Radiol Clin North Am. Oncogene. In the next step, preosteoblasts are recruited from the mesenchymal stem cell population and differentiate into osteoblasts. This remarkable process of bone degradation and formation is synchronized by direct cell contact and a variety of secreted factors (Table 1). 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. Trabecular bone is the major site of bone turnover under normal conditions and in diseases of bone loss or formation. 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. 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. eCollection 2021 Dec. Nat Rev Cancer. 10.1210/en.142.12.5050. PubMed Cancer. volume12, Articlenumber:215 (2010) This article is part of a review series on New pathways of metastasis, edited by Lewis Chodosh. Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. 2009, 175: 1255-1269. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. The authors declare that they have no competing interests. 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]. Clin Orthop Relat Res. Dysfunctional Runx2 results in the developmental arrest of osteoblasts and inhibition of osteogenesis. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. 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. 2009, 15: 5829-5839. HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer. Unable to load your collection due to an error, Unable to load your delegates due to an error. Front Biosci (Schol Ed). At least three major growth factors sequestered in the matrix are activated by MMPs. 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. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. Cells of the immune system, T cells and dendritic cells can also express RANKL. 10.1359/jbmr.060610. Primarily they spread to spine, but lung cancer is known to metastasize to the . RANKL and other pro-osteoclastogenic cytokines are increased with a concomitant reduction in OPG, resulting in more osteoclast formation and bone degradation. Metastatic breast cancer cells tend to spread to the bones more often than they do to other parts of the body. Ooi LL, Zheng Y, Stalgis-Bilinski K, Dunstan CR: The bone remodeling environment is a factor in breast cancer bone metastasis. Clin Exp Metastasis. 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 cells that have spread to the bone are breast cancer cells. 10.1007/s00784-009-0268-2. 2000 Jun 15;88(12 Suppl):2979-88. doi: 10.1002/1097-0142(20000615)88:12+<2979::aid-cncr13>3.0.co;2-u. 10.1158/0008-5472.CAN-09-4092. PTHrP is expressed in the primary tumors of about 50% of patients and in more than 90% of breast cancer bone metastasis samples [18]. 2010. As might be expected from the nature of the osteolytic process, that is, the degradation of bone, the microenvironment contains many proteases. In the context of the current discussion, cancer cells may initiate the process. Terms and Conditions, -, Cancer Metastasis Rev. 10.1038/sj.bjc.6602417. Disclaimer, National Library of Medicine 10.1007/s10585-007-9112-8. PTH/PTHrP, TNF-, prostaglandins (PGE2), IL-1, IL-11, FGF-2, and IGF-1 have been reported to increase RANKL production. The role of lining cells. Myeloma cells may also produce RANKL and directly affect osteoclasts [28]. Cite this article. Clarke BL, Khosla S: Physiology of bone loss. official website and that any information you provide is encrypted Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. 10.1038/sj.bjc.6601437. Carlsten H: Immune responses and bone loss: the estrogen connection. 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. prostate = blastic/sclerotic . Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD: Role of IGF-I signaling in regulating osteoclastogenesis. 2022 Aug 23;14:2519-2531. doi: 10.2147/CMAR.S369910. Osteocytes may act as mechanosensing cells and initiate the process when microfractures and loading are involved. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA: Molecular biology of bone metastasis. Article Clin Cancer Res. government site. Osteoclasts derive from mononuclear myeloid precursors that fuse to form pre-osteoclasts. At least three essential molecules, TGF-, IGF, and VEGF, need to be activated by MMPs before they can function. Another drug, teriparatide (Forteo), the amino-terminal 34 amino acids of parathyroid hormone, has been used for many years to treat osteoporosis. Int J Cancer. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. 10.1023/A:1026526703898. 10.1016/j.ctrv.2008.03.008. 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. For example, OPN is produced by many breast cancer cells and has a strong clinical correlation with poor prognosis and decreased survival [37]. Assessment; Bone; Bone-targeted therapy; Detection; Mechanism of bone metastases; Metastasis; Therapy. 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. Epub 2018 Jan 5. Matrix degradation appears to be only one of the roles of MMPs. Lerner UH: Bone remodeling in post-menopausal osteoporosis. Bone metastases in breast cancer may be osteolytic, osteoblastic, or mixed blastic and lytic. 2004, 26: 179-184. Osteoblasts and bone stromal cells can respond to a variety of substances that upregulate RANKL. 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. Article Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases. Cells of the monocyte-macrophage lineage are stimulated to form osteoclast progenitor cells. Accessibility Bussard KM, Venzon DJ, Mastro AM: Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. https://doi.org/10.1186/bcr2781. They also are regulators of other molecules important in the vicious cycle. Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. Bone. Springer Nature. PubMed Central PGE2 is associated with inflammation, cell growth, tumor development and metastasis [42]. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. The receptor binding activity in turn causes an increase in production of RANKL. Estrogen also increases osteoblast pro-collagen synthesis and decreases osteoblast apoptosis [63]. 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. IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. 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. 10.1016/S8756-3282(03)00086-3. The main symptoms of breast cancer that has spread to bone are: PMC 2008, 3: e3537-10.1371/journal.pone.0003537. This site needs JavaScript to work properly. TGF- is one of the most prominent. We are in the process of adding osteoclasts to the system to create a rudimentary in vitro bone remodeling unit. Careers. Other cells of the osteoblastic lineage include bone lining cells and osteocytes. Osteocytes are terminally differentiated osteoblasts that become embedded in the bone matrix at the end of the deposition phase of remodeling. PDGF is a dimeric protein consisting of two of four possible subunits. They activate latent molecules released from the matrix. 2008, 68: 7795-7802. The majority of bone metastases are asymptomatic. 2010, 70: 1835-1844. IL-8, a proinflammatory CXC chemokine, is secreted by monocytes, endothelial cells and osteoblasts. Accessibility 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]. 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. 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. Where do the MMPs come from? Pratap and colleagues [40] found that Runx2 responds to TGF- stimulation by activating the expression of Indian hedgehog (IHH), which further increases the level of PTHrP. Survival Prediction in Patients Treated Surgically for Metastases of the Appendicular Skeleton-An External Validation of 2013-SPRING Model. Nat Cell Biol. Metastastic human breast cancer cells (MDA-MB-231) added to this culture attach, penetrate the tissue and form single cell files characteristic of metastases seen in pathologic tissues. 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]. 2000, 1: 331-341. PubMedGoogle Scholar. Marie PJ: Transcription factors controlling osteoblastogenesis. In this context, RANKL increases in the presence of inflammatory agents from infectious organisms, such as lipopolysaccharide, CpGpDNA and viral double-stranded DNA [41]. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. MMP-9 is important in the cascade leading to activation of VEGFA. What initiates remodeling in the non-tumor-containing bone? 10.1158/0008-5472.CAN-09-3194. Article 10.1158/0008-5472.CAN-09-2758. Clipboard, Search History, and several other advanced features are temporarily unavailable. Raica M, Anca M: Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. VEGF also forms a complex with the extracellular matrix [31, 55]. Clements ME, Holtslander L, Edwards C, Todd V, Dooyema SDR, Bullock K, Bergdorf K, Zahnow CA, Connolly RM, Johnson RW. MeSH 10.1158/1078-0432.CCR-09-0426. Please enable it to take advantage of the complete set of features! Google Scholar. 10.1038/sj.emboj.7600729. 2004, 21: 427-435. Most breast cancer metastasis to bone results in osteolytic lesions. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. Biochem Biophys Res Commun. Bone. Br J Cancer. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. Cancer Res. blastic (bone formation), or mixed lesions (Fig 2). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Clin Adv Hematol Oncol. 1988 Jun;7(2):143-88 10.1007/s10585-004-1867-6. Biochem Biophys Res Commun. 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. 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. Clin Breast Cancer. However, PTHrP does not directly stimulate osteoclast differentiation, but rather stimulates other cells to increase RANKL and decrease OPG production. Cancer Res. While the case for the importance of MMPs as metastasis regulators is strong, they themselves are regulated by tissue inhibitors of metalloproteinase (TIMPs). Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. PloS one. Marie L, Braik D, Abdel-Razeq N, Abu-Fares H, Al-Thunaibat A, Abdel-Razeq H. Cancer Manag Res. The mean standardized uptake value (SUV) for tumor was 7.1 versus 2.1 for benign lesions. 10.1097/00003086-200004000-00013. Federal government websites often end in .gov or .mil. 2006, 23: 345-356. Cancer. 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. Laufer I, Lis E, Pisinski L, Akhurst T, Bilsky MH. TGF- is well-known for its role in osteolytic bone metastasis. 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]. Andrea M Mastro. The https:// ensures that you are connecting to the Juarez P, Guise TA: TGF-beta in cancer and bone: Implications for treatment of bone metastases. 10.1210/er.19.1.18. 2005, 310: 270-281. 10.1158/0008-5472.CAN-08-4437. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. Those leading to excess bone deposition are considered osteoblastic. 10.1002/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I. Smolle MA, Musser E, Bergovec M, Friesenbichler J, Wibmer CL, Leitner L, Srensen MS, Petersen MM, Brcic I, Szkandera J, Scheipl S, Leithner A. Curr Opin Support Palliat Care. 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. It's the most advanced stage of breast cancer. Careers. It inhibits the differentiation of osteoclasts by competitive binding with RANKL. 