Thus, the ratio of RANKL to OPG is critical for osteoclast activation. 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. 2005, 5 (Suppl): S46-53. Another growth factor sequestered in the matrix is IGF. MMPs are involved in the bone remodeling process after osteoclasts are finished. J Bone Oncol. 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]. The .gov means its official. Bone metastases in breast cancer may be osteolytic, osteoblastic, or mixed blastic and lytic. Breast cancer is often compared with prostate cancer, which metastasizes to the skeleton with a similar frequency. 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. The receptor binding activity in turn causes an increase in production of RANKL. 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. 2023;2582:343-353. doi: 10.1007/978-1-0716-2744-0_24. The ratio of RANKL to OPG determines the extent of the osteoclast activity and bone degradation. 2010, 70: 412-424. Unfortunately, some of the therapies used for breast cancer patients may exacerbate the problem. Surprisingly, this treatment did not affect angiogenesis in the bone. Zheng Y, Zhou H, Modzelewski JR, Kalak R, Blair JM, Seibel MJ, Dunstan CR: Accelerated bone resorption, due to dietary calcium deficiency, promotes breast cancer tumor growth in bone. Myeloma cells produce factors that upregulate osteoblast production of M-CSF and RANKL and downregulate production of OPG. Sanchez-Fernandez MA, Gallois A, Riedl T, Jurdic P, Hoflack B: Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling. Mol Cancer Ther. By using this website, you agree to our Cells of the osteoblast lineage are derived from mesenchymal stem cells, and are represented in this unit by osteoblasts, bone lining cells and osteocytes. Clements ME, Holtslander L, Edwards C, Todd V, Dooyema SDR, Bullock K, Bergdorf K, Zahnow CA, Connolly RM, Johnson RW. These molecules not only help support tumor cells, but also are osteoclastogenic. Other cells of the osteoblastic lineage include bone lining cells and osteocytes. Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. Epidemiological studies have also correlated the increase in breast cancer rates with decreasing sunlight exposure. Zambonin Zallone A, Teti A, Primavera MV: Resorption of vital or devitalized bone by isolated osteoclasts in vitro. Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. AMM, the senior investigator and corresponding author, has worked in the area of breast cancer metastasis to bone for over 12 years. 2023 BioMed Central Ltd unless otherwise stated. This area has been likened to an extracellular lysosome [11]. 2010, 70: 1835-1844. The https:// ensures that you are connecting to the 10.1016/S8756-3282(03)00086-3. The blastic bone lesions are caused when the cancer cells release the fluids. Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. Metastases leading to overall bone loss are classified as osteolytic. Nevertheless, the inaccessibility, opacity and size of the skeleton make it difficult to study even in laboratory animals. Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, Hussain S, van Wijnen AJ, Stein JL, Stein GS, Lian JB: Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. 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. Further stimulation results in large multinuclear cells capable of bone resorption. These capacities are essential for any cancer cells to develop distant metastases in organs such as lungs and liver as well as bone. 3 Cancer. 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. However, more accessible and defined [76] models are needed. Exp Cell Res. Google Scholar. 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 The cells that have spread to the bone are breast cancer cells. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. EMBO J. Correspondence to It binds to two class III tyrosine kinase receptors, PDGFR and PDGFR, leading to activation of several signaling molecules. Bone is the most common site of metastasis for breast cancer. 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. [Management of bone metastases from breast cancer]. HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer. 10.1158/1078-0432.CCR-09-0426. Privacy Breast Cancer Research 10.1158/0008-5472.CAN-09-3194. However, the MMPs may be involved in matrix remodeling once the osteoclasts are finished. 10.1007/s10585-006-9044-8. 10.1007/s00784-009-0268-2. 2008, 3: e3537-10.1371/journal.pone.0003537. statement and 2010, 70: 6150-6160. Breast Cancer Res 12, 215 (2010). 2000, 373: 104-114. Several groups have developed in vivo models in which bone or bone substitutes are implanted in animals. Cancer Res. Bone. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. eCollection 2022. Google Scholar. 