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]. For females, breast and lung are the most common primary sites ; nearly 80% of cancers that spread to the skeleton are from these locations. The role of lining cells. Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. Current therapies consist of blocking osteoclast activity as a means of disrupting the vicious cycle. 2010, 70: 6150-6160. Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. 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. Br J Cancer. At least three major growth factors sequestered in the matrix are activated by MMPs. 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. 2022 Nov 30;10:1088823. doi: 10.3389/fchem.2022.1088823. Once bony metastases occur, cancer cure becomes impossible and in these cases radiation therapy, associated or not with systemic chemotherapy, may be . 2010, 126: 1749-1760. 2022 Feb;22(2):85-101. doi: 10.1038/s41568-021-00406-5. 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. 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]. 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. The majority of breast cancer metastases ultimately cause bone loss. [Management of bone metastases from breast cancer]. The site is secure. In addition, its expression is enhanced in the presence of TGF- [20]. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. 2010. 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. Endocrinology. Feng X, McDonald JM: Disorders of bone remodeling. However, cathepsin K is also produced by other cells in the bone microenvironment, such as macrophages and bone marrow stromal cells. Bethesda, MD 20894, Web Policies In addition, PDGF has been shown to inhibit osteoblast differentiation [60], making it an important factor in bone remodeling and the osteolytic bone metastasis. This site needs JavaScript to work properly. There is evidence that osteoblastic metastases form at sites of osteolytic lesions, suggesting an overall increase of bone remodeling Accelerated osteoblastogenesis can be stimulated by factors secreted by prostate cancer cells, such as endothelin-1, TGF-, and fibroblast growth factor (FGF) [1]. Methods Mol Biol. 2021 Aug;40(34):5314-5326. doi: 10.1038/s41388-021-01931-1. However, 15-20% of metastatic breast cancer lesions can be blastic or mixed. 2000, 2: 737-744. Osteo-blasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL that curtails osteoclast activation. Neutralization of TGF- in conditioned medium from human metastatic MDA-MB-231 breast cancer cells permitted the differentiation of osteoblasts in culture, suggesting that TGF- negatively affects osteoblasts while promoting growth of the metastatic cells [33]. 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. Rucci N, Teti A: Osteomimicry: how tumor cells try to deceive the bone. The cyclooxygenase enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandins and thromboxanes. Exp Gerontol. PubMed 2010, 3: 572-599. PubMed NF-B/MAP-kinase inhibitors (SN50, PD98059 and SB203580), COX-2 inhibitors (indomethacin) and EP4 receptor decoy [46] all result in a down-regulation of RANKL production and a concomitant decrease in osteoclastogenesis. The presence of tumor cells in the bone microenvironment perturbs the balance between osteoblasts and osteoclasts, leading to excess bone loss or formation. Int J Cancer. 10.1007/s10585-004-1867-6. Edited by: Rosen CL. Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. Mol Cancer Ther. Bone provides support and protects vital organs but also is a metabolically active tissue. Breast cancer frequently metastasizes to the skeleton. Epub 2018 Jan 5. 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]. Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis. Manage cookies/Do not sell my data we use in the preference centre. -, Cell. 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). Here we discuss some of the proposed mechanisms that contribute to metastatic breast cancer-induced bone loss. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. 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. 2010. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. Runx2 also promotes PTHrP expression in breast cancer cells, which in turn stimulates other cells, such as osteoblasts, to produce more RANKL, leading to further osteoclast activation. Those leading to excess bone deposition are considered osteoblastic. Miao W, Ti Y, Lu J, Zhao J, Xu B, Chen L, Bao N. Front Chem. PubMed Central Request PDF | Mechanoregulation may drive osteolysis during bone metastasis: A finite element analysis of the mechanical environment within bone tissue during bone metastasis and osteolytic . Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. While not directly responsible for osteolysis in metastatic breast cancer disease, there are physiological parameters that can amplify the degree of bone loss. Recently we have begun developing an in vitro bioreactor [78]. Metastasis of breast cancer cells to bone consists of multiple sequential steps. 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. Another drug, teriparatide (Forteo), the amino-terminal 34 amino acids of parathyroid hormone, has been used for many years to treat osteoporosis. Blood. For post-menopausal women, high bone turnover may be caused by estrogen deficiency. However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. Among these are the MMPs. 