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. There are many suspected factors, such as microfractures, loss of mechanical loading, hormones, cytokines, calcium levels and inflammation. It improves the quality of life by preventing fractures but does not prolong life [73]. However, teriparatide is associated with an increased risk of osteosarcoma and exacerbation of skeletal metastases because of its effect on bone turnover [75]. Bone is the most common site of metastasis for breast cancer. This remarkable process of bone degradation and formation is synchronized by direct cell contact and a variety of secreted factors (Table 1). Dysfunctional Runx2 results in the developmental arrest of osteoblasts and inhibition of osteogenesis. PubMedGoogle Scholar. 10.1097/00003086-200004000-00013. Bethesda, MD 20894, Web Policies It binds to two class III tyrosine kinase receptors, PDGFR and PDGFR, leading to activation of several signaling molecules. 10.1016/j.yexcr.2007.09.021. Once bony metastases occur, cancer cure becomes impossible and in these cases radiation therapy, associated or not with systemic chemotherapy, may be . Breast Cancer Res. Osteo-blasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL that curtails osteoclast activation. Osteomimetic factors include osteopontin (OPN), osteocalcin, osteonectin, bone sialoprotein, RANKL and PTHrP. Careers. 2006, 85: 596-607. 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. 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. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. 1970, 86: 1436-1440. Bisphosphonates binding to hydroxyapatite are ingested by osteoclasts and cause their apoptosis. The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. This molecule is also produced by metastatic breast cancer cells [49]. It inhibits the differentiation of osteoclasts by competitive binding with RANKL. Cancer Res. They also are regulators of other molecules important in the vicious cycle. J Clin Oncol. 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. 10.1158/0008-5472.CAN-09-2758. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. 2005, 5 (Suppl): S46-53. Bone. 2004, 21: 427-435. break). Mundy GR, Sterling JL: Metastatic solid tumors to bone. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL. 2 Of interest is that patients with blastic (versus osteolytic) bone metastases have been reported to have prolonged survival. J Bone Miner Res. Aldridge SE, Lennard TW, Williams JR, Birch MA: Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. 2008, Washington, DC: American Society for Bone and Mineral Research, 374-378. full_text. 2008, 473: 98-105. quiz S30, CAS PubMed Central It is required to drive mesenchymal cells to become osteoblasts. -, Cell. PubMed 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. Adv Drug Deliv Rev. 10.1158/1535-7163.MCT-08-0153. 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. Clin Cancer Res. The skeleton is constantly undergoing remodeling. 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. Breast cancer bone metastases: pathogenesis and therapeutic targets. 10.1177/154405910608500704. Cancer. For example, OPN is produced by many breast cancer cells and has a strong clinical correlation with poor prognosis and decreased survival [37]. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. To date, osteoclasts have been the primary target of drug therapies. Where do the MMPs come from? 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. official website and that any information you provide is encrypted Google Scholar. 2010, 70: 6150-6160. As might be expected from the nature of the osteolytic process, that is, the degradation of bone, the microenvironment contains many proteases. PubMed J Dent Res. 2008, 7: 2807-2816. The PGE2-mediated production of RANKL induces osteoclastogenesis via RANK. This site needs JavaScript to work properly. 10.1158/0008-5472.CAN-08-4437. 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. In addition, production of inflammatory cytokines (that is, IL-6, TNF-, M-CSF, IL-1) is suppressed by estrogen [64]. Bone provides support and protects vital organs but also is a metabolically active tissue. Epub 2018 Jan 5. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. Elazar V, Adwan H, Bauerle T, Rohekar K, Golomb G, Berger MR: Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis. This information is not easily obtained with in vitro studies. Bone. Google Scholar. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. Clin Oral Investig. 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 The cancer cells affect osteoblast morphology and extracellular matrix. Guise TA: Parathyroid hormone-related protein and bone metastases. prostate = blastic/sclerotic . Metastases leading to overall bone loss are classified as osteolytic. