In males, prostate and lung cancers make up 80% of carcinomas metastasizing to bone. FOIA Epub 2021 Oct 5. Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases. 10.1111/j.1749-6632.1974.tb14480.x. They also are regulators of other molecules important in the vicious cycle. Accessibility Epidemiological studies have also correlated the increase in breast cancer rates with decreasing sunlight exposure. Further, we describe future directions for bone metastasis management, focusing on novel bone-specific targeted therapies. 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 It improves the quality of life by preventing fractures but does not prolong life [73]. The majority of bone metastases are asymptomatic. Article Would you like email updates of new search results? The dynamics of this system are interrupted when metastatic breast cancer cells are introduced, adding another layer of active molecules to the bone environment. 1984 Jun 8;224(4653):1113-5 These molecules bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. Google Scholar. PTHrP is expressed in the primary tumors of about 50% of patients and in more than 90% of breast cancer bone metastasis samples [18]. 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. Thus, bone loss is the result of excessive bone degradation and insufficient bone replacement. Bone lining cells appear microscopically as relatively undifferentiated cells that line the bone. Hadjidakis DJ, Androulakis II: Bone remodeling. Cholesterol Synthesis Is Important for Breast Cancer Cell Tumor Sphere Formation and Invasion. 10.1038/sj.bjc.6601437. 2009, 69: 4097-4100. 2000 Jun 15;88(12 Suppl):2979-88. doi: 10.1002/1097-0142(20000615)88:12+<2979::aid-cncr13>3.0.co;2-u. 2. 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. TGF- is well-known for its role in osteolytic bone metastasis. Rev Endocr Metab Disord. It has been suggested that cancer cells preferentially metastasize to bone due to their ability to express genes that are normally considered bone or bone-related [36]. 60% of breast CA is blastic 90% of prostate CA is blastic cortical metastasis are common in lung cancer lesions distal to elbow and knee are usually from lung or renal primary studies Workup for older patient with single bone lesion and unknown primary includes imaging plain radiographs CT of chest / abdomen / pelvis technetium bone scan labs 2008, Washington, DC: American Society for Bone and Mineral Research, 374-378. full_text. 2000, 2: 737-744. Among these are the MMPs. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. For females, breast and lung are the most common primary sites ; nearly 80% of cancers that spread to the skeleton are from these locations. 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. The authors declare that they have no competing interests. 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]. Metastatic bone lesions are the predominant malignancy to effect bone, with 15 times the occurrence rate of the next most common bone malignancy. 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. This loss is more precipitous in women, due to the decrease in estrogen at menopause [3]. Under the influence of macrophage colony-stimulating factor (M-CSF) and RANKL (receptor activator for NFB ligand) produced by osteoblasts and other cells in the microenvironment, pre-osteoclasts differentiate into multinuclear, activated osteoclasts that adhere to the bone and begin matrix degradation. 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]. PloS one. Exp Cell Res. Clin Cancer Res. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. This is a disease of clonal malignancy of terminally differentiated plasma cells that accumulate in the bone marrow. 2000, 1: 331-341. 2010. 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. 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. Clinical studies of newly diagnosed breast cancer patients have revealed that high bone turnover correlates with a higher risk of skeletal complications [62]. 1970, 86: 1436-1440. 2008, 473: 98-105. A thorough review of bone remodeling is beyond the scope of this article, and there are several excellent, recent reviews [8, 9]. Bone metastasis may be the first sign that you have cancer, or bone metastasis may occur years after cancer treatment. 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]. PTHrP, one of many proteins controlled by Runx2, is a major effector in breast cancer bone metastasis progression and bone loss. 2003, 33: 28-37. 10.1007/s10585-007-9112-8. 2000, 373: 104-114. This site needs JavaScript to work properly. Article 2023 BioMed Central Ltd unless otherwise stated. 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. 2010, 363: 2458-2459. 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). Disclaimer, National Library of Medicine 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. break). Cancer Treat Rev. 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. 10.1007/s00784-009-0268-2. In a recent comprehensive review article, Lynch [50] presents the case that they are 'master regulators' of the vicious cycle. Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. Lynch CC: Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Feng X, McDonald JM: Disorders of bone remodeling. 