Ann N Y Acad Sci. J Bone Miner Res. Bone metastases result in lesions or injury to the bone tissue. An official website of the United States government. 1999, 59: 1987-1993. EMBO J. The authors declare that they have no competing interests. Bisphosphonates binding to hydroxyapatite are ingested by osteoclasts and cause their apoptosis. 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]. 2000, 373: 104-114. Edited by: Rosen CL. Breast, prostate, and lung cancers represent the main sources of bone metastases, with prostate and lung cancers being most common in males and breast cancer being most common in females . Kang JS, Alliston T, Delston R, Derynck R: Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. However, both bone degradation and deposition likely occur early in the metastatic process. Parathyroid hormone-related protein and bone metastases. These cells fuse to form multinucleated, but non-functional pre-osteoclasts. 2001, 37: 106-113. 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. 10.1196/annals.1365.035. In this process, the older bone doesn't break down while the new bone forms. This release of fluids and substances soon turns on the osteoblasts, which leads to the formation of new bone. 10.1038/sj.bjc.6601437. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA: Molecular biology of bone metastasis. PMC They also are regulators of other molecules important in the vicious cycle. Chemotherapy may bring about ovarian failure and premature menopause [1]. 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. 1991 Jul 12;66(1):107-19 CAS The .gov means its official. Mercer RR, Miyasaka C, Mastro AM: Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. PubMed These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. -, Proc Natl Acad Sci U S A. N Engl J Med. In normal bone remodeling, osteoclasts secrete PDGF, which acts as a chemoattractant to recruit pre-osteoblasts to the site of bone repair [58]. However, once bone metastasis has occurred, the aim has been to break the osteolytic cycle by targeting osteoclasts. Cancer Cell. Several of these RANKL inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis. Exp Cell Res. 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]. Breast cancer is often compared with prostate cancer, which metastasizes to the skeleton with a similar frequency. 2010, 48: 483-495. 10.1158/0008-5472.CAN-08-4437. Verbruggen ASK, McCarthy EC, Dwyer RM, McNamara LM. 10.1158/0008-5472.CAN-10-2179. The receptor binding activity in turn causes an increase in production of RANKL. Careers. The normal processes of bone resorption and formation are remarkably well balanced. 2004, 21: 427-435. Ganapathy V, Ge R, Grazioli A, Xie W, Banach-Petrosky W, Kang Y, Lonning S, McPherson J, Yingling JM, Biswas S, Mundy GR, Reiss M: Targeting the transforming growth factor-beta pathway inhibits human basal-like breast cancer metastasis. 2009, 11: R56-10.1186/bcr2345. 10.1177/154405910608500703. Clusters of osteoblasts produce osteoid, composed of collagen, osteonectin, chondroitin sulfate and other non-mineral molecules, which matures and is then mineralized over several months [12]. It is estimated that 85% of individuals with advanced disease harbor bone metastases [1]. Further, we describe future directions for bone metastasis management, focusing on novel bone-specific targeted therapies. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. Cancer. Nevertheless, the inaccessibility, opacity and size of the skeleton make it difficult to study even in laboratory animals. However, 15-20% of metastatic breast cancer lesions can be blastic or mixed. McHayleh W, Ellerman J, Roodman D: Hematologic malignancies and bone. We present therapeutic options for bone metastasis using a multidisciplinary approach. 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. Clinical evidence indicates that this drug can reduce the rate of bone loss, but is not curative. Would you like email updates of new search results? This information is not easily obtained with in vitro studies. Article Lytic lesions are caused by cancer cells causing old bone to break down without new bone being . Cancer Res. The presence of tumor cells in the bone microenvironment perturbs the balance between osteoblasts and osteoclasts, leading to excess bone loss or formation. 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. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD: Role of IGF-I signaling in regulating osteoclastogenesis. 2010. Before There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. PGE2 is associated with inflammation, cell growth, tumor development and metastasis [42]. The .gov means its official. 10.2353/ajpath.2009.080906. The site is secure. Gradient Boosting Machine Identified Predictive Variables for Breast Cancer Patients Pre- and Post-Radiotherapy: Preliminary Results of an 8-Year Follow-Up Study. 2010, 8: 159-160. 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. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. 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. PubMed Central Lung cancer is the third most common site of origin of metastatic cancer deposits in bone, after breast and prostate cancer. 10.1158/0008-5472.CAN-09-3194. Other cells of the osteoblastic lineage include bone lining cells and osteocytes. Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. Methods Mol Biol. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM: Molecular mechanisms of breast cancer metastases to bone. 2012 Aug;39(8):1174-7. Osteoblast differentiation is suppressed; new osteoid production is no longer able to keep pace with bone resorption. 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). Clipboard, Search History, and several other advanced features are temporarily unavailable. Evidence to support the concept that there is an intimate relationship between breast cancer cells and osteoclasts is described using an in vivo bone metastasis model in which human breast cancer cells are inoculated into the left ventricle of nude mice. J Dent Res. Thus, cathepsin K is a key molecule not only in osteoclastic breakdown of collagen but also in angiogenesis and production of proinflammatory cytokines. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. Google Scholar. While not directly responsible for osteolysis in metastatic breast cancer disease, there are physiological parameters that can amplify the degree of bone loss. Once bony metastases occur, cancer cure becomes impossible and in these cases radiation therapy, associated or not with systemic chemotherapy, may be . Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 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. In the bone, OPN is involved in the differentiation and activity of osteoclasts, and inhibition of mineral deposition in the osteoid [37]. Google Scholar. Studies with MMP9-null mice indicate its importance in tumor progression in ovarian cancer, prostate cancer and bone metastasis [56]. 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]. Those leading to excess bone deposition are considered osteoblastic. 8600 Rockville Pike Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Another growth factor sequestered in the matrix is IGF. This molecule is also produced by metastatic breast cancer cells [49]. Unable to load your collection due to an error, Unable to load your delegates due to an error. 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 10.1056/NEJMe1010459. 2010, [Epub ahead of print]. However, the MMPs may be involved in matrix remodeling once the osteoclasts are finished. Before In the highly metastatic, COX-2-expressing breast cancer cell line Hs578T, treatment with the selective COX-2 inhibitor Ns-398 markedly decreased the production of MMP1, 2, 3, and 13 in a dose-dependent manner. Proteolytic cleavage of SPARC releases biologically active cleavage products that affect angiogenesis factors such as VEGF, platelet-derived growth factor (PDGF) and FGF-2. 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. 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. 2000, 1: 331-341. 10.1016/S0959-8049(00)00363-4. The entry of breast cancer cells into the bone micro-environment synergistically increases the complexity of cell-cell interactions. Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. For example, a hydroxyapatite scaold pre-loaded with bone morphogenetic protein-2 enhanced the growth rate of mammary tumor cells in the scaold [77]. BMC Cancer. Federal government websites often end in .gov or .mil. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. Andrea M Mastro. Correspondence to 10.3322/canjclin.57.1.43. Breast Cancer Res 12, 215 (2010). sharing sensitive information, make sure youre on a federal 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. Guise TA: Parathyroid hormone-related protein and bone metastases. 10.1158/0008-5472.CAN-09-2758. Mol Cancer Ther. Exp Cell Res. Breast cancer cells also cause inhibition of osteoblast differentiation and adhesion, downregulation of collagen synthesis and increased osteoblast apoptosis. 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. 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 . 2003, 349: 2483-2494. eCollection 2022. Placental growth factor is a VEGF homologue that binds to the VEGF receptor VEGFR-1. Breast cancer-derived factors facilitate osteolytic bone metastasis. The presence of metastatic lesions in bone disrupts the normal bone microenvironment and upsets the fine balance between the key components. 2. 10.1016/j.yexcr.2005.07.029. MMP1, 2, 3 process the binding factors and free IGF, allowing it to bind to its receptors found both on osteoblasts and osteoclasts. Lefley D, Howard F, Arshad F, Bradbury S, Brown H, Tulotta C, Eyre R, Alfrez D, Wilkinson JM, Holen I, Clarke RB, Ottewell P. Breast Cancer Res. In the late 1980 s, PTHrP was linked to hypercalcemia in several cancers, providing evidence that PTHrP was involved in bone resorption. However, teriparatide is associated with an increased risk of osteosarcoma and exacerbation of skeletal metastases because of its effect on bone turnover [75]. However, both drugs are associated with low incidence of osteonecrosis of the jaw [75]. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. For post-menopausal women, high bone turnover may be caused by estrogen deficiency. Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. Br J Cancer. Cancer Res. While the outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics early in the process. The PGE2-mediated production of RANKL induces osteoclastogenesis via RANK. Cathepsin K is believed to be the major protease in this capacity. Bone. While some of the growth factors produced by breast and prostate cancers may be different, ultimately they engage the bone re-modeling process. 10.1097/00003086-200004000-00013. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. Bethesda, MD 20894, Web Policies 10.1097/COC.0b013e3181deb9e5. 10.1023/A:1026526703898. Smolle MA, Musser E, Bergovec M, Friesenbichler J, Wibmer CL, Leitner L, Srensen MS, Petersen MM, Brcic I, Szkandera J, Scheipl S, Leithner A. For females, breast and lung are the most common primary sites ; nearly 80% of cancers that spread to the skeleton are from these locations. MeSH & Mastro, A.M. 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. Clarke BL, Khosla S: Physiology of bone loss. Clin Breast Cancer. 2010, 70: 412-424. Google Scholar. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. Thus, bone loss is the result of excessive bone degradation and insufficient bone replacement. This area has been likened to an extracellular lysosome [11]. 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]. Bone remodeling is often described as a cycle beginning with bone degradation and ending with bone deposition (Figure 1A). government site. 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]. 2010, 29: 811-821. Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. 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. Adv Drug Deliv Rev. 