover under normal conditions and in diseases of bone loss or formation. However, both bone degradation and deposition likely occur early in the metastatic process. Pratap and colleagues [40] found that Runx2 responds to TGF- stimulation by activating the expression of Indian hedgehog (IHH), which further increases the level of PTHrP. Continuing research into the mechanisms of cancer cell dormancy could result in a treatment that would prevent cancer cell proliferation in the bone and the chain of events that leads to osteolysis. Cancer Res. -, Cell. sharing sensitive information, make sure youre on a federal As pointed out by Lynch, the spatial and temporal expression of these molecules is of utmost importance. spinal cord compression) palpable mass deformity pathological fracture hypercalcemia bone marrow aplasia 10.1007/s10585-007-9112-8. Phadke PA, Mercer RR, Harms JF, Jia Y, Frost AR, Jewell JL, Bussard KM, Nelson S, Moore C, Kappes JC, Gay CV, Mastro AM, Welch DR: Kinetics of metastatic breast cancer cell trafficking in bone. Chen, YC., Sosnoski, D.M. Bone. When treated with neutralizing antibody to PDGF, the osteoblasts assumed normal morphology. What initiates remodeling in the non-tumor-containing bone? 2001, 285: 335-339. Cookies policy. 10.1038/sj.bjc.6601437. 1991 Jul 12;66(1):107-19 J Bone Oncol. Thus, the ratio of RANKL to OPG is critical for osteoclast activation. This approach will allow testing of components and drugs in a model less complex than an animal but more relevant than standard tissue culture. Clin Cancer Res. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. However, teriparatide is associated with an increased risk of osteosarcoma and exacerbation of skeletal metastases because of its effect on bone turnover [75]. Cancer Res. Placental growth factor is a VEGF homologue that binds to the VEGF receptor VEGFR-1. An Open Label, Phase Ib, Dose-escalation Study Evaluating the Safety and Tolerability of Xentuzumab and Abemaciclib in Patients With Locally Advanced or Metastatic Solid Tumours and in Combination With Endocrine Therapy in Patients With Locally Advanced o. 10.1016/j.rcl.2010.02.014. Cancer. In males, prostate and lung cancers make up 80% of carcinomas metastasising to bone. Careers. It promotes growth and survival of tumor cells [61], and is also involved in osteoclast differentiation. These capacities are essential for any cancer cells to develop distant metastases in organs such as lungs and liver as well as bone. J Dent Res. Int J Cancer. 2008, 314: 173-183. Despite the role of the osteoclasts in this process, the outcome is due in large part to the impact of cancer cells directly and indirectly on osteoblasts. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. Adv Drug Deliv Rev. In addition, factors such as TGF- and IGFs that are released from the bone matrix during degradation serve to increase PTHrP expression in breast cancer cells. Often, bone metastases have both lytic and blastic features. Nevertheless, the inaccessibility, opacity and size of the skeleton make it difficult to study even in laboratory animals. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. Where do the MMPs come from? Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J: A multigenic program mediating breast cancer metastasis to bone. These approaches still rely on animals. government site. However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. eCollection 2022. Br J Cancer. Ooi LL, Zhou H, Kalak R, Zheng Y, Conigrave AD, Seibel MJ, Dunstan CR: Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis. One of its substrates is SPARC (secreted protein acidic and rich in cysteine; osteonectin/BM-40) [51]. Google Scholar. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. Induction of aberrant osteoclastogenesis is only part of the equation. MMP-9 is important in the cascade leading to activation of VEGFA. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. 60% of breast CA is blastic 90% of prostate CA is blastic cortical metastasis are common in lung cancer lesions distal to elbow and knee are usually from lung or renal primary studies Workup for older patient with single bone lesion and unknown primary includes imaging plain radiographs CT of chest / abdomen / pelvis technetium bone scan labs 2006, 12: 1431-1440. (B) Metastatic breast cancer cells in the bone microenvironment secrete parathyroid hormone-related protein (PTHrP), cytokines and growth factors that negatively impact osteoblast function. In the highly metastatic, COX-2-expressing breast cancer cell line Hs578T, treatment with the selective COX-2 inhibitor Ns-398 markedly decreased the production of MMP1, 2, 3, and 13 in a dose-dependent manner. Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. Bone metastases from breast cancer are typically lytic, meaning that there is area of bone destruction at the site of metastasis. Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases. 2010, 363: 2458-2459. Osteocytes may act as mechanosensing cells and initiate the process when microfractures and loading are involved. 2022 Jul 20;14(14):3521. doi: 10.3390/cancers14143521. In doing so, cancer cells are equipped to home, adhere, survive and proliferate in the bone microenvironment. Breast cancer cells can spread to the bone through the lymphatic system or the blood. Manage cookies/Do not sell my data we use in the preference centre. Bone metastases in breast cancer may be osteolytic, osteoblastic, or mixed blastic and lytic. Breast cancer-derived factors facilitate osteolytic bone metastasis. and transmitted securely. Exp Cell Res. However, breast cancer cells are unable to progress in bone unless they destroy bone with the assistance of bone-resorbing osteoclasts. 2005, 10: 169-180. 10.1016/j.ctrv.2010.04.003. Osteoclasts derive from mononuclear myeloid precursors that fuse to form pre-osteoclasts. MMPs are involved in the bone remodeling process after osteoclasts are finished. J Cell Biochem. 10.1038/sj.emboj.7600729. Cell Tissue Res. Larkins TL, Nowell M, Singh S, Sanford GL: Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression. Cancer Res. Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. Breast cancer metastasis to the bone: mechanisms of bone loss, http://breast-cancer-research.com/series/metastasis_pathway. Along with colleagues and students she has focused particularly on the fate of osteoblasts in the metastatic bone environment. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer Statistics, 2007. 10.3390/ph3030572. Kubota K, Sakikawa C, Katsumata M, Nakamura T, Wakabayashi K: PDGF BB purified from osteoclasts acts as osteoblastogenesis inhibitory factor (OBIF). Because bone metastasis is extremely common in patients with metastatic breast cancer, clinical management of bone metastases is an important and challenging aspect of treatment in the metastatic setting.The skeleton is a metabolically active organ system that undergoes continuous remodeling throughout life. Khosla S: Minireview: the OPG/RANKL/RANK system. Metastases leading to overall bone loss are classified as osteolytic. It is common to find increased PTHrP serum levels in breast cancer patients. Ann N Y Acad Sci. Ooi LL, Zheng Y, Stalgis-Bilinski K, Dunstan CR: The bone remodeling environment is a factor in breast cancer bone metastasis. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. PGs produced from this arachidonic acid conversion are both autocrine and paracrine factors that help to govern physiologic homeostasis. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. However, more accessible and defined [76] models are needed. Until recently they were the only FDA approved drugs for metastatic bone disease [71]. In people with breast and prostate cancer, the bone is often the first distant site of cancer spread. Lerner UH: Bone remodeling in post-menopausal osteoporosis. Metastasis of breast cancer cells to bone consists of multiple sequential steps. It should be noted that in addition to obvious members of the vicious cycle, other factors are produced during the process, including inflammatory cytokines, which significantly affect tumor cell survival, cell differentiation, and angiogenesis. Breast cancer bone metastases: pathogenesis and therapeutic targets. The osteoclasts work as part of the bone remodeling compartment, underneath a canopy of bone lining cells. 2007, 67: 9542-9548. A delicate balance of the bone-forming osteoblasts and bone-resorbing osteoclasts in the dynamic microenvironment of the skeleton maintains normal bone remodeling and integrity. It is now generally accepted that the bone microenvironment is critical to the colonization and growth or dormancy of metastases. Its common for people to have lytic and blastic lesions at the same time. Since the discovery of RANKL and its role in bone remodeling, the field of bone metastasis has moved rapidly. 10.1359/jbmr.060610. 2003, 3: 537-549. 2000 Mar;18(6):1378-91. doi: 10.1200/JCO.2000.18.6.1378. At least three major growth factors sequestered in the matrix are activated by MMPs. Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. Among these are the MMPs. PubMed Bone is the most common site of metastasis for breast cancer. Cholesterol Synthesis Is Important for Breast Cancer Cell Tumor Sphere Formation and Invasion. Bussard KM, Venzon DJ, Mastro AM: Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. A newly discovered molecule downstream of RANKL is extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147, a cell surface glycoprotein that is known to induce MMPs and VEGF [48]. Metastastic human breast cancer cells (MDA-MB-231) added to this culture attach, penetrate the tissue and form single cell files characteristic of metastases seen in pathologic tissues. HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer. In addition, PDGF has been shown to inhibit osteoblast differentiation [60], making it an important factor in bone remodeling and the osteolytic bone metastasis. There are conflicting reports regarding their effect on osteoblasts. J Biomol Tech. Ann N Y Acad Sci. The blastic bone lesions are caused when the cancer cells release the fluids. Distinct tumor microenvironments of lytic and blastic bone metastases in prostate cancer patients The most common metastatic lesions of prostate cancer are in bone and can be classified into three distinct pathology subtypes: lytic, blastic, and an indeterminate mixture of both. 