10.1007/s10585-004-1867-6. 10.1016/S8756-3282(03)00086-3. They also are regulators of other molecules important in the vicious cycle. 10.1016/j.yexcr.2007.09.021. 2007, 67: 9542-9548. 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. Epidemiological studies have also correlated the increase in breast cancer rates with decreasing sunlight exposure. Other molecules made by multiple myeloma cells, such as IL-3, IL-7 and soluble frizzle-related protein-2, also inhibit osteoblast differentiation [27]. In the bone, OPN is involved in the differentiation and activity of osteoclasts, and inhibition of mineral deposition in the osteoid [37]. 2006, 6: 181-10.1186/1471-2407-6-181. Endocrinology. The normal processes of bone resorption and formation are remarkably well balanced. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM: Molecular mechanisms of breast cancer metastases to bone. 2003, 3: 537-549. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. 10.1196/annals.1365.035. We present therapeutic options for bone metastasis using a multidisciplinary approach. 10.1210/er.19.1.18. More than 2 out of 3 breast and prostate cancers that . IGF, insulin-like growth factor; MCP-1, monocyte chemotactic protein-1; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. Bookshelf Article 2010, 87: 401-406. Thus, cathepsin K is a key molecule not only in osteoclastic breakdown of collagen but also in angiogenesis and production of proinflammatory cytokines. While they are categorized into functional groups, it should be noted that many of these factors are multifunctional and must be considered within the context of the bone remodeling system as a whole. Bookshelf 8600 Rockville Pike Part of this uncertainty is because we do not fully understand all of the cell, cytokine and growth factor interactions that occur in the bone microenvironment. It has high affinity for type I collagen, the most abundant matrix protein. Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. CAS 2005, 92: 1531-1537. Cancer Cell. 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]. In the final stages of metastatic osteolytic breast cancer disease, the cancer cells, fueled by growth factors released from the degraded matrix, expand unchecked. 2000, 1: 331-341. Coleman R, Gnant M: New results from the use of bisphosphonates in cancer patients. Would you like email updates of new search results? Due to this, the bones get harder and cause the condition called sclerosis. It promotes growth and survival of tumor cells [61], and is also involved in osteoclast differentiation. Osteomimetic factors include osteopontin (OPN), osteocalcin, osteonectin, bone sialoprotein, RANKL and PTHrP. Guise [18] demonstrated that increasing the expression of PTHrP in cancer cells enhanced osteolytic lesions in vivo, while decreasing the expression reduced the number and size of lesions. It can contribute to tumor cell survival, proliferation, adhesion, and migration. Cancer Res. 2021 Aug;40(34):5314-5326. doi: 10.1038/s41388-021-01931-1. 2002, 13: 62-71. 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. Coenegrachts L, Maes C, Torrekens S, Van Looveren R, Mazzone M, Guise TA, Bouillon R, Stassen JM, Carmeliet P, Carmeliet G: Anti-placental growth factor reduces bone metastasis by blocking tumor cell engraftment and osteoclast differentiation. 2001, 37: 106-113. 10.1056/NEJMoa030847. Methods Mol Biol. J Bone Miner Res. Myeloma cells may also produce RANKL and directly affect osteoclasts [28]. 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. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. Clipboard, Search History, and several other advanced features are temporarily unavailable. The blastic bone lesions are caused when the cancer cells release the fluids. 2005, 208: 194-206. 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. Further stimulation results in large multinuclear cells capable of bone resorption. When treated with neutralizing antibody to PDGF, the osteoblasts assumed normal morphology. 2003, 349: 2483-2494. Denosumab (Prolia), the latest drug to enter the field, is a monoclonal antibody to RANKL. 2006, 85: 584-595. Springer Nature. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. Chen, YC., Sosnoski, D.M. In people with breast and prostate cancer, the bone is often the first distant site of cancer spread. 1984, 235: 561-564. 2007, 6: 2609-2617. In the context of the current discussion, cancer cells may initiate the process. For example, the use of aromatase inhibitors increases the risk for osteoporosis. This article is part of a review series on New pathways of metastasis, edited by Lewis Chodosh. 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]. PDGF can function as a mitogen for cells of mesenchymal origin and possesses chemoattractant properties, making it an important factor in cell proliferation and migration. PubMed . 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. The bone microenvironment. What Are The Symptoms Of Bone Metastasis In Breast Cancer. Cancer Res. Osteocytes are terminally differentiated osteoblasts that become embedded in the bone matrix at the end of the deposition phase of remodeling. Clin Pharmacol Ther. Cancer Res. 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. COX-2 activity in breast cancer cells has also been found to modulate the expression and activity of MMPs. 10.1016/j.rcl.2010.02.014. Unable to load your collection due to an error, Unable to load your delegates due to an error. volume12, Articlenumber:215 (2010) -, Proc Natl Acad Sci U S A. 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. