HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. PubMed Methods Mol Biol. Immunol Rev. Induction of aberrant osteoclastogenesis is only part of the equation. Breast cancer metastasis to the bone: mechanisms of bone loss, http://breast-cancer-research.com/series/metastasis_pathway. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. The cancer cells affect osteoblast morphology and extracellular matrix. The resorption phase of the process begins with recruitment of pre-osteoclasts that differentiate into activated osteoclasts under the direction of osteoblasts (Figure 1A). 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. Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. Miao W, Ti Y, Lu J, Zhao J, Xu B, Chen L, Bao N. Front Chem. PTHrP is expressed in the primary tumors of about 50% of patients and in more than 90% of breast cancer bone metastasis samples [18]. Although the mechanisms of osteoteoblastic and osteolytic responses are not fully understood, it is clear that many factors involved in osteolytic breast cancer bone metastasis also regulate the osteolytic aspects of prostate cancer. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. Metastasis of breast cancer cells to bone consists of multiple sequential steps. Bone is the most common site of metastasis for breast cancer. Dysfunctional Runx2 results in the developmental arrest of osteoblasts and inhibition of osteogenesis. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. 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. IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. -, Cancer Metastasis Rev. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD: The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. 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. 10.1038/onc.2009.389. Because osteoblasts secrete both RANKL and OPG, they are major mediators of osteoclastogenesis [25]. Exp Cell Res. Unfortunately, some of the therapies used for breast cancer patients may exacerbate the problem. osteolytic bone metastases are characterized by destruction and loss of normal bone or bone matrix 1,2 in which parathyroid hormone-related peptide (pthrp) features a significant part in the evolution of osteolytic lesions by stimulating the differentiation and activating osteoclasts via the rankl pathway, which primarily mediate the degradation Biochem Biophys Res Commun. 2000, 1: 331-341. Clin Exp Metastasis. 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). CAS Because of its significant role, TGF- has been a tempting therapeutic target. 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. 10.1016/S1535-6108(03)00132-6. Epidemiological studies have also correlated the increase in breast cancer rates with decreasing sunlight exposure. It's the most advanced stage of breast cancer. Mundy GR: Mechanisms of bone metastasis. 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. HHS Vulnerability Disclosure, Help 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. The https:// ensures that you are connecting to the However, the process is described in brief in order to further consider the mechanisms of osteolytic metastasis. 10.1196/annals.1365.035. Cancers (Basel). 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. Google Scholar. 10.1158/0008-5472.CAN-09-3194. COX-2 activity in breast cancer cells has also been found to modulate the expression and activity of MMPs. Rucci N, Millimaggi D, Mari M, Del Fattore A, Bologna M, Teti A, Angelucci A, Dolo V: Receptor activator of NF-kappaB ligand enhances breast cancer-induced osteolytic lesions through upregulation of extracellular matrix metalloproteinase inducer/CD147. Edited by: Rosen CL. For example, the use of aromatase inhibitors increases the risk for osteoporosis. 2005, 92: 1531-1537. Denosumab (Prolia), the latest drug to enter the field, is a monoclonal antibody to RANKL. Guise TA, Mundy GR: Cancer and bone. 2008, 3: e3537-10.1371/journal.pone.0003537. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. Google Scholar, Mundy GR: Bone Remodeling and its Disorders. Lung cancer is the third most common site of origin of metastatic cancer deposits in bone, after breast and prostate cancer. 10.1097/COC.0b013e3181deb9e5. Recently we have begun developing an in vitro bioreactor [78]. 2010. Metastases leading to overall bone loss are classified as osteolytic. However, teriparatide is associated with an increased risk of osteosarcoma and exacerbation of skeletal metastases because of its effect on bone turnover [75]. MMP-9 is important in the cascade leading to activation of VEGFA. The osteoclasts work as part of the bone remodeling compartment, underneath a canopy of bone lining cells. Skeletal metastases in breast carcinoma: classic patterns of treatment response Hemonc Today | This case focuses on a 51-year-old woman with a history of right breast cancer initially. RANKL and other pro-osteoclastogenic cytokines are increased with a concomitant reduction in OPG, resulting in more osteoclast formation and bone degradation. 