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM: Molecular mechanisms of breast cancer metastases to bone. These capacities are essential for any cancer cells to develop distant metastases in organs such as lungs and liver as well as bone. Curr Opin Support Palliat Care. Ohshiba T, Miyaura C, Ito A: Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. 2022 Jul 20;14(14):3521. doi: 10.3390/cancers14143521. This is a disease of clonal malignancy of terminally differentiated plasma cells that accumulate in the bone marrow. Denosumab (Prolia), the latest drug to enter the field, is a monoclonal antibody to RANKL. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. Once osteoblasts finish bone deposition, they undergo apoptosis, remain in the matrix as osteocytes or revert to thin bone-lining cells. Edited by: Rosen CL. Breast cancer-derived factors facilitate osteolytic bone metastasis. The .gov means its official. Cathepsin K is believed to be the major protease in this capacity. 1973, 28: 316-321. Prostate. An official website of the United States government. 10.1002/(SICI)1097-0142(19971015)80:8+<1572::AID-CNCR7>3.0.CO;2-M. Karaplis AC, Goltzman D: PTH and PTHrP effects on the skeleton. Eur J Cancer. 2010, 87: 401-406. 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. 1999, 59: 1987-1993. Juarez P, Guise TA: TGF-beta in cancer and bone: Implications for treatment of bone metastases. Gan To Kagaku Ryoho. Metastatic breast cancer cells tend to spread to the bones more often than they do to other parts of the body. 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). Orr and colleagues [5] have determined MMPs sufficient to resorb bone in vitro and to contribute to the process in vivo. Osteoblastic or blastic metastases cause an area of the bone to look denser or sclerotic. The blastic bone lesions are caused when the cancer cells release the fluids. 2010. 10.1196/annals.1365.035. Thus, bone loss is the result of excessive bone degradation and insufficient bone replacement. -. Chemotherapy may bring about ovarian failure and premature menopause [1]. 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. 10.1158/0008-5472.CAN-07-1046. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. 10.1016/j.rcl.2010.02.014. However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. For example, a hydroxyapatite scaold pre-loaded with bone morphogenetic protein-2 enhanced the growth rate of mammary tumor cells in the scaold [77]. VEGF also forms a complex with the extracellular matrix [31, 55]. Home; Study Search; Study Details From Other Databases In males, prostate and lung cancers make up 80% of carcinomas metastasizing to bone. Cancer Res. Takahashi T, Uehara H, Bando Y, Izumi K: Soluble EP2 neutralizes prostaglandin E2-induced cell signaling and inhibits osteolytic tumor growth. 2006, 6: 181-10.1186/1471-2407-6-181. It is now known that PGE2 signaling through its receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form mature osteoclasts. official website and that any information you provide is encrypted 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]. Purpose: This is a study in adult patients with different types of cancer. Furthermore, the molecules activated by MMPs also have counter molecules creating a network of accelerators and decelerators centered around MMPs. Metastatic breast cancer (also called stage IV or advanced breast cancer) is not a specific type of breast cancer. 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. [Management of bone metastases from breast cancer]. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. 10.1016/S1535-6108(03)00132-6. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. The presence of tumor cells in the bone microenvironment perturbs the balance between osteoblasts and osteoclasts, leading to excess bone loss or formation. Rucci N, Teti A: Osteomimicry: how tumor cells try to deceive the bone. Khosla S: Minireview: the OPG/RANKL/RANK system. Cells of the immune system, T cells and dendritic cells can also express RANKL. 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 . However, this approach has not entirely solved the problem. MMPs are involved in the bone remodeling process after osteoclasts are finished. 10.1097/COC.0b013e3181deb9e5. 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. For post-menopausal women, high bone turnover may be caused by estrogen deficiency. Lipton A: Bone continuum of cancer. 2009, 69: 4097-4100. Other molecules made by multiple myeloma cells, such as IL-3, IL-7 and soluble frizzle-related protein-2, also inhibit osteoblast differentiation [27]. American Society of Clinical Oncology Bisphosphonates Expert Panel. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. A thorough review of bone remodeling is beyond the scope of this article, and there are several excellent, recent reviews [8, 9]. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. Nemeth JA, Harb JF, Barroso U, He Z, Grignon DJ, Cher ML: Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. 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. Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. Understanding the mechanisms of osteolysis should be the key to designing the cure. While not directly responsible for osteolysis in metastatic breast cancer disease, there are physiological parameters that can amplify the degree of bone loss. By knowing the typical behavior of the metastatic lesion - lytic or blastic - you can help sort between the types to make the mnemonic even more useful. Bone Rep. 2022 Jun 12;17:101597. doi: 10.1016/j.bonr.2022.101597. At the tissue level, PDGF is involved in bone formation, wound healing, erythropoiesis and angiogenesis as well as tumor growth and lesion development [57]. 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 Mol Cancer Ther. Terms and Conditions, Biochem Biophys Res Commun. Oncogene. Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. 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]. Breast cancer cells also cause inhibition of osteoblast differentiation and adhesion, downregulation of collagen synthesis and increased osteoblast apoptosis. PDGF is a dimeric protein consisting of two of four possible subunits. Ooi LL, Zheng Y, Stalgis-Bilinski K, Dunstan CR: The bone remodeling environment is a factor in breast cancer bone metastasis. Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. The https:// ensures that you are connecting to the The majority of breast cancer metastases ultimately cause bone loss. 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]. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. At least three essential molecules, TGF-, IGF, and VEGF, need to be activated by MMPs before they can function. On x-rays, these metastases show up as spots that are whiter than the bone around them. 2010, 8: 159-160. However, the MMPs may be involved in matrix remodeling once the osteoclasts are finished. 10.2741/S110. PubMed Several MMPs (MMP2, 3, 9) can release TGF- from the latent state, allowing it to become active. The mechanisms for suppressed osteoblast activity are not clear but Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, is believed to inhibit osteoblast differentiation [29]. 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. Grey A: Teriparatide for bone loss in the jaw. 10.1016/j.abb.2008.02.030. It was also noted that tumor cells caused other cells in the bone (for example, lymphocytes) to produce molecules such as prostaglandins (PGs) that can affect bone [4]. The average survival after the diagnosis of a breast cancer metastasis to bone has dramatically . 10.1016/j.yexcr.2005.07.029. 2009, 175: 1255-1269. Osteoblasts derive from mesenchymal stem cells in the marrow under control of Runx2, a key osteoblastic transcription factor. 2021 Aug;40(34):5314-5326. doi: 10.1038/s41388-021-01931-1. CA Cancer J Clin. Bone metastasis can cause pain and broken bones. Ann N Y Acad Sci. Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. It has also been suggested that Runx2 is ectopically expressed in bone-destined metastatic breast cancer cells. Bookshelf Provided by the Springer Nature SharedIt content-sharing initiative. 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]. Would you like email updates of new search results? 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. As seen in the images here, multiple, confluent sclerotic, blastic bony lesions are typical of metastatic breast cancer. 10.1016/j.ctrv.2008.03.008. 2006, 23: 345-356. Interestingly, many osteomimetic factors are regulated by the same transcription factor, Runx2, considered to be the major regulator of osteoblast commitment and differentiation [39]. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. 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]. PubMed Central 2008, Washington, DC: American Society for Bone and Mineral Research, 379-382. full_text. 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. 2012 Aug;39(8):1174-7. Trabecular bone is the major site of bone turnover under normal conditions and in diseases of bone loss or formation. 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). 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. Proff P, Romer P: The molecular mechanism behind bone remodelling: a review. 2010, 3: 572-599. Mercer RR, Mastro AM: Cytokines secreted by bone-metastatic breast cancer cells alter the expression pattern of f-actin and reduce focal adhesion plaques in osteoblasts through PI3K. In reality the system is much more complex (Table 1). 2005, 10: 169-180. 2001, 37: 106-113. TGF- is well-known for its role in osteolytic bone metastasis.
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