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. eCollection 2022 Dec. Edwards CM, Clements ME, Vecchi LA 3rd, Johnson JA, Johnson RW. Osteoblasts and bone stromal cells can respond to a variety of substances that upregulate RANKL. official website and that any information you provide is encrypted Eventually, bone remodeling ceases as both osteoblasts and osteoclasts are lost. The results of an in vivo study showed that OPN-deficient mice showed significantly reduced bone metastasis [38]. 10.1210/en.142.12.5050. The https:// ensures that you are connecting to the 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. Mercer RR, Miyasaka C, Mastro AM: Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. Google Scholar. SPARC cleavage also coincides with an increase in inflammatory cytokines such as IL-6 and IL-8 [51]. Exp Cell Res. Matrix degradation appears to be only one of the roles of MMPs. It can activate both Smad-dependent and Smad-independent signal pathways to induce preosteolytic factors such as PTHrP [23]. Runx2 downregulates proliferation and induces p21, RANKL, MMP2, MMP9, MMP13, VEGF, OPN, bone sialoprotein and PTHrP protein expression to promote osteoblast differentiation, bone development and turnover [39]. Pharmaceuticals. Neutralization of TGF- in conditioned medium from human metastatic MDA-MB-231 breast cancer cells permitted the differentiation of osteoblasts in culture, suggesting that TGF- negatively affects osteoblasts while promoting growth of the metastatic cells [33]. Purpose: This is a study in adult patients with different types of cancer. -, Cell. 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). Another growth factor sequestered in the matrix is IGF. Myeloma cells produce factors that upregulate osteoblast production of M-CSF and RANKL and downregulate production of OPG. J Cell Biochem. 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. Raica M, Anca M: Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. There are conflicting reports regarding their effect on osteoblasts. There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. 2009, 11: R56-10.1186/bcr2345. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, Blair HC, Roodman GD: Osteoclasts are important for bone angiogenesis. Lynch CC: Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Once activated the large multinucleated osteoclasts attach to the bone surface creating a resorption lacuna, a sealed zone in which acid and proteolytic enzymes, such as cathepsin K, are released and degrade the bone matrix. These cells fuse to form multinucleated, but non-functional pre-osteoclasts. For example, a hydroxyapatite scaold pre-loaded with bone morphogenetic protein-2 enhanced the growth rate of mammary tumor cells in the scaold [77]. 2010, 70: 412-424. Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. 10.1097/COC.0b013e3181deb9e5. Cancer Res. However, PTHrP does not directly stimulate osteoclast differentiation, but rather stimulates other cells to increase RANKL and decrease OPG production. PubMedGoogle Scholar. Article Bussard KM, Venzon DJ, Mastro AM: Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. Clusters of osteoblasts produce osteoid, composed of collagen, osteonectin, chondroitin sulfate and other non-mineral molecules, which matures and is then mineralized over several months [12]. Miao W, Ti Y, Lu J, Zhao J, Xu B, Chen L, Bao N. Front Chem. prostate = blastic/sclerotic . Other cells of the osteoblastic lineage include bone lining cells and osteocytes. 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. Cookies policy. 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. government site. Part of 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. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. break). American Society of Clinical Oncology Bisphosphonates Expert Panel. Recently, we have found that metastatic breast cancer cells have profound effects on osteoblasts in culture [22] and in animals [31, 32]. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. Osteo-blasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL that curtails osteoclast activation. (B) Metastatic breast cancer cells in the bone microenvironment secrete parathyroid hormone-related protein (PTHrP), cytokines and growth factors that negatively impact osteoblast function. Ann N Y Acad Sci. Google Scholar. Mundy GR, Sterling JL: Metastatic solid tumors to bone. This loss is more precipitous in women, due to the decrease in estrogen at menopause [3]. Of the bisphosphonates, zoledronic acid is the most potent. While some of the growth factors produced by breast and prostate cancers may be different, ultimately they engage the bone re-modeling process. Breast cancer bone metastases: pathogenesis and therapeutic targets. Because of its significant role, TGF- has been a tempting therapeutic target. 2012 Aug;39(8):1174-7. 2005, 5 (Suppl): S46-53. Correspondence to Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. Thus, the ratio of RANKL to OPG is critical for osteoclast activation. 10.1038/35036374. In males, prostate and lung cancers make up 80% of carcinomas metastasizing to bone. Recently, Roy and colleagues [69] investigated this association in a mouse model of autoimmune arthritis and found that arthritic mice had an increase in both lung and bone metastasis compared to the non-arthritic mice. 2010. The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. Clin Adv Hematol Oncol. 10.1016/j.ctrv.2008.03.008. Studies with MMP9-null mice indicate its importance in tumor progression in ovarian cancer, prostate cancer and bone metastasis [56]. To date, osteoclasts have been the primary target of drug therapies. Gradient Boosting Machine Identified Predictive Variables for Breast Cancer Patients Pre- and Post-Radiotherapy: Preliminary Results of an 8-Year Follow-Up Study. 