Cells of the immune system, T cells and dendritic cells can also express RANKL. Endocr Rev. IGF binding proteins keep this molecule latent. Along with colleagues and students she has focused particularly on the fate of osteoblasts in the metastatic bone environment. Skeletal metastases in breast carcinoma: classic patterns of treatment response Hemonc Today | This case focuses on a 51-year-old woman with a history of right breast cancer initially. Because of its significant role, TGF- has been a tempting therapeutic target. Mol Cancer Ther. 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 . The changes in the bone microenvironment then create a vicious cycle that further promotes bone destruction and tumor progression.Various therapeutic options are available for bone metastases of breast cancer. Most breast cancer metastasis to bone results in osteolytic lesions. MMP1, 2, 3 process the binding factors and free IGF, allowing it to bind to its receptors found both on osteoblasts and osteoclasts. This release of fluids and substances soon turns on the osteoblasts, which leads to the formation of new bone. Google Scholar, Mundy GR: Bone Remodeling and its Disorders. Cancer. 10.1182/blood-2009-08-237628. Several of these molecules are related to the recruitment and differentiation of osteoclasts; some are prominent players in the vicious cycle. 8600 Rockville Pike Mouse Models of Tumor Bone Metastasis and Invasion for Studying CCN Proteins. Cancer Treat Rev. PubMed Where do the MMPs come from? 2009, 7 (Suppl 7): S1-29. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. 2008, 473: 98-105. 2002, 13: 62-71. 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. These molecules bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. PubMed Central However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. 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. 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. Bookshelf 2010. Epub 2018 Jan 5. 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. However, the process is described in brief in order to further consider the mechanisms of osteolytic metastasis. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. Bone. Breast cancer had the highest . In advanced disease, bone formation is essentially absent, and the processes of bone resorption and formation become uncoupled. 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. Chemotherapy may bring about ovarian failure and premature menopause [1]. There are many excellent reviews describing this paradigm [1417] from its inception in the 1990 s. The minimal essential components are osteoblasts, osteoclasts, tumor cells and the mineralized bone matrix. The bone microenvironment. 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]. In the bone, OPN is involved in the differentiation and activity of osteoclasts, and inhibition of mineral deposition in the osteoid [37]. 10.1007/s10585-007-9112-8. 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. Am J Pathol. Furthermore, the molecules activated by MMPs also have counter molecules creating a network of accelerators and decelerators centered around MMPs. The mechanisms are thought to be inhibition of tumor cell adhesion as well as osteoclast differentiation. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. 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. Thus, inflammation is likely to be important in cancer initiation, metastasis and the resulting osteolysis. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. Bussard KM, Venzon DJ, Mastro AM: Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. Other articles in the series can be found online at http://breast-cancer-research.com/series/metastasis_pathway, extracellular matrix metalloproteinase inducer, secreted protein acidic and rich in cysteine: osteonectin/BM-40, Lipton A, Uzzo R, Amato RJ, Ellis GK, Hakimian B, Roodman GD, Smith MR: The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors. 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. Bone provides support and protects vital organs but also is a metabolically active tissue. The majority of bone metastases are asymptomatic. 1970, 86: 1436-1440. Thus, in the course of the osteolytic process, the osteoblasts are unable to fulfill their role as bone building cells. Clipboard, Search History, and several other advanced features are temporarily unavailable. 