2006, 12: 1431-1440. Other molecules made by multiple myeloma cells, such as IL-3, IL-7 and soluble frizzle-related protein-2, also inhibit osteoblast differentiation [27]. The https:// ensures that you are connecting to the 2005, 310: 270-281. 2010. Br J Cancer. Federal government websites often end in .gov or .mil. Br J Cancer. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. Estrogen has also been shown to promote osteoclast apoptosis and inhibit activation of mature osteoclasts. 10.1016/j.abb.2008.02.030. 2001, 285: 335-339. By using this website, you agree to our Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. It can activate both Smad-dependent and Smad-independent signal pathways to induce preosteolytic factors such as PTHrP [23]. Edited by: Rosen CL. Clinical studies of newly diagnosed breast cancer patients have revealed that high bone turnover correlates with a higher risk of skeletal complications [62]. Epub 2015 Dec 4. Clinical Characteristics, Prognostic Factors and Treatment Outcomes of Patients with Bone-Only Metastatic Breast Cancer. Osteoblasts derive from mesenchymal stem cells in the marrow under control of Runx2, a key osteoblastic transcription factor. quiz S30, CAS HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer. Stopeck A: Denosumab findings in metastatic breast cancer. Andrea M Mastro. 2018 Mar;96:63-78. doi: 10.1016/j.biocel.2018.01.003. 2 Of interest is that patients with blastic (versus osteolytic) bone metastases have been reported to have prolonged survival. 10.1016/j.yexcr.2005.07.029. Here we discuss some of the proposed mechanisms that contribute to metastatic breast cancer-induced bone loss. Both RANKL and VEGF can induce osteoclast formation [48], and MMPs play a role in bone matrix degradation. Bisphosphonates binding to hydroxyapatite are ingested by osteoclasts and cause their apoptosis. 10.1038/onc.2009.389. spinal cord compression) palpable mass deformity pathological fracture hypercalcemia bone marrow aplasia For example, a hydroxyapatite scaold pre-loaded with bone morphogenetic protein-2 enhanced the growth rate of mammary tumor cells in the scaold [77]. Unable to load your collection due to an error, Unable to load your delegates due to an error. This feature accounts for the variable sensitivity and specificity of different imaging modalities. Cell Tissue Res. Front Biosci (Schol Ed). 2007, 24: 599-608. Biochem Biophys Res Commun. . COX-2 activity in breast cancer cells has also been found to modulate the expression and activity of MMPs. There is evidence that bisphosphonates also contribute to tumor cell death, especially in combination with chemotherapy [72]. 10.1158/0008-5472.CAN-08-4437. Clin Exp Metastasis. 10.1007/s10911-005-5399-8. HHS Vulnerability Disclosure, Help blastic (bone formation), or mixed lesions (Fig 2). Google Scholar. Identification of a stimulator or protector of osteoblasts would be a major improvement in treatment for osteolytic breast cancer as well as other diseases of bone loss. Chemotherapy may bring about ovarian failure and premature menopause [1]. 10.1177/154405910608500703. Cancer. The main symptoms of breast cancer that has spread to bone are: Lefley D, Howard F, Arshad F, Bradbury S, Brown H, Tulotta C, Eyre R, Alfrez D, Wilkinson JM, Holen I, Clarke RB, Ottewell P. Breast Cancer Res. TGF- is one of the most prominent. Those leading to excess bone deposition are considered osteoblastic. Halpern J, Lynch CC, Fleming J, Hamming D, Martin MD, Schwartz HS, Matrisian LM, Holt GE: The application of a murine bone bioreactor as a model of tumor: bone interaction. Article In addition, other cells not specific for bone but likely to be found in the bone (macrophages, neutrophils and T lymphocytes) produce MMPs. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. Clin Exp Metastasis. Bone metastasis may be the first sign that you have cancer, or bone metastasis may occur years after cancer treatment. 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]. Breast cancer bone metastases: pathogenesis and therapeutic targets. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. 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. Cancer Cell. PGE2 is associated with inflammation, cell growth, tumor development and metastasis [42]. It has high affinity for type I collagen, the most abundant matrix protein. 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. Radiol Clin North Am. Laufer I, Lis E, Pisinski L, Akhurst T, Bilsky MH. Inflammation associated with bone fractures and arthritic joints has been anecdotally associated with the appearance of bone metastasis, often many years after the primary tumor has been treated. There is also evidence that molecules in conditioned medium from PC-3 cells alone [34], or from both PC-3 cells and MC3T3-E1 osteoblasts [35], promote osteoclastogenesis. Their multifunctionality demonstrates their importance. While the case for the importance of MMPs as metastasis regulators is strong, they themselves are regulated by tissue inhibitors of metalloproteinase (TIMPs). Proteolytic cleavage of SPARC releases biologically active cleavage products that affect angiogenesis factors such as VEGF, platelet-derived growth factor (PDGF) and FGF-2. Interestingly, many osteomimetic factors are regulated by the same transcription factor, Runx2, considered to be the major regulator of osteoblast commitment and differentiation [39]. Feng X, McDonald JM: Disorders of bone remodeling. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. It was recently reported that mice deficient in vitamin D or calcium showed increased metastatic tumor growth and accelerated rates of bone resorption [66, 67]. 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, 6: 181-10.1186/1471-2407-6-181. Clin Exp Metastasis. Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. Am J Clin Oncol. Home; Study Search; Study Details From Other Databases Furthermore, the molecules activated by MMPs also have counter molecules creating a network of accelerators and decelerators centered around MMPs. Akech and colleagues [34] recently reported that Runx2 (Runt-related transcription factor 2) is produced by the highly metastatic prostate cancer cell PC-3, and positively correlates to the severity of osteolytic disease. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD: The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. PubMed Central 1988 Jun;7(2):143-88 Thus, the ratio of RANKL to OPG is critical for osteoclast activation. 2022 Jul 20;14(14):3521. doi: 10.3390/cancers14143521. It is estimated that osteolytic lesions occur in 60 to 95% of myeloma patients [1, 27]. 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. Breast cancer cells also cause inhibition of osteoblast differentiation and adhesion, downregulation of collagen synthesis and increased osteoblast apoptosis. 2022 Aug 23;14:2519-2531. doi: 10.2147/CMAR.S369910. Lipton A: Bone continuum of cancer. Once breast cancer cells arrest in bone, bone is a storehouse of a variety of cytokines and growth factors and thus provides an extremely fertile environment for the cells to grow. 2005, 24: 2543-2555. Smolle MA, Musser E, Bergovec M, Friesenbichler J, Wibmer CL, Leitner L, Srensen MS, Petersen MM, Brcic I, Szkandera J, Scheipl S, Leithner A. 1974, 230: 473-475. Before EMBO J. However, cathepsin K is also produced by other cells in the bone microenvironment, such as macrophages and bone marrow stromal cells. California Privacy Statement, Breast Cancer Res 12, 215 (2010). Several groups have developed in vivo models in which bone or bone substitutes are implanted in animals. The dynamics of this system are interrupted when metastatic breast cancer cells are introduced, adding another layer of active molecules to the bone environment. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. In middle aged and elderly women, calcium and/or vitamin D deficiencies are quite common, as is the incidence of breast cancer [65]. Osteoblastic or blastic metastases cause an area of the bone to look denser or sclerotic. Marie L, Braik D, Abdel-Razeq N, Abu-Fares H, Al-Thunaibat A, Abdel-Razeq H. Cancer Manag Res. Aldridge SE, Lennard TW, Williams JR, Birch MA: Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. The blastic bone lesions are caused when the cancer cells release the fluids. While some of the growth factors produced by breast and prostate cancers may be different, ultimately they engage the bone re-modeling process. In the next step, preosteoblasts are recruited from the mesenchymal stem cell population and differentiate into osteoblasts. Radiotracer is taken up only by activated osteoblasts and as such, bone scans are quite often negative even with extensive skeletal involvement by myeloma [ 5 ]. Lytic lesions should have radiologic evidence of calcication . Metastatic breast cancer cells tend to spread to the bones more often than they do to other parts of the body. Understanding the mechanisms of osteolysis should be the key to designing the cure. Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. 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. This approach will allow testing of components and drugs in a model less complex than an animal but more relevant than standard tissue culture. Clipboard, Search History, and several other advanced features are temporarily unavailable. The resorption phase of the process begins with recruitment of pre-osteoclasts that differentiate into activated osteoclasts under the direction of osteoblasts (Figure 1A). (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. Exp Cell Res. For females, breast and lung are the most common primary sites ; nearly 80% of cancers that spread to the skeleton are from these locations. 2009, 7 (Suppl 7): S1-29. While the outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics early in the process. Ganapathy V, Ge R, Grazioli A, Xie W, Banach-Petrosky W, Kang Y, Lonning S, McPherson J, Yingling JM, Biswas S, Mundy GR, Reiss M: Targeting the transforming growth factor-beta pathway inhibits human basal-like breast cancer metastasis. PubMed However, more accessible and defined [76] models are needed. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. 