2009, 175: 1255-1269. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFB ligand) and several osteoclastogenic cytokines. Ohshiba T, Miyaura C, Ito A: Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. Bone remodeling is often described as a cycle beginning with bone degradation and ending with bone deposition (Figure 1A). 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. 2022 Jul 20;14(14):3521. doi: 10.3390/cancers14143521. 1999, London: Martin Dunitz Ltd. Raisz LG, Mundy GR, Luben RA: Skeletal reactions to neoplasms. With rare exceptions, cancer that has spread to the bones can't be cured. Clinical Characteristics, Prognostic Factors and Treatment Outcomes of Patients with Bone-Only Metastatic Breast Cancer. When the bone loss is extensive, the osteoblasts are absent from the lesion [32]. Bone. PubMed Central Abstract Metastasis of breast cancer cells to bone consists of multiple sequential steps. Estrogen has also been shown to promote osteoclast apoptosis and inhibit activation of mature osteoclasts. 2010, 36: 615-620. In doing so, cancer cells are equipped to home, adhere, survive and proliferate in the bone microenvironment. Lerner UH: Bone remodeling in post-menopausal osteoporosis. Once osteoblasts finish bone deposition, they undergo apoptosis, remain in the matrix as osteocytes or revert to thin bone-lining cells. 2000 Mar;18(6):1378-91. doi: 10.1200/JCO.2000.18.6.1378. Metastases leading to overall bone loss are classified as osteolytic. Rodrguez-Toms E, Arenas M, Baiges-Gaya G, Acosta J, Araguas P, Malave B, Casta H, Jimnez-Franco A, Benavides-Villarreal R, Sabater S, Sol-Alberich R, Camps J, Joven J. Antioxidants (Basel). The presence of metastatic lesions in bone disrupts the normal bone microenvironment and upsets the fine balance between the key components. Current therapeutic targets are indicated in green. 1993 Jun 1;90(11):5021-5 The clinical outcomes of bone pain, pathologic fractures, nerve compression syndrome, and metabolic disturbances leading to hypercalcemia and acid/base imbalance severely reduce the quality of life [3]. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. In reality the system is much more complex (Table 1). It's not the same as having cancer that starts in the bone. 2006, 12: 1431-1440. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. Cancer Res. Other drugs on the horizon target TGF-, and cathepsin K. Various approaches, including kinase inhibitors, ligand-neutralizing antibodies and anti-sense molecules, are being investigated [33]. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. While the case for the importance of MMPs as metastasis regulators is strong, they themselves are regulated by tissue inhibitors of metalloproteinase (TIMPs). 10.1158/0008-5472.CAN-07-1046. Metastasis of breast cancer cells to bone consists of multiple sequential steps. Bone metastases are areas of cancer that develop when breast cancer cells travel to the bones. However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. PTHrP, one of many proteins controlled by Runx2, is a major effector in breast cancer bone metastasis progression and bone loss. 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. eCollection 2022. PubMed Central Several of these molecules are related to the recruitment and differentiation of osteoclasts; some are prominent players in the vicious cycle. 2008, Washington, DC: American Society for Bone and Mineral Research, 374-378. full_text. This release of fluids and substances soon turns on the osteoblasts, which leads to the formation of new bone. 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]. Google Scholar, Mundy GR: Bone Remodeling and its Disorders. 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. 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. MMP-9 is important in the cascade leading to activation of VEGFA. COX-2 inhibition also partially attenuated the ability of two breast cancer cell lines to degrade and invade extracellular matrix components such as laminin and collagen [47]. Surprisingly, this treatment did not affect angiogenesis in the bone. The PGE2-mediated production of RANKL induces osteoclastogenesis via RANK. 1998, 19: 18-54. Teriparatide, in contrast to bisphosphonates and denosumab, acts on osteoblasts to stimulate bone formation. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. Federal government websites often end in .gov or .mil. As might be expected from the nature of the osteolytic process, that is, the degradation of bone, the microenvironment contains many proteases. Kinder M, Chislock E, Bussard KM, Shuman L, Mastro AM: Metastatic breast cancer induces an osteoblast inflammatory response. 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Cox-2 activity in breast cancer Identified Predictive Variables for breast cancer patients Pre- and Post-Radiotherapy: Preliminary of! With Bone-Only Metastatic breast cancer well balanced osteoblasts finish bone deposition, they undergo apoptosis, in! A critical role in cancer patients with decreasing sunlight exposure, Vecchi LA 3rd, RW. Is critical for osteoclast activation tumors to bone metastasis progression and bone metastasis progression and metastasis pubmed Central of..., Shuman L, Mastro AM: Metastatic solid tumors to bone consists of multiple sequential.. Is a monoclonal antibody to RANKL that curtails osteoclast activation N, brook E, Bussard KM Shuman! Society for bone metastasis 38 ] adhesion, and several other advanced features are unavailable. 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