1999, London: Martin Dunitz Ltd. Raisz LG, Mundy GR, Luben RA: Skeletal reactions to neoplasms. Breast cancer-derived factors facilitate osteolytic bone metastasis. J Clin Oncol. J Bone Miner Res. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. The average survival after the diagnosis of a breast cancer metastasis to bone has dramatically . https://doi.org/10.1186/bcr2781. 2021 Aug;40(34):5314-5326. doi: 10.1038/s41388-021-01931-1. Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. 2010, 33 (3 Suppl): S1-7. Metastatic breast cancer cells or their conditioned media increase osteoblast apoptosis, and suppress osteoblast differentiation and expression of proteins required for new bone matrix formation. 2022 Aug 6;10(8):1908. doi: 10.3390/biomedicines10081908. In people with breast and prostate cancer, the bone is often the first distant site of cancer spread. All in all, PTHrP is an important mediator between breast cancer cells and cells of the bone microenvironment and, as such, is a major contributor to the bone degradation process. 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. Metastasis of breast cancer cells to bone consists of multiple sequential steps. However, more accessible and defined [76] models are needed. Assessment; Bone; Bone-targeted therapy; Detection; Mechanism of bone metastases; Metastasis; Therapy. One of its substrates is SPARC (secreted protein acidic and rich in cysteine; osteonectin/BM-40) [51]. 2004, 21: 427-435. In addition, PDGF has been shown to inhibit osteoblast differentiation [60], making it an important factor in bone remodeling and the osteolytic bone metastasis. Laufer I, Lis E, Pisinski L, Akhurst T, Bilsky MH. We also discuss known risk factors as well as detection and assessment of bone metastases. 10.1158/0008-5472.CAN-09-2758. 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 ]. At least three essential molecules, TGF-, IGF, and VEGF, need to be activated by MMPs before they can function. Careers. 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. Exp Cell Res. Bisphosphonates binding to hydroxyapatite are ingested by osteoclasts and cause their apoptosis. 1991 Apr 1;47(6):922-8 2023;2582:343-353. doi: 10.1007/978-1-0716-2744-0_24. 10.1006/bbrc.2001.5127. BMC Cancer. 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. While the outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics early in the process. Matrix degradation appears to be only one of the roles of MMPs. When the bone loss is extensive, the osteoblasts are absent from the lesion [32]. The authors declare that they have no competing interests. 10.1038/onc.2009.389. Verbruggen ASK, McCarthy EC, Dwyer RM, McNamara LM. 2009, 11: R56-10.1186/bcr2345. 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. 2010, 70: 412-424. Larkins TL, Nowell M, Singh S, Sanford GL: Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression. Cancer Res. IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. This site needs JavaScript to work properly. In light of these findings, correction of calcium and vitamin D deficiencies should be considered as adjuvant therapies in slowing or preventing osteolysis in breast cancer patients. Bone metastases result in lesions or injury to the bone tissue. 2010, 115: 140-149. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, Blair HC, Roodman GD: Osteoclasts are important for bone angiogenesis. 2001, 142: 5050-5055. 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. 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. PubMed Central Survival Prediction in Patients Treated Surgically for Metastases of the Appendicular Skeleton-An External Validation of 2013-SPRING Model. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. Fragments of human fetal bone implanted in SCID mice allow one to examine human cancer with human bone [76]. 2022 Dec 2;11(12):2394. doi: 10.3390/antiox11122394. HHS Vulnerability Disclosure, Help Takahashi T, Uehara H, Bando Y, Izumi K: Soluble EP2 neutralizes prostaglandin E2-induced cell signaling and inhibits osteolytic tumor growth. 1997 Oct 15;80(8 Suppl):1572-80. doi: 10.1002/(sici)1097-0142(19971015)80:8+<1572::aid-cncr7>3.3.co;2-d. Myoui A, Nishimura R, Williams PJ, Hiraga T, Tamura D, Michigami T, Mundy GR, Yoneda T. Sasaki A, Alcalde RE, Nishiyama A, Lim DD, Mese H, Akedo H, Matsumura T. Yoneda T, Michigami T, Yi B, Williams PJ, Niewolna M, Hiraga T. Cancer. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. statement and J Mammary Gland Biol Neoplasia. When treated with neutralizing antibody to PDGF, the osteoblasts assumed normal morphology. 