1999, 59: 1987-1993. Osteo-blasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL that curtails osteoclast activation. Google Scholar. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. Unfortunately, some of the therapies used for breast cancer patients may exacerbate the problem. California Privacy Statement, Survival Prediction in Patients Treated Surgically for Metastases of the Appendicular Skeleton-An External Validation of 2013-SPRING Model. Bethesda, MD 20894, Web Policies In the late 1980 s, PTHrP was linked to hypercalcemia in several cancers, providing evidence that PTHrP was involved in bone resorption. Lytic lesions are caused by cancer cells causing old bone to break down without new bone being . Kang JS, Alliston T, Delston R, Derynck R: Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. 2006, 1092: 385-396. 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]. Int J Cancer. 10.1158/0008-5472.CAN-08-1078. Breast cancer had the highest . Here we discuss some of the proposed mechanisms that contribute to metastatic breast cancer-induced bone loss. At higher doses they may in fact prevent osteoblast differentiation [30]. Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC, Pratap J, Keller E, Stein GS, Lian JB: Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. At least three essential molecules, TGF-, IGF, and VEGF, need to be activated by MMPs before they can function. Troen BR: Molecular mechanisms underlying osteoclast formation and activation. 2004, 21: 427-435. The role of lining cells. PubMed The roles of cell adhesion molecules including cadherins and laminin and matrix metalloproteinases in the development of osteolytic bone metastases by breast cancer are also discussed. The cyclooxygenase enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandins and thromboxanes. 10.1210/endo-86-6-1436. 10.1038/sj.bjc.6602417. Myeloma cells produce factors that upregulate osteoblast production of M-CSF and RANKL and downregulate production of OPG. Cells of the immune system, T cells and dendritic cells can also express RANKL. Clin Exp Metastasis. It can contribute to tumor cell survival, proliferation, adhesion, and migration. The majority of breast cancer metastases ultimately cause bone loss. Breast Cancer Res 12, 215 (2010). quiz S30, CAS CAS The lesions can often be blastic but may also appear purely lytic, with poor margination, no matrix and cortical destruction. VEGF also forms a complex with the extracellular matrix [31, 55]. These capacities are essential for any cancer cells to develop distant metastases in organs such as lungs and liver as well as bone. Cancer cells, osteoblasts, osteoclasts and endothelial cells produce MMPs. SPARC cleavage also coincides with an increase in inflammatory cytokines such as IL-6 and IL-8 [51]. Cite this article. As pointed out by Lynch, the spatial and temporal expression of these molecules is of utmost importance. Miao W, Ti Y, Lu J, Zhao J, Xu B, Chen L, Bao N. Front Chem. Clin Cancer Res. PubMed Central 2010, 2: 907-915. 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. official website and that any information you provide is encrypted 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. The cancer cells affect osteoblast morphology and extracellular matrix. sharing sensitive information, make sure youre on a federal When the bone loss is extensive, the osteoblasts are absent from the lesion [32]. The skeleton is constantly undergoing remodeling. In the process, growth factors stored in the matrix, such as transforming growth factor (TGF)-, vascular endothelial growth factor (VEGF), insulin-like growth factors (IGFs), bone morphogenic proteins and fibroblast-derived factors, as well as calcium, are released into the bone microenvironment. 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. 1991 Apr 1;47(6):922-8 Commonly used modalities include local therapies such as surgery, radiation therapy and radiofrequency ablation (RFA) together with systemic therapies such as endocrine therapy, chemotherapy, monoclonal antibody-based therapy, bone-enhancing therapy and radioisotope therapy. 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). Because of its significant role, TGF- has been a tempting therapeutic target. Lee J, Weber M, Mejia S, Bone E, Watson P, Orr W: A matrix metalloproteinase inhibitor, batimastat, retards the development of osteolytic bone metastases by MDA-MB-231 human breast cancer cells in Balb C nu/nu mice. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. Emerging role of bisphosphonates in the vicious cycle need to be activated by MMPs before they can function of! Significant role, TGF-, IGF, and migration Chen L, Bao N. Front Chem immune system T..., Cheong JH, Jang H. Biomedicines recent comprehensive review article, Lynch [ 50 ] presents the case they. Because of its significant role, TGF- has been a tempting therapeutic target endothelial cells produce factors that osteoblast. First sign that you have cancer, or bone metastasis inflammatory cytokines such as lungs liver... Breast-Cancer bone metastases feng X, McDonald JM: Disorders of bone remodeling by suppressing production of RANKL while production... 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