2. FOIA 2010, 33 (3 Suppl): S1-7. PMC A thorough review of bone remodeling is beyond the scope of this article, and there are several excellent, recent reviews [8, 9]. The average survival after the diagnosis of a breast cancer metastasis to bone has dramatically . 1970, 86: 1436-1440. Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. They follow the osteoclasts, reforming the bone matrix. 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]. 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. Bookshelf COX-2 activity in breast cancer cells has also been found to modulate the expression and activity of MMPs. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. Abstract Metastasis of breast cancer cells to bone consists of multiple sequential steps. 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. Metastatic bone lesions are the predominant malignancy to effect bone, with 15 times the occurrence rate of the next most common bone malignancy. Bone is the most common site of metastasis for breast cancer. Surprisingly, this treatment did not affect angiogenesis in the bone. The results of an in vivo study showed that OPN-deficient mice showed significantly reduced bone metastasis [38]. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. Metastatic breast cancer is breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body (most often the bones, lungs, liver or brain). 2010, 70: 8329-8338. Epub 2021 Oct 5. 2010, 9: 122-10.1186/1476-4598-9-122. PTHrP, one of many proteins controlled by Runx2, is a major effector in breast cancer bone metastasis progression and bone loss. These approaches still rely on animals. PubMed 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 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. J Clin Oncol. Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. 2010, 2: 907-915. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. These findings led to a flurry of studies to develop COX and prostaglandin inhibitors as cures for bone metastasis. In males, prostate and lung cancers make up 80% of carcinomas metastasizing to bone. 2006, 21: 1350-1358. CAS Lipton A: Bone continuum of cancer. It is interesting that cancer cells often remain dormant in bone for many years before they begin to grow. Retrieval of the bone at specific times gives a snapshot of the status of metastases. However, teriparatide is associated with an increased risk of osteosarcoma and exacerbation of skeletal metastases because of its effect on bone turnover [75]. (A) The bone remodeling unit consists of osteoblasts, which produce osteoid, bone matrix, and osteoclasts, which degrade mineralized bone. However, more accessible and defined [76] models are needed. 2009, 3: 213-218. Stopeck [74] recently reported the results of a clinical trial in which denosumab was found to be superior to zoledronic acid in preventing skeletal-related events in breast, prostate and multiple myeloma patients. Their function is not clear except that their retraction is necessary for bone resorption to begin [10]. Of the bisphosphonates, zoledronic acid is the most potent. Both RANKL and VEGF can induce osteoclast formation [48], and MMPs play a role in bone matrix degradation. government site. Myeloma cells produce factors that upregulate osteoblast production of M-CSF and RANKL and downregulate production of OPG. Until recently they were the only FDA approved drugs for metastatic bone disease [71]. Ann N Y Acad Sci. 2003, 33: 28-37. Morrissey C, Lai JS, Brown LG, Wang YC, Roudiffer MP, Coleman IM, Gulati R, Vakar-Lopez F, True LD, Corey E, Nelson PS, Vessella RL: The expression of osteoclastogenesis-associated factors and osteoblast response to osteolytic prostate cancer cells. This molecule is also produced by metastatic breast cancer cells [49]. 2018 Mar;96:63-78. doi: 10.1016/j.biocel.2018.01.003. Am J Pathol. This information is not easily obtained with in vitro studies. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. 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 has high affinity for type I collagen, the most abundant matrix protein. Breast cancer metastasis to the bone: mechanisms of bone loss. Federal government websites often end in .gov or .mil. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. Bone metastases may cause pain, may make the bones more susceptible to fractures, and may cause increased levels of calcium in the blood. This approach will allow testing of components and drugs in a model less complex than an animal but more relevant than standard tissue culture. Manage cookies/Do not sell my data we use in the preference centre. What can be done to stop osteolytic metastasis? 1997, 80 (8 Suppl): 1572-1580. In contrast to breast cancer, prostate bone metastasis often results in osteoblastic lesions. Symptoms when breast cancer has spread to the bones . Am J Clin Oncol. Breast cancer had the highest . Bone metastasis may be the first sign that you have cancer, or bone metastasis may occur years after cancer treatment. 1984, 235: 561-564. 2006, 85: 584-595. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Breast cancer bone metastases: pathogenesis and therapeutic targets. Lynch CC: Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. As pointed out by Lynch, the spatial and temporal expression of these molecules is of utmost importance. Epidemiological studies have also correlated the increase in breast cancer rates with decreasing sunlight exposure. Mol Cancer Ther. 2003, 38: 605-614. 2009, 7 (Suppl 7): S1-29.
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