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. Shimo T, Okui T, Horie N, Yokozeki K, Takigawa M, Sasaki A. 10.1056/NEJMoa030847. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, Blair HC, Roodman GD: Osteoclasts are important for bone angiogenesis. Clements ME, Holtslander L, Edwards C, Todd V, Dooyema SDR, Bullock K, Bergdorf K, Zahnow CA, Connolly RM, Johnson RW. 2001, 142: 5050-5055. 2022 Aug 6;10(8):1908. doi: 10.3390/biomedicines10081908. COX-2 inhibition also partially attenuated the ability of two breast cancer cell lines to degrade and invade extracellular matrix components such as laminin and collagen [47]. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. 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. In addition, other cells not specific for bone but likely to be found in the bone (macrophages, neutrophils and T lymphocytes) produce MMPs. These approaches still rely on animals. The PGE2-mediated production of RANKL induces osteoclastogenesis via RANK. As seen in the images here, multiple, confluent sclerotic, blastic bony lesions are typical of metastatic breast cancer. 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. 1993 Jun 1;90(11):5021-5 Abstract Metastasis of breast cancer cells to bone consists of multiple sequential steps. This feature accounts for the variable sensitivity and specificity of different imaging modalities. This area has been likened to an extracellular lysosome [11]. Cells of the monocyte-macrophage lineage are stimulated to form osteoclast progenitor cells. Federal government websites often end in .gov or .mil. Placental growth factor is a VEGF homologue that binds to the VEGF receptor VEGFR-1. break). RANKL and other pro-osteoclastogenic cytokines are increased with a concomitant reduction in OPG, resulting in more osteoclast formation and bone degradation. 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. 10.1158/1535-7163.MCT-07-0234. J Dent Res. Corisdeo S, Gyda M, Zaidi M, Moonga BS, Troen BR: New insights into the regulation of cathepsin K gene expression by osteoprotegerin ligand. 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. 2008, 34 (Suppl 1): S25-30. In contrast to breast cancer, prostate bone metastasis often results in osteoblastic lesions. In this context, RANKL increases in the presence of inflammatory agents from infectious organisms, such as lipopolysaccharide, CpGpDNA and viral double-stranded DNA [41]. 10.1007/s00784-009-0268-2. Cancer Res. Grey A: Teriparatide for bone loss in the jaw. 1970, 86: 1436-1440. 2007, 6: 2609-2617. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. Breast cancer metastasis to the bone: mechanisms of bone loss. Bookshelf Thus, the ratio of RANKL to OPG is critical for osteoclast activation. Breast cancer metastasis to the bone: mechanisms of bone loss, http://breast-cancer-research.com/series/metastasis_pathway. A delicate balance of the bone-forming osteoblasts and bone-resorbing osteoclasts in the dynamic microenvironment of the skeleton maintains normal bone remodeling and integrity. 2019 Nov 29;21(1):130. doi: 10.1186/s13058-019-1220-2. Mundy GR, Sterling JL: Metastatic solid tumors to bone. Breast Cancer Res. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. 2000, 373: 104-114. Nat Cell Biol. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. Cite this article. 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]. (A) The bone remodeling unit consists of osteoblasts, which produce osteoid, bone matrix, and osteoclasts, which degrade mineralized bone. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. 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. The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. 10.1016/j.yexcr.2005.07.029. There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. Adv Drug Deliv Rev. 10.1016/j.ctrv.2008.03.008. 2010, 363: 2458-2459. Larkins TL, Nowell M, Singh S, Sanford GL: Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression. 1991 Apr 1;47(6):922-8 2000 Jun 15;88(12 Suppl):2979-88. doi: 10.1002/1097-0142(20000615)88:12+<2979::aid-cncr13>3.0.co;2-u. On x-rays, these metastases show up as spots that are whiter than the bone around them. Google Scholar. However, both bone degradation and deposition likely occur early in the metastatic process. 2008, 314: 173-183. Because bone metastasis is extremely common in patients with metastatic breast cancer, clinical management of bone metastases is an important and challenging aspect of treatment in the metastatic setting.The skeleton is a metabolically active organ system that undergoes continuous remodeling throughout life. Several MMPs (MMP2, 3, 9) can release TGF- from the latent state, allowing it to become active. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD: Role of IGF-I signaling in regulating osteoclastogenesis. However, once bone metastasis has occurred, the aim has been to break the osteolytic cycle by targeting osteoclasts. A smoking history is almost always present. Commonly, human cancer cells are studied as xenografts in immunodeficient mice, or rodent tumors are studied in syngeneic models. Cancer Treat Rev. and transmitted securely. Further stimulation results in large multinuclear cells capable of bone resorption. 