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. CA Cancer J Clin. 10.1002/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I. Osteoclasts derive from mononuclear myeloid precursors that fuse to form pre-osteoclasts. 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). 2019 Nov 29;21(1):130. doi: 10.1186/s13058-019-1220-2. Kubota K, Sakikawa C, Katsumata M, Nakamura T, Wakabayashi K: PDGF BB purified from osteoclasts acts as osteoblastogenesis inhibitory factor (OBIF). Keywords: 10.1006/bbrc.2001.5127. On x-rays, these metastases show up as spots that are whiter than the bone around them. It is now generally accepted that the bone microenvironment is critical to the colonization and growth or dormancy of metastases. Ohshiba T, Miyaura C, Ito A: Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. Their multifunctionality demonstrates their importance. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. 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). Provided by the Springer Nature SharedIt content-sharing initiative. Endocrinology. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. This loss is more precipitous in women, due to the decrease in estrogen at menopause [3]. Biochem Biophys Res Commun. 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. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. 2010, 29: 811-821. 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]. 1997, 80 (8 Suppl): 1572-1580. Breast cancer cells also cause inhibition of osteoblast differentiation and adhesion, downregulation of collagen synthesis and increased osteoblast apoptosis. Breast cancer-derived factors facilitate osteolytic bone metastasis. PubMed 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. Please enable it to take advantage of the complete set of features! 1998, 19: 18-54. Grey A: Teriparatide for bone loss in the jaw. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. 1988 Jun;7(2):143-88 However, once bone metastasis has occurred, the aim has been to break the osteolytic cycle by targeting osteoclasts. The site is secure. 8600 Rockville Pike 10.1016/S1535-6108(03)00132-6. As might be expected from the nature of the osteolytic process, that is, the degradation of bone, the microenvironment contains many proteases. The resorption phase of the process begins with recruitment of pre-osteoclasts that differentiate into activated osteoclasts under the direction of osteoblasts (Figure 1A). break). Raica M, Anca M: Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. 2006, 23: 345-356. Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. For females, breast and lung are the most common primary sites ; nearly 80% of cancers that spread to the skeleton are from these locations. 2001, 142: 5050-5055. Gradient Boosting Machine Identified Predictive Variables for Breast Cancer Patients Pre- and Post-Radiotherapy: Preliminary Results of an 8-Year Follow-Up Study. Cortical bone provides strength and protection while trabecular bone is the most metabolically active. 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. SPARC cleavage also coincides with an increase in inflammatory cytokines such as IL-6 and IL-8 [51]. 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]. 7, Chapter Below are the links to the authors original submitted files for images. 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. 2010. 10.1038/sj.emboj.7600729. 2010, 36: 615-620. What can be done to stop osteolytic metastasis? 2004, 21: 427-435. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. 2006, 12: 1431-1440. Lytic lesions are caused by cancer cells causing old bone to break down without new bone being . Where do the MMPs come from? 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. In this context, RANKL increases in the presence of inflammatory agents from infectious organisms, such as lipopolysaccharide, CpGpDNA and viral double-stranded DNA [41]. Andrea M Mastro. It is common to find increased PTHrP serum levels in breast cancer patients. 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. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. HHS Vulnerability Disclosure, Help Just as osteoblasts are a critical partner in normal bone remodeling, they are vital to the metastatic osteolytic process. Thus, inflammation is likely to be important in cancer initiation, metastasis and the resulting osteolysis. Annu Rev Pathol. In people with breast and prostate cancer, the bone is often the first distant site of cancer spread. It's not the same as having cancer that starts in the bone. Bone remodeling is often described as a cycle beginning with bone degradation and ending with bone deposition (Figure 1A). Kang JS, Alliston T, Delston R, Derynck R: Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. Parathyroid hormone-related protein and bone metastases. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. 2009, 11: R56-10.1186/bcr2345. Klein DC, Raisz LG: Prostaglandins: stimulation of bone resorption in tissue culture. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. According to this paradigm, the tumor cells produce a variety of growth factors, most notably parathyroid hormone-related protein (PTHrP) [18]. Bone metastasis may be the first sign that you have cancer, or bone metastasis may occur years after cancer treatment. MMP1, 2, 3 process the binding factors and free IGF, allowing it to bind to its receptors found both on osteoblasts and osteoclasts. Nat Cell Biol. Osteoblasts derive from mesenchymal stem cells in the marrow under control of Runx2, a key osteoblastic transcription factor. TGF- is well-known for its role in osteolytic bone metastasis. Cancer Res. 10.1359/jbmr.060610. Several of these molecules are related to the recruitment and differentiation of osteoclasts; some are prominent players in the vicious cycle. We present therapeutic options for bone metastasis using a multidisciplinary approach. Chen, YC., Sosnoski, D.M. Clin Pharmacol Ther. Symptoms can arise in a number of scenarios 1,3,6: local bone pain soft tissue mass resulting in: direct compression of adjacent structures by extraosseous soft tissue mass (e.g. 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 . Shimo T, Okui T, Horie N, Yokozeki K, Takigawa M, Sasaki A. Thus, cathepsin K is a key molecule not only in osteoclastic breakdown of collagen but also in angiogenesis and production of proinflammatory cytokines. When the bone loss is extensive, the osteoblasts are absent from the lesion [32]. Cancer Cell. It is estimated that osteolytic lesions occur in 60 to 95% of myeloma patients [1, 27]. Disclaimer, National Library of Medicine 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. Cancer Res. Gan To Kagaku Ryoho. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. 2007, 6: 2609-2617. Teriparatide, in contrast to bisphosphonates and denosumab, acts on osteoblasts to stimulate bone formation. 2007, 24: 599-608. 10.1023/A:1026526703898. We also discuss known risk factors as well as detection and assessment of bone metastases. 1970, 86: 1436-1440. 1991 Apr 1;47(6):922-8 2003, 89: 2031-2037. Epub 2015 Dec 4. Thus, in the course of the osteolytic process, the osteoblasts are unable to fulfill their role as bone building cells. 2010, 363: 2458-2459. 2000 Mar;18(6):1378-91. doi: 10.1200/JCO.2000.18.6.1378. Mastro AM, Vogler EA: A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. Osteoblasts produce macrophage colony stimulating factor (M-CSF) and receptor activator of NFB ligand (RANKL), which bind to their respective receptors, c-fms and RANK, on pre-osteoclasts to bring about osteoclast differentiation and activation. The PGE2-mediated production of RANKL induces osteoclastogenesis via RANK. Osteocytes may act as mechanosensing cells and initiate the process when microfractures and loading are involved. While COX-1 is constitutively expressed in most tissues, COX-2 expression appears to be limited to brain, kidney, bone, reproductive organs and some neoplasms. 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. 2005, 10: 169-180. spinal cord compression) palpable mass deformity pathological fracture hypercalcemia bone marrow aplasia 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. 2008, 314: 173-183. 10.1016/S0006-291X(02)02937-6. Because of its significant role, TGF- has been a tempting therapeutic target. PGE2 is associated with inflammation, cell growth, tumor development and metastasis [42]. Clin Oral Investig. Google Scholar. Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. Oncogene. The average survival after the diagnosis of a breast cancer metastasis to bone has dramatically . Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2010. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. Ann N Y Acad Sci. 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. 10.1007/s10585-007-9112-8. 10.1158/0008-5472.CAN-09-2758. 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. Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. The skeleton is constantly undergoing remodeling. The results of an in vivo study showed that OPN-deficient mice showed significantly reduced bone metastasis [38]. FOIA 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]. However, PTHrP does not directly stimulate osteoclast differentiation, but rather stimulates other cells to increase RANKL and decrease OPG production. Marie PJ: Transcription factors controlling osteoblastogenesis.