In the young adult, bone mass reaches its peak, but with increasing age there is a slow loss of mass. Several MMPs (MMP2, 3, 9) can release TGF- from the latent state, allowing it to become active. Please enable it to take advantage of the complete set of features! This article is part of a review series on New pathways of metastasis, edited by Lewis Chodosh. Google Scholar. It is now known that PGE2 signaling through its receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form mature osteoclasts. 10.1016/S0006-291X(02)02937-6. Bone. Cancer Treat Rev. It has high affinity for type I collagen, the most abundant matrix protein. 2010, 33 (3 Suppl): S1-7. Those leading to excess bone deposition are considered osteoblastic. They also are regulators of other molecules important in the vicious cycle. TGF- is well-known for its role in osteolytic bone metastasis. 10.1016/j.yexcr.2005.07.029. Lerner UH: Bone remodeling in post-menopausal osteoporosis. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. 7. It has been suggested that cancer cells preferentially metastasize to bone due to their ability to express genes that are normally considered bone or bone-related [36]. Cancer Treat Rev. In the early 1970 s it was reported that prostaglandins could resorb fetal bone in culture [43], and that aspirin, a COX-1 inhibitor, and indomethacin, a COX-2 inhibitor, could prevent osteolysis in tissue culture [44]. Oncogene. Bookshelf HHS Vulnerability Disclosure, Help Khosla S: Minireview: the OPG/RANKL/RANK system. Cytokines such as IL-6, IL-8 and IL-11 secreted by breast cancer cells also promote osteoclast differentiation and bone resorption. In the 1960s and 70s it was proposed that bone degradation might result from the physical pressure of the tumor on the bone and/or direct resorption of the bone by tumor cells. volume12, Articlenumber:215 (2010) Article 2010, 115: 140-149. Careers. Bone provides support and protects vital organs but also is a metabolically active tissue. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted 10.1016/j.yexcr.2007.09.021. The use of blocking antibodies to placental growth factor in two xenograft mouse/human models greatly decreased the numbers and size of osteolytic lesions [61]. 10.1023/A:1026526703898. Raica M, Anca M: Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. BMC Cancer. PMC Studies with MMP9-null mice indicate its importance in tumor progression in ovarian cancer, prostate cancer and bone metastasis [56]. Cancer Res. 2022 Aug 23;14:2519-2531. doi: 10.2147/CMAR.S369910. On x-rays, these metastases show up as spots that are whiter than the bone around them. 2 Of interest is that patients with blastic (versus osteolytic) bone metastases have been reported to have prolonged survival. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. FOIA At first glance it would seem ideal to pair bisphosphonates or denosumab with teriparatide since the former two block bone resorption and the latter stimulates bone deposition. Myeloma cells produce factors that upregulate osteoblast production of M-CSF and RANKL and downregulate production of OPG. Federal government websites often end in .gov or .mil. 10.1158/1535-7163.MCT-07-0234. Stopeck A: Denosumab findings in metastatic breast cancer. Among these are the MMPs. Cortical bone provides strength and protection while trabecular bone is the most metabolically active. Mouse Models of Tumor Bone Metastasis and Invasion for Studying CCN Proteins. Annu Rev Pathol. 10.1038/onc.2009.389. They follow the osteoclasts, reforming the bone matrix. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. Clin Adv Hematol Oncol. Chronic inflammation has long been considered a risk factor in cancer initiation [68]. 10.1007/s10585-007-9112-8. 1991 Apr 1;47(6):922-8 2010, 70: 412-424. Andrea M Mastro. Because of its significant role, TGF- has been a tempting therapeutic target. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM: Molecular mechanisms of breast cancer metastases to bone. It improves the quality of life by preventing fractures but does not prolong life [73]. 2003, 300: 957-964. Further, we describe future directions for bone metastasis management, focusing on novel bone-specific targeted therapies. -, Cell. Meanwhile, COX-2 produced by breast cancer cells and osteoblasts increases the localized PGE2 concentration, which can directly bind to osteoblasts, promoting RANKL expression and further stimulating osteoclast differentiation. These findings led to a flurry of studies to develop COX and prostaglandin inhibitors as cures for bone metastasis. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. -, Proc Natl Acad Sci U S A. NF-B/MAP-kinase inhibitors (SN50, PD98059 and SB203580), COX-2 inhibitors (indomethacin) and EP4 receptor decoy [46] all result in a down-regulation of RANKL production and a concomitant decrease in osteoclastogenesis. VEGF also forms a complex with the extracellular matrix [31, 55]. 2000, 2: 737-744. Breast Cancer Res 12, 215 (2010). Front Biosci (Schol Ed). Cancer. 10.1038/sj.emboj.7600729. 2009, 175: 1255-1269. Cancer Res. 10.1158/0008-5472.CAN-09-4092. Rucci N, Millimaggi D, Mari M, Del Fattore A, Bologna M, Teti A, Angelucci A, Dolo V: Receptor activator of NF-kappaB ligand enhances breast cancer-induced osteolytic lesions through upregulation of extracellular matrix metalloproteinase inducer/CD147. Bookshelf Metastatic breast cancer cells tend to spread to the bones more often than they do to other parts of the body. IGF binding proteins keep this molecule latent. When a patient has a metastasis and no site of origin can be found (a metastasis of unknown origin) the most likely site is the lung or kidney. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL. 2023;2582:343-353. doi: 10.1007/978-1-0716-2744-0_24. The .gov means its official. Orr and colleagues [5] have determined MMPs sufficient to resorb bone in vitro and to contribute to the process in vivo. However, 15-20% of metastatic breast cancer lesions can be blastic or mixed. The roles of cell adhesion molecules including cadherins and laminin and matrix metalloproteinases in the development of osteolytic bone metastases by breast cancer are also discussed. The PGE2-mediated production of RANKL induces osteoclastogenesis via RANK. Its common for people to have lytic and blastic lesions at the same time. 2023 BioMed Central Ltd unless otherwise stated. HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. 2007, 6: 2609-2617. In a series of in vitro, ex vivo and in vivo experiments, Ohshiba and colleagues [45] demonstrated that direct cell-cell contact between breast cancer cells and osteoblasts caused an increase in COX-2 expression in the osteoblasts due to activation of the NFB/mitogen-activated protein (MAP) kinase pathway. For females, breast and lung are the most common primary sites ; nearly 80% of cancers that spread to the skeleton are from these locations. Proff P, Romer P: The molecular mechanism behind bone remodelling: a review. 8600 Rockville Pike 2008, 3: e3537-10.1371/journal.pone.0003537. Aldridge SE, Lennard TW, Williams JR, Birch MA: Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. The results of an in vivo study showed that OPN-deficient mice showed significantly reduced bone metastasis [38]. There are two types of lesions: lytic lesions, which destroy bone material; and blastic lesions, which fill the bone with extra cells. An official website of the United States government. However, there is no guarantee that inhibition of osteolytic lesions would prevent the growth of cancer cells in the bone or their spread to other organs. Cite this article. 2022 Feb;22(2):85-101. doi: 10.1038/s41568-021-00406-5. Cookies policy. J Dent Res. 1993 Jun 1;90(11):5021-5 2006, 85: 596-607. 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. In a study by Mercer and Mastro [59], osteoblasts treated with conditioned media from MDA-MB-231 breast cancer cells displayed disorganized F-actin fibrils and reduced focal adhesion plaques. 10.1016/S0959-8049(00)00363-4. 10.1038/sj.bjc.6601437. N Engl J Med. Radiol Clin North Am. Exp Cell Res. Trabecular bone is the major site of bone turnover under normal conditions and in diseases of bone loss or formation. J Biomol Tech. Survival Prediction in Patients Treated Surgically for Metastases of the Appendicular Skeleton-An External Validation of 2013-SPRING Model. The resorption phase of the process begins with recruitment of pre-osteoclasts that differentiate into activated osteoclasts under the direction of osteoblasts (Figure 1A). The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. These molecules bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. While there is evidence that the breast cancer cell matrix metalloproteinases (MMPs) can resorb bone in vitro and contribute to bone degradation in vivo [5], it is now well accepted that osteoclasts are largely responsible for osteolytic metastatic lesions [6]. Bone metastases in breast cancer may be osteolytic, osteoblastic, or mixed blastic and lytic. . 10.1210/en.142.12.5050. More than half of people who develop stage IV breast cancer have bone metastasis. Drugs of the bisphosphonate family have been used for many years as the standard of care. Edited by: Rosen CL. Mundy GR: Mechanisms of bone metastasis. sharing sensitive information, make sure youre on a federal The mean standardized uptake value (SUV) for tumor was 7.1 versus 2.1 for benign lesions. Surprisingly, this treatment did not affect angiogenesis in the bone. PDGF is a dimeric protein consisting of two of four possible subunits. Accessibility Denosumab has recently been approved by the FDA for treatment of osteoporosis in women with high risk of fractures and is being considered for treatment of bone metastasis. Administration of bisphosphonates may slow osteolytic lesion progression and stabilize or increase overall bone density, but does not bring about healing [1, 16, 26]. Metastatic cancer cells tend to colonize the heavily vascularized areas of the skeleton, such as the red marrow of the long bones, sternum, pelvis, ribs and vertebrae, where they disrupt not only bone physiology but also hematopoiesis and the immune system [3]. It's the most advanced stage of breast cancer. The entry of breast cancer cells into the bone micro-environment synergistically increases the complexity of cell-cell interactions. 10.1007/s10585-006-9044-8. 10.1016/S8756-3282(03)00086-3. The purpose of this study is to find a safe dose of: - Xentuzumab in combination with abemaciclib - Xentuzumab in combination with abemaciclib and hormonal therapies The study also tests whether these medicines make tumours shrink in participants with lung and breast cancer. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. A working model to describe the bone remodeling compartment in the presence of metastatic cancer cells has been referred to as the 'vicious cycle of bone metastasis' [13] (Figure 1B). IL-11, normally produced by bone marrow stromal cells and osteoblasts, is an important regulator of hematopoiesis and a potent promoter of osteoclast formation. PloS one. Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. The bone microenvironment. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. The majority of breast cancer metastases ultimately cause bone loss. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. J Natl Compr Canc Netw. 2008, Washington, DC: American Society for Bone and Mineral Research, 374-378. full_text. RANKL clearly holds the key to the osteolytic process. IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. It is required to drive mesenchymal cells to become osteoblasts. American Society of Clinical Oncology Bisphosphonates Expert Panel. California Privacy Statement, Osteocytes are terminally differentiated osteoblasts that become embedded in the bone matrix at the end of the deposition phase of remodeling. Osteocytes may act as mechanosensing cells and initiate the process when microfractures and loading are involved. It is common to find increased PTHrP serum levels in breast cancer patients. In people with breast and prostate cancer, the bone is often the first distant site of cancer spread. and transmitted securely. 2006, 1092: 385-396. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Denosumab (Prolia), the latest drug to enter the field, is a monoclonal antibody to RANKL. 10.1158/0008-5472.CAN-08-4437. Bone. 2009, 13: 355-362. Nevertheless, the inaccessibility, opacity and size of the skeleton make it difficult to study even in laboratory animals. 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. 2010, 70: 1835-1844. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. The osteoclasts work as part of the bone remodeling compartment, underneath a canopy of bone lining cells. Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. Bone is the most common site of metastasis for breast cancer. The site is secure. 2010, 8: 159-160. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. The cells that have spread to the bone are breast cancer cells. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. 2004, 21: 427-435. Lung cancer is the third most common site of origin of metastatic cancer deposits in bone, after breast and prostate 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. Yang Y, Ren Y, Ramani VC, Nan L, Suva LJ, Sanderson RD: Heparanase enhances local and systemic osteolysis in multiple myeloma by upregulating the expression and secretion of RANKL. Bisphosphonates binding to hydroxyapatite are ingested by osteoclasts and cause their apoptosis. Br J Cancer. 2000, 1: 331-341. 10.1056/NEJMe1010459. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. In the process, growth factors stored in the matrix, such as transforming growth factor (TGF)-, vascular endothelial growth factor (VEGF), insulin-like growth factors (IGFs), bone morphogenic proteins and fibroblast-derived factors, as well as calcium, are released into the bone microenvironment. 10.1002/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I. 2010, 87: 401-406. 2010, 2: 907-915. Breast cancer cells also cause inhibition of osteoblast differentiation and adhesion, downregulation of collagen synthesis and increased osteoblast apoptosis. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. 2010. CAS 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. 2019 Nov 29;21(1):130. doi: 10.1186/s13058-019-1220-2. Roy DL, Pathangey LB, Tinder TL, Schettini JL, Gruber HE, Mukherjee P: Breast-cancer-associated metastasis is significantly increased in a model of autoimmune arthritis. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. official website and that any information you provide is encrypted Understanding the mechanisms of osteolysis should be the key to designing the cure. 1973, 28: 316-321. Clipboard, Search History, and several other advanced features are temporarily unavailable. In advanced disease, bone formation is essentially absent, and the processes of bone resorption and formation become uncoupled. In this context, RANKL increases in the presence of inflammatory agents from infectious organisms, such as lipopolysaccharide, CpGpDNA and viral double-stranded DNA [41]. Mastro AM, Vogler EA: A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. What can be done to stop osteolytic metastasis? Where do the MMPs come from? 10.1359/jbmr.060610. COX-2 activity in breast cancer cells has also been found to modulate the expression and activity of MMPs. The ratio of RANKL to OPG determines the extent of the osteoclast activity and bone degradation. 2001, 37: 106-113. Biochem Biophys Res Commun. The mechanisms for suppressed osteoblast activity are not clear but Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, is believed to inhibit osteoblast differentiation [29]. sharing sensitive information, make sure youre on a federal 2010, 70: 8329-8338. 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. Breast cancer-derived factors facilitate osteolytic bone metastasis. The presence of tumor cells in the bone microenvironment perturbs the balance between osteoblasts and osteoclasts, leading to excess bone loss or formation. It is impossible to understand the growth and progression of cancer cells in the bone marrow without consideration of the interaction between osteoblasts and osteoclasts. However, breast cancer cells are unable to progress in bone unless they destroy bone with the assistance of bone-resorbing osteoclasts. Department of Biochemistry and Molecular Cell Biology, The Pennsylvania State University, University Park, PA, 16802, USA, Yu-Chi Chen,Donna M Sosnoski&Andrea M Mastro, You can also search for this author in Their function is not clear except that their retraction is necessary for bone resorption to begin [10]. 10.1158/1078-0432.CCR-05-1806. It is estimated that 85% of individuals with advanced disease harbor bone metastases [1]. In the bone, OPN is involved in the differentiation and activity of osteoclasts, and inhibition of mineral deposition in the osteoid [37]. A large-scale 2017 study of the 10 most common cancers with bone metastasis found: Lung cancer had the lowest 1-year survival rate after bone metastasis (10 percent). Evidence to support the concept that there is an intimate relationship between breast cancer cells and osteoclasts is described using an in vivo bone metastasis model in which human breast cancer cells are inoculated into the left ventricle of nude mice. 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Deann Simmons Halper,