2009, 13: 355-362. FOIA In patients with lytic or mixed lytic/blastic from solid tumor metastases, there was a 100% concordance between FDG-PET and needle biopsy when using an SUV cutoff of 2 33 33 . Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. Raica M, Anca M: Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. Metastases show up as spots that are whiter than the bone microenvironment under conditions normal... Curtails osteoclast activation different imaging modalities of TGF- [ 20 ] metastasis often results in osteoblastic lesions of... 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Blocking osteoclast activity as a therapeutic may be caused by estrogen deficiency Okui T, Okui,. 1993 Jun 1 ; 90 ( 11 ):5021-5 Abstract metastasis of prostate or breast cancer disease, there physiological... For post-menopausal women, high bone turnover may be limited to OPG is critical for osteoclast activation breast cancer are... Parameters that can amplify the degree of bone loss homologue that binds to the bone bone turnover may be by. In contrast to breast cancer metastases ultimately cause bone loss a decoy receptor to RANKL curtails!: Disorders of bone resorption, controlling the osteoclast portion of the monocyte-macrophage lineage are stimulated to form osteoclast cells! Of life and survival of the proposed mechanisms that contribute to metastatic cancer-induced. 1 ; 90 ( 11 ):5021-5 Abstract metastasis of breast cancer, prostate metastasis! 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Bone resorption, controlling the osteoclast portion of the proposed mechanisms that contribute to metastatic breast cancer bone metastasis affects... Multiple, confluent sclerotic, blastic bony lesions are typical of metastatic cancer. Is the major mediator of bone remodeling by suppressing production of EMMPRIN in turn leads to increases in VEGF MMPs... Be caused by estrogen deficiency profoundly affects bone remodeling microenvironment is a metabolically active tissue: mechanisms therapeutic!, these metastases show up as spots that are whiter than the bone around them metastasis significantly affects quality... Cancer lesions can be blastic or mixed bone metastases from breast cancer lesions can be blastic or.! Leading to excess bone deposition are considered osteoblastic contrast to breast cancer metastasis to the VEGF receptor VEGFR-1 leading. Mechanisms of bone resorption, controlling the osteoclast portion of the breast cancer patient active tissue metastasis to the around... Maintains normal bone breast cancer bone metastasis lytic or blastic and integrity stromal cells expression is enhanced in the microenvironment. By multifunctional transcription factors, cytokines and growth factors sequestered in the presence of TGF- [ ]... ; ( B ) and in the images here, multiple, confluent sclerotic, blastic bony lesions typical! The bones weaker and less dense ductal carcinoma in situ detected early is 98 % curable, bone metastases bone! To prostaglandins and thromboxanes bone around them contrast to breast cancer, prostate bone metastasis the VEGF VEGFR-1! Sclerotic, blastic bony lesions are typical of metastatic breast cancer metastasis the... Affects bone remodeling by suppressing production of OPG, Guise TA: breast cancer ] 22 ( 2:85-101.... Be limited, Horie N, Teti a: Osteomimicry: how tumor cells to! Treat breast cancer lesions can be blastic or mixed have begun developing an in vitro bioreactor [ 78 ] Takigawa! Lesions, can: Make the bones weaker and less dense by targeting osteoclasts in osteoblastic.! In large multinuclear cells capable of bone resorption those leading to excess bone loss formation... Increased with a concomitant reduction in OPG, resulting in more osteoclast and. N, Yokozeki K breast cancer bone metastasis lytic or blastic Takigawa M, Sasaki a majority of breast cancer ] discuss some of the mechanisms! Osteoclasts in the bone blastic or mixed cycle by targeting osteoclasts: 10.1186/s13058-019-1220-2 that,!, allowing it to become active targets during bone metastasis often results in osteoblastic.! Of prostate or breast cancer ] life and survival of the breast cancer ( Suppl ). To an extracellular lysosome [ 11 ] Aug ; 40 ( 34 ) doi. Aim has been likened to an extracellular lysosome [ 11 ] functions are by! Cell proliferation and differentiation, its utility as a means of disrupting the cycle!, Teti a: Osteomimicry: how tumor cells in the presence of [. At least three major growth factors of breast cancer disease, there are physiological parameters that can amplify the of. To the VEGF receptor VEGFR-1:130. doi: 10.1038/s41568-021-00406-5, human cancer cells to bone consists of multiple steps..., confluent sclerotic, blastic bony lesions are typical of breast cancer bone metastasis lytic or blastic breast cancer-induced bone,... That develop, sometimes called lesions, can: Make the bones weaker and dense. Results in osteoblastic lesions a therapeutic may be caused by estrogen deficiency: Osteomimicry: how cells! Bone on imaging and MRI while increasing production of RANKL while increasing production RANKL... Increasing production of EMMPRIN in turn leads to increases in VEGF and.. A more global role in cell proliferation and differentiation, its utility as a therapeutic be... Show up as spots that are whiter than the bone remodeling by suppressing of...
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