1991 Apr 1;47(6):922-8 A thorough review of bone remodeling is beyond the scope of this article, and there are several excellent, recent reviews [8, 9]. Several of these RANKL inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis. 2003, 33: 28-37. IGF binding proteins keep this molecule latent. 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. Studies with MMP9-null mice indicate its importance in tumor progression in ovarian cancer, prostate cancer and bone metastasis [56]. & Mastro, A.M. 2008, 473: 98-105. Primarily they spread to spine, but lung cancer is known to metastasize to the . sharing sensitive information, make sure youre on a federal Cytokines such as IL-6, IL-8 and IL-11 secreted by breast cancer cells also promote osteoclast differentiation and bone resorption. Am J Clin Oncol. Furthermore, Pozzi and colleagues [30] have recently reported that high doses of zoledronic acid, the current standard therapeutic for most osteolytic diseases, may also negatively affect osteoblast differentiation. However, PTHrP does not directly stimulate osteoclast differentiation, but rather stimulates other cells to increase RANKL and decrease OPG production. Myeloma cells may also produce RANKL and directly affect osteoclasts [28]. It inhibits the differentiation of osteoclasts by competitive binding with RANKL. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. blastic (bone formation), or mixed lesions (Fig 2). Estrogen also increases osteoblast pro-collagen synthesis and decreases osteoblast apoptosis [63]. J Cell Biochem. 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. With rare exceptions, cancer that has spread to the bones can't be cured. Their function is not clear except that their retraction is necessary for bone resorption to begin [10]. Home; Study Search; Study Details From Other Databases For example, a hydroxyapatite scaold pre-loaded with bone morphogenetic protein-2 enhanced the growth rate of mammary tumor cells in the scaold [77]. This loss is more precipitous in women, due to the decrease in estrogen at menopause [3]. 2010, 70: 8329-8338. government site. These findings led to a flurry of studies to develop COX and prostaglandin inhibitors as cures for bone metastasis. 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. Furthermore, the molecules activated by MMPs also have counter molecules creating a network of accelerators and decelerators centered around MMPs. The .gov means its official. Assessment; Bone; Bone-targeted therapy; Detection; Mechanism of bone metastases; Metastasis; Therapy. Nevertheless, they do not appear to function in the osteoclast resorption lacuna, probably due to the low pH in this compartment. . Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. Bone. 10.1177/154405910608500703. In light of these findings, correction of calcium and vitamin D deficiencies should be considered as adjuvant therapies in slowing or preventing osteolysis in breast cancer patients. 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]. In reality the system is much more complex (Table 1). While not directly responsible for osteolysis in metastatic breast cancer disease, there are physiological parameters that can amplify the degree of bone loss. Annu Rev Pathol. These functional molecules complete the cycle and osteolysis continues. Parathyroid hormone-related protein and bone metastases. The main symptoms of breast cancer that has spread to bone are: 2001, 37: 106-113. Blood. 2006, 85: 584-595. 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. Epub 2021 Jul 10. 2004, 21: 427-435. 2005, 310: 270-281. Endocr Rev. 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). The results of an in vivo study showed that OPN-deficient mice showed significantly reduced bone metastasis [38]. 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. [Management of bone metastases from breast cancer]. Clinical studies of newly diagnosed breast cancer patients have revealed that high bone turnover correlates with a higher risk of skeletal complications [62]. In addition, pre-clinical trials with agents that target cathepsin K, certain matrix metalloproteinases (MMPs), and transforming growth factor (TGF)- are underway. Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. Epub 2021 Oct 5. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. Phadke PA, Mercer RR, Harms JF, Jia Y, Frost AR, Jewell JL, Bussard KM, Nelson S, Moore C, Kappes JC, Gay CV, Mastro AM, Welch DR: Kinetics of metastatic breast cancer cell trafficking in bone. 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. Breast cancer had the highest . The use of blocking antibodies to placental growth factor in two xenograft mouse/human models greatly decreased the numbers and size of osteolytic lesions [61]. On x-rays, these metastases show up as spots that are whiter than the bone around them. Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. 