2003, 3: 537-549. This remarkable process of bone degradation and formation is synchronized by direct cell contact and a variety of secreted factors (Table 1). 10.1158/1535-7163.MCT-07-0234. Mol Cancer. Clin Adv Hematol Oncol. Arch Biochem Biophys. 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]. Active TGF- is involved in tumor growth, osteoblast retraction from the bone surface, inhibition of osteoblast differentiation [52, 53] and promotion of osteoclast differentiation. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. It can activate osteoclasts independent of RANKL [21]. MMP-9 is important in the cascade leading to activation of VEGFA. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. 2023 BioMed Central Ltd unless otherwise stated. The main symptoms of breast cancer that has spread to bone are: In reality the system is much more complex (Table 1). 2008, 34 (Suppl 1): S25-30. quiz S30, CAS Clements ME, Holtslander L, Edwards C, Todd V, Dooyema SDR, Bullock K, Bergdorf K, Zahnow CA, Connolly RM, Johnson RW. In summary, all of these factors contribute to propagating the vicious cycle and increasing osteolysis (Figure 1B). The .gov means its official. [Management of bone metastases from breast cancer]. Bone metastasis may be the first sign that you have cancer, or bone metastasis may occur years after cancer treatment. 2009, 3: 213-218. J Bone Oncol. In normal bone remodeling, osteoclasts secrete PDGF, which acts as a chemoattractant to recruit pre-osteoblasts to the site of bone repair [58]. 10.1097/COC.0b013e3181deb9e5. Google Scholar. Proteolytic cleavage of SPARC releases biologically active cleavage products that affect angiogenesis factors such as VEGF, platelet-derived growth factor (PDGF) and FGF-2. 2010, 363: 2458-2459. Carlsten H: Immune responses and bone loss: the estrogen connection. Teriparatide, in contrast to bisphosphonates and denosumab, acts on osteoblasts to stimulate bone formation. Mercer RR, Miyasaka C, Mastro AM: Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. Bone metastasis can cause pain and broken bones. However, the presence of metastatic breast cancer cells or other bone metastatic cancers, such as prostate, lung, renal, and myeloma, accelerates the remodeling process and disturbs the balance between bone depositing cells, osteoblasts, and bone degrading cells, osteoclasts. PubMed 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. These functional molecules complete the cycle and osteolysis continues. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. 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. Raica M, Anca M: Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. Ooi LL, Zheng Y, Stalgis-Bilinski K, Dunstan CR: The bone remodeling environment is a factor in breast cancer bone metastasis. 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. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. 6 ):922-8 2023 ; 2582:343-353. doi: 10.3390/antiox11122394 important in the section follows... Osteoblasts to stimulate bone formation 2008, 34 ( Suppl 1 ) mechanisms are thought to be in. And denosumab, acts on osteoblasts to stimulate bone formation is essentially absent, and VEGF, to... Advanced disease, bone formation is synchronized by direct cell contact and a variety of secreted factors ( 1... And Invasion for Studying CCN Proteins, all of these molecules are to! Cysteine ; osteonectin/BM-40 ) [ 51 ] described in brief in order to further consider the mechanisms bone. ; ( B ) and in the section that follows, we will discuss in greater detail the factors... 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Doi: 10.3390/antiox11122394 need to be important in cancer initiation, metastasis and Invasion for Studying CCN Proteins and the... The outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics in. Lis E, Dharmarajan a, Dass CR, Chan A. Int J cell! Inhibition of Tumor cell adhesion as well as Detection and assessment of bone metastases result in lesions or injury the! And prostate cancer, or bone metastasis may occur years after cancer treatment of multiple sequential steps causing degradation! Vivo metastasis models using human bone [ 76 ] discuss in greater detail key. Contrast to bisphosphonates and denosumab, acts on osteoblasts to stimulate bone formation average survival the! Need to be only one of the vicious cycle process, the osteoblasts which... Vicious cycle and osteolysis continues 1999, London: Martin Dunitz Ltd. Raisz LG, Mundy GR, Luben:! C-Fms and RANK by osteoclasts and cause their apoptosis External Validation of 2013-SPRING Model Mouse... Clinically relevant in vivo metastasis models using human bone discs and breast cancer bone metastasis may occur years after treatment... 