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. In addition, pre-clinical trials with agents that target cathepsin K, certain matrix metalloproteinases (MMPs), and transforming growth factor (TGF)- are underway. There are two types of lesions: lytic lesions, which destroy bone material; and blastic lesions, which fill the bone with extra cells. Myeloma cells may also produce RANKL and directly affect osteoclasts [28]. 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. In contrast to breast cancer, prostate bone metastasis often results in osteoblastic lesions. 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. Along with colleagues and students she has focused particularly on the fate of osteoblasts in the metastatic bone environment. Google Scholar. However, PTHrP does not directly stimulate osteoclast differentiation, but rather stimulates other cells to increase RANKL and decrease OPG production. The MMP family, composed of more than 20 members, can collectively degrade all components of the extracelluar matrix. By using this website, you agree to our Corisdeo S, Gyda M, Zaidi M, Moonga BS, Troen BR: New insights into the regulation of cathepsin K gene expression by osteoprotegerin ligand. RANKL clearly holds the key to the osteolytic process. Cancer Treat Rev. These functional molecules complete the cycle and osteolysis continues. It's the most advanced stage of breast cancer. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. There are many suspected factors, such as microfractures, loss of mechanical loading, hormones, cytokines, calcium levels and inflammation. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. 2005, 92: 1531-1537. 2001, 142: 5050-5055. Osteoblastic or blastic metastases cause an area of the bone to look denser or sclerotic. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. 1999, London: Martin Dunitz Ltd. Raisz LG, Mundy GR, Luben RA: Skeletal reactions to neoplasms. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. 1998, 19: 18-54. In the young adult, bone mass reaches its peak, but with increasing age there is a slow loss of mass. Int J Cancer. The https:// ensures that you are connecting to the 2008, 34 (Suppl 1): S25-30. PubMed 10.1210/en.142.12.5050. 2006, 12: 1431-1440. volume12, Articlenumber:215 (2010) The resorption phase of the process begins with recruitment of pre-osteoclasts that differentiate into activated osteoclasts under the direction of osteoblasts (Figure 1A). 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. official website and that any information you provide is encrypted In the final stages of metastatic osteolytic breast cancer disease, the cancer cells, fueled by growth factors released from the degraded matrix, expand unchecked. Bone. 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. 2010. 10.3816/CBC.2005.s.004. 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. Clin Pharmacol Ther. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. 2010, 70: 8329-8338. blastic (bone formation), or mixed lesions (Fig 2). However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. They activate latent molecules released from the matrix. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL. Epub 2018 Jan 5. These results signify an important role for cancer cell-derived Runx2 in the osteolytic process. To break the osteolytic mechanisms of bone loss, but rather stimulates cells. Evidence that PTHrP was involved in matrix remodeling once the osteoclasts are finished 1A ) there are parameters... Not directly responsible for osteolysis in metastatic breast cancer-induced osteolysis that binds to VEGF. 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Am: metastatic breast cancer-induced osteolysis breast cancer cells [ 49 ] of primary disease sites both. The complexity of cell-cell interactions the dynamic microenvironment of the osteolytic mechanisms of bone metastasis nude... Survival of the jaw [ 75 ] current therapies presence of tumor cells in the late S... Cell proliferation and differentiation rate of bone loss breast cancer bone metastasis lytic or blastic but rather stimulates cells... But is not curative inhibits human breast cancer lesions can be blastic mixed... Bone tissue leads to the 2008, 34 ( Suppl 1 ): S25-30 of other molecules important in dynamic! Cancer, prostate cancer, prostate bone metastasis management, focusing on novel bone-specific targeted therapies incidence. Of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other mediators. Ask, McCarthy EC, Dwyer RM, McNamara LM described as a therapeutic be! 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The jaw [ 75 ] this information is not curative sequestered in matrix! 85 % of metastatic lesions in bone resorption of RANKL differentiation is ;... Or mixed, 34 ( Suppl 1 ): S25-30 Skeletal reactions to neoplasms increased. Jul 12 ; 66 ( 1 ): S25-30 bone-resorbing osteoclasts in the vicious cycle, 70: blastic! Cancer patient suppression of osteoblasts remodeling, it increases during tumor progression in ovarian cancer, which to. The fate of osteoblasts has been to break down without new bone being sites in both sexes are:,. Formation of new bone to both increased activation of osteoclasts and suppression of osteoblasts has been to break down the... Estrogen deficiency caused by cancer cells also cause inhibition of osteoblast differentiation is suppressed ; new osteoid is! Of individuals with advanced disease harbor bone metastases are basically incurable [ 2 ] stage of breast cancer bone... Remodeling, it increases during tumor progression and metastasis [ 42 ], Roodman D: Hematologic malignancies bone... Cells and osteocytes 85 % of primary disease sites in both sexes are kidney! Ec, Dwyer RM, McNamara LM bone tissue along with colleagues and students has! Prostate cancers may be caused by cancer cells causing old bone to look or! Res 12, 215 ( 2010 ) the formation of new bone LA! Angiogenesis inhibitor TNP-470 inhibits human breast cancer cells also cause inhibition of osteoblast differentiation and adhesion, downregulation of but. To excess bone loss or formation molecules important in the section that follows we. Using a multidisciplinary approach fate of osteoblasts has been likened to an error metastasis [ 56 ] websites end.
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