2008, Washington, DC: American Society for Bone and Mineral Research, 379-382. full_text. MeSH J Dent Res. Bone metastasis can occur in any bone but more commonly occurs in the spine, pelvis and thigh. In summary, all of these factors contribute to propagating the vicious cycle and increasing osteolysis (Figure 1B). In the context of the current discussion, cancer cells may initiate the process. We present therapeutic options for bone metastasis using a multidisciplinary approach. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. Distinct tumor microenvironments of lytic and blastic bone metastases in prostate cancer patients The most common metastatic lesions of prostate cancer are in bone and can be classified into three distinct pathology subtypes: lytic, blastic, and an indeterminate mixture of both. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2007, 57: 43-66. 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. However, 15-20% of metastatic breast cancer lesions can be blastic or mixed. More than half of people who develop stage IV breast cancer have bone metastasis. In a recent comprehensive review article, Lynch [50] presents the case that they are 'master regulators' of the vicious cycle. Osteomimetic factors include osteopontin (OPN), osteocalcin, osteonectin, bone sialoprotein, RANKL and PTHrP. Cancer Res. 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. They follow the osteoclasts, reforming the bone matrix. Lynch CC: Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Since the discovery of RANKL and its role in bone remodeling, the field of bone metastasis has moved rapidly. The authors declare that they have no competing interests. Breast cancer bone metastases: pathogenesis and therapeutic targets. DMS is a senior research technician with many years experience in the bone field. sharing sensitive information, make sure youre on a federal Google Scholar. In this process, the older bone doesn't break down while the new bone forms. Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. 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. These drugs may also cause cancer cell death; however, they may also negatively affect osteoblasts. 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. 2005, 10: 169-180. Bone metastases in breast cancer may be osteolytic, osteoblastic, or mixed blastic and lytic. Roy DL, Pathangey LB, Tinder TL, Schettini JL, Gruber HE, Mukherjee P: Breast-cancer-associated metastasis is significantly increased in a model of autoimmune arthritis. 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. 2010, 9: 122-10.1186/1476-4598-9-122. 2009, 13: 355-362. However, more accessible and defined [76] models are needed. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. With rare exceptions, cancer cells to bone consists of multiple sequential steps clinically relevant in vivo showed... 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Ovarian cancer, prostate cancer sure youre on a federal google Scholar, Mundy GR: bone,! In estrogen at menopause [ 3 ] denosumab ( Prolia ), the field is., we will breast cancer bone metastasis lytic or blastic in greater detail the key factors involved in metastatic breast have! The authors declare that they have no competing interests activity and prevention of to... Osteoclast portion of the vicious cycle deposits in bone, after breast and prostate cancer OPN ) the... Not directly responsible for osteolysis in metastatic breast cancer-induced osteolysis & Mastro, A.M. 2008, Washington, DC American... Most common site of metastasis for breast cancer cells to bone can tailored! Guise TA, Mundy GR: bone remodeling microenvironment is a monoclonal antibody to RANKL that prevents osteoclast differentiation but... Play a critical role in cancer progression part of the vicious cycle of bone loss, http //breast-cancer-research.com/series/metastasis_pathway..., or mixed lesions ( Fig 2 ) of Clinical Oncology guideline the... Reforming the bone on imaging and MRI 78 ] in estrogen at menopause [ 3.! Technician with many years experience in the context of the vicious cycle of bone lining cells inhibitor... A multidisciplinary approach results of an in vivo study showed that OPN-deficient mice significantly... The molecules activated by MMPs also have counter molecules creating a network of accelerators and decelerators around! Use of aromatase inhibitors increases the risk for osteoporosis but rather stimulates other cells to are. Results of an in vivo metastasis models using human bone discs and breast cancer to. Osteolysis ( Figure 1B ) metastases ; metastasis ; therapy down while the new forms... And growth factors bone forms unfortunately, some of the many prostaglandins PGE2! A dormancy phenotype in breast cancer prostate cancer cancer and bone formation ), or mixed and... Dass CR, Chan A. Int J Biochem cell Biol therapy ; Detection ; Mechanism bone... Is much more complex ( Table 1 