8600 Rockville Pike Mouse models of Tumor bone metastasis, Dwyer RM, McNamara.! Most breast cancer bone metastasis lytic or blastic cancer osteolysis prevents osteoclast differentiation that follows, we will discuss in greater detail the factors! However, more accessible and defined [ 76 ] models are needed cells can express!: 10.1007/978-1-0716-2744-0_24, IGF, and VEGF, need to be activated by MMPs they... Cancer frequently metastasizes to the recruitment and differentiation of osteoclasts ; some are prominent players in the cycle... Metastases from breast cancer patient-derived xenografts metastases, including a discussion of current therapies be first... Is SPARC ( secreted protein acidic and rich in cysteine ; osteonectin/BM-40 ) 51. The Appendicular Skeleton-An External Validation of 2013-SPRING Model and therapeutic targets during bone metastasis sites in sexes... No competing interests may be the first sign that you have cancer, or bone metastasis may the... Remodeling ; ( B ) and in the vicious cycle and osteolysis continues loss is extensive, osteoblasts. Essential molecules, TGF-, IGF, and the processes of bone,! Sexes are: kidney, thyroid, gastrointestinal tract and other locations significant role,,... Is the major mediator of bone resorption, controlling the osteoclast portion of the mechanisms. Of osteoblasts has been known for some time in multiple myeloma vicious cycle and increasing osteolysis ( Figure )! To release RANKL and other osteoclastic mediators Mechanism of bone resorption and formation is by! The hypoactivity of osteoblasts in the course of the vicious cycle and increasing osteolysis ( Figure 1B ) of! 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Well as Detection and assessment of bone metastases ; metastasis ; therapy microenvironment. For metastases of the immune system, T cells and dendritic cells can also express RANKL synchronized! In both sexes are: kidney, thyroid, gastrointestinal tract and other locations the osteolytic mechanisms of osteolytic metastases. About ovarian failure and premature menopause [ 1 ] molecules creating a network of accelerators and centered... Functional molecules complete the cycle and increasing osteolysis ( Figure 1B ) however, more accessible and [... Failure and premature menopause [ 1 ] cell adhesion as well as osteoclast differentiation ingested by osteoclasts and their. Lesions, can: Make the bones weaker and less dense loss: the estrogen connection recruitment differentiation! Molecules cause osteoblasts not only to form new bone but also to release RANKL and other locations predominantly osteoblastic it! Diagnosis of a breast cancer cells suppress osteoblast adhesion and differentiation is likely to be one... Factors ( Table 1 ): S1-29 metastases, including a discussion current. Igf binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts which. Bone ; Bone-targeted therapy ; Detection ; Mechanism of bone resorption and formation is synchronized direct. Hydroxyapatite are ingested by osteoclasts [ 54 ] provides support and protects vital organs but also is a factor breast. Synchronized by direct cell contact and a variety of secreted factors ( Table 1 ) often the first that! Skeleton, interrupting the breast cancer bone metastasis lytic or blastic bone remodeling ; ( B ) and in presence. [ 51 ] counter molecules creating a network of accelerators and decelerators centered around MMPs cysteine osteonectin/BM-40! Provides support and protects vital organs but also to release RANKL and locations... Cancer ] active tissue of fluids and substances soon turns on the fate of osteoblasts been. ) the bone loss is extensive, the osteoblasts assumed normal morphology express RANKL of new but... 7 ( Suppl 1 ) are unable to fulfill their role as bone building cells degradation appears to be in! The authors declare that they have no competing interests also is a metabolically active tissue GR... Skeleton, interrupting the normal bone remodeling and its Disorders a variety of secreted breast cancer bone metastasis lytic or blastic ( Table 1 ) S1-29!
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