10.1182/blood-2009-08-237628. Clin Cancer Res. Keywords: This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. Bendre M, Montague DC, Peery T, Akel NS, Gaddy D, Suva LJ: Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. 2010, 115: 140-149. 1998, 19: 18-54. Bone. PubMed Because of its significant role, TGF- has been a tempting therapeutic target. 2008, 314: 173-183. Kang JS, Alliston T, Delston R, Derynck R: Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. official website and that any information you provide is encrypted Thus, cathepsin K is a key molecule not only in osteoclastic breakdown of collagen but also in angiogenesis and production of proinflammatory cytokines. Although the mechanisms of osteoteoblastic and osteolytic responses are not fully understood, it is clear that many factors involved in osteolytic breast cancer bone metastasis also regulate the osteolytic aspects of prostate cancer. It's the most advanced stage of breast cancer. Chronic inflammation has long been considered a risk factor in cancer initiation [68]. In a recent comprehensive review article, Lynch [50] presents the case that they are 'master regulators' of the vicious cycle. Once osteoclasts are activated, they degrade bone matrix through several proteolytic enzymes, including MMPs and cathepsin K. Although cathepsin K is the major bone resorbing protease, MMPs, which are secreted by many cells, may be the 'master regulator' of the entire mechanism. In doing so, cancer cells are equipped to home, adhere, survive and proliferate in the bone microenvironment. 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 CA Cancer J Clin. Osteo-blasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL that curtails osteoclast activation. PubMed A thorough review of bone remodeling is beyond the scope of this article, and there are several excellent, recent reviews [8, 9]. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. In summary, all of these factors contribute to propagating the vicious cycle and increasing osteolysis (Figure 1B). 10.1056/NEJMe1010459. Arch Biochem Biophys. CAS Clipboard, Search History, and several other advanced features are temporarily unavailable. N Engl J Med. It improves the quality of life by preventing fractures but does not prolong life [73]. 10.1111/j.1749-6632.1974.tb14480.x. Of the bisphosphonates, zoledronic acid is the most potent. Cancer cells, osteoblasts, osteoclasts and endothelial cells produce MMPs. J Mammary Gland Biol Neoplasia. However, breast cancer cells are unable to progress in bone unless they destroy bone with the assistance of bone-resorbing osteoclasts. Provided by the Springer Nature SharedIt content-sharing initiative. When treated with neutralizing antibody to PDGF, the osteoblasts assumed normal morphology. Annu Rev Pathol. Cells of the osteoblast lineage are derived from mesenchymal stem cells, and are represented in this unit by osteoblasts, bone lining cells and osteocytes. While drugs that inhibit osteoclast differentiation or activity are vital to treating osteolysis, therapies designed to restore osteoblast number and function will be required to fully resolve osteolytic lesions. The majority of breast cancer metastases ultimately cause bone loss. Rucci N, Teti A: Osteomimicry: how tumor cells try to deceive the bone. Cancers (Basel). 10.1158/0008-5472.CAN-09-2758. Mouse Models of Tumor Bone Metastasis and Invasion for Studying CCN Proteins. -. 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. 10.1158/0008-5472.CAN-09-4092. Clinical evidence indicates that this drug can reduce the rate of bone loss, but is not curative. Bone. 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. -, Science. Many metastatic breast cancer cell lines have been found to also secrete PDGF, which has a strong impact on osteoblast development. In addition, PDGF has been shown to inhibit osteoblast differentiation [60], making it an important factor in bone remodeling and the osteolytic bone metastasis. 2010, 70: 6537-6547. The role of lining cells. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. Due to this, the bones get harder and cause the condition called sclerosis. Bussard KM, Venzon DJ, Mastro AM: Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. 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. HHS Vulnerability Disclosure, Help Clin Oral Investig. The https:// ensures that you are connecting to the Grey A: Teriparatide for bone loss in the jaw. These factors can stimulate the tumor cells to proliferate and produce more growth factors and more PTHrP, further perpetuating the vicious cycle of bone metastasis. Raica M, Anca M: Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. We are in the process of adding osteoclasts to the system to create a rudimentary in vitro bone remodeling unit. It can contribute to tumor cell survival, proliferation, adhesion, and migration. Bone metastases are areas of cancer that develop when breast cancer cells travel to the bones. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD: Role of IGF-I signaling in regulating osteoclastogenesis. Powles TJ, Clark SA, Easty DM, Easty GC, Neville AM: The inhibition by aspirin and indomethacin of osteolytic tumor deposits and hypercalcaemia in rats with Walker tumour, and its possible application to human breast cancer. Mastro AM, Vogler EA: A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. In people with breast and prostate cancer, the bone is often the first distant site of cancer spread. 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. PTH/PTHrP, TNF-, prostaglandins (PGE2), IL-1, IL-11, FGF-2, and IGF-1 have been reported to increase RANKL production. Even in adults it is estimated that about 10% of the bone is renewed each year [7]. At least three major growth factors sequestered in the matrix are activated by MMPs. Because osteoblasts secrete both RANKL and OPG, they are major mediators of osteoclastogenesis [25]. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. 10.1016/S0959-8049(00)00363-4. J Dent Res. Would you like email updates of new search results? 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]. The entry of breast cancer cells into the bone micro-environment synergistically increases the complexity of cell-cell interactions. 2010, 29: 811-821. Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. Orr and colleagues [5] have determined MMPs sufficient to resorb bone in vitro and to contribute to the process in vivo. There is evidence in both humans and animals that bone loss in osteolytic metastasis is partly due to the failure of the osteoblasts to produce new osteoid for the bone matrix. In the late 1980 s, PTHrP was linked to hypercalcemia in several cancers, providing evidence that PTHrP was involved in bone resorption. Methods Mol Biol. Mol Cancer Ther. 1973, 28: 316-321. It is now known that PGE2 signaling through its receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form mature osteoclasts. Nevertheless, the inaccessibility, opacity and size of the skeleton make it difficult to study even in laboratory animals. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Ann N Y Acad Sci. However, this approach has not entirely solved the problem. According to this paradigm, the tumor cells produce a variety of growth factors, most notably parathyroid hormone-related protein (PTHrP) [18]. Verbruggen ASK, McCarthy EC, Dwyer RM, McNamara LM. 2003, 89: 2031-2037. HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. The osteoclasts work as part of the bone remodeling compartment, underneath a canopy of bone lining cells. Bookshelf Google Scholar. 10.1158/1535-7163.MCT-08-0153. As pointed out by Lynch, the spatial and temporal expression of these molecules is of utmost importance. 2003, 349: 2483-2494. Cancer cells also can elicit an increase in osteoblast production of several other osteoclastogenic cytokines, such as monocyte chemotactic protein-1 (MCP-1) and IL-6, IL-8 and TNF [22]. 7. N Engl J Med. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. It is estimated that 85% of individuals with advanced disease harbor bone metastases [1]. 2009, 13: 355-362. Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases. Thus, the capacity of breast cancer cells to collaborate with osteoclasts is likely to be specific and is likely critical for them to cause osteolytic bone metastases. Evidence from an intratibial bone metastasis model indicates that when highly aggressive metastatic MDA-MB-231 cells express dysfunctional Runx2 or small hair-pin RNA for Runx2, both osteoclastogenesis and osteolytic lesions decrease [40]. Troen BR: Molecular mechanisms underlying osteoclast formation and activation. What can be done to stop osteolytic metastasis? In many cases, osteolytic and osteoblastic changes occur simulta-neously.28 Up to half of all bone metastases from breast cancer tend to show osteolytic changes.5,7,29-31 However, because all types of bone metastases show . FOIA There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. FOIA 2012 Aug;39(8):1174-7. These types of tumors are called osteolytic, or simply lytic. An official website of the United States government. 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). In patients with lytic or mixed lytic/blastic from solid tumor metastases, there was a 100% concordance between FDG-PET and needle biopsy when using an SUV cutoff of 2 33 33 . Metastases leading to overall bone loss are classified as osteolytic. Clin Pharmacol Ther. 1999, London: Martin Dunitz Ltd. Raisz LG, Mundy GR, Luben RA: Skeletal reactions to neoplasms. Cancer. However, both drugs are associated with low incidence of osteonecrosis of the jaw [75]. Research in the Mastro Laboratory has been funded by grants from the US Army Medical and Materiel Command Breast Cancer Research Program (DAMD 17-02-1-0358, W81XWH-06-1-0432, W81XWH-08-1-0488, W81XWH-06-0363), The Susan G Komen Breast Cancer Foundation (BCTR0601044 and BCTR104406), and with supplementary aid from the National Foundation for Cancer Research, Center for Metastasis Research. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. In addition, pre-clinical trials with agents that target cathepsin K, certain matrix metalloproteinases (MMPs), and transforming growth factor (TGF)- are underway. 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