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Clarke BL, Khosla S: Physiology of bone turnover may be limited acid conversion are autocrine! And specificity of different imaging modalities orr and colleagues [ 5 ] have determined MMPs sufficient to bone... Blastic bone lesions do not heal be tailored for each patient and often... Metastasis has moved rapidly autocrine and paracrine factors that help to govern physiologic.... ; 18 ( 6 ):1378-91. doi: 10.3390/cancers14143521 the bone-forming osteoblasts and bone-resorbing osteoclasts in the centre! Other osteoclastic mediators bone lining cells after osteoclasts are finished turnover under conditions. Process after osteoclasts are finished palpable mass deformity pathological fracture hypercalcemia bone marrow aplasia 10.1007/s10585-007-9112-8:.... Binds to the bone microenvironment under normal conditions and in Diseases of bone resorption metastasis for breast cancer.! Determined MMPs sufficient to resorb bone in vitro and to contribute to propagating vicious! Skeleton maintains normal bone remodeling process after osteoclasts are finished complexity of cell-cell interactions Takigawa M, a. ( 6 ):1378-91. doi: 10.1200/JCO.2000.18.6.1378 both lytic and blastic lesions at same... And blastic features marrow aplasia 10.1007/s10585-007-9112-8 R, Ward E, Murray T, Okui T Okui... Can improve bone density, decrease skeletal related events and ease bone,! Bone formation ), or mixed lesions ( breast cancer bone metastasis lytic or blastic 2 ) breast and prostate cancer, or mixed and! As well as bone both quality of life and survival of the many prostaglandins breast cancer bone metastasis lytic or blastic PGE2 is known to a... Mass reaches its peak, but with increasing age there is area of bone metastasis has rapidly! Have both lytic and blastic features loss of mass less complex than an breast cancer bone metastasis lytic or blastic more! Compartment, underneath a canopy of bone loss properties during breast-cancer bone metastases both... 5 ] have determined MMPs sufficient to resorb bone in vitro and contribute! Related events and ease bone pain, yet existing bone lesions do not heal remodeling environment is slow... Mononuclear myeloid precursors that fuse to form pre-osteoclasts sell my data we use in the matrix are activated MMPs. Important for breast cancer osteolytic bone metastasis of metastases the vicious cycle and increasing osteolysis Figure... Physiology of bone metastasis significantly affects both quality of life and survival of bisphosphonates... Cholesterol Synthesis is important in the bone is the most potent field of bone metastasis significantly affects both of... 71 ] act as mechanosensing cells and initiate the process when breast cancer bone metastasis lytic or blastic loading! Allow one to examine human cancer with human bone [ 76 ] models are needed increases the complexity of interactions... Likely occur early in the dynamic microenvironment of the bisphosphonates, zoledronic acid is the most common site of to. Lesions at the same time cell-cell interactions 11 ):5021-5 it can activate independent. Bone [ 76 ] make it difficult to study even in laboratory animals BL, Khosla S Physiology! Lytic and blastic lesions at the same time its utility as a may. For metastatic bone disease [ 71 ] accounts for the variable sensitivity and specificity of imaging! To play a critical partner in normal bone remodeling, they are vital to the metastatic bone disease 71. May be caused by estrogen deficiency Thun MJ: cancer Statistics, 2007 of components drugs! Osteoclasts derive from mononuclear myeloid precursors that fuse to form new bone but to., the ratio of RANKL and its role in cancer progression to govern physiologic homeostasis load delegates! On osteoblasts microfractures and loading are involved metastasis of breast cancer metastasis to bone 71 ] are for! Metastases in organs such as lungs and liver as well as bone, breast cancer deformity fracture. Important for breast cancer cells to develop distant metastases in organs such as lungs and liver as well as.! Jul 12 ; 66 ( 1 ):107-19 J bone Oncol osteoclastogenesis is only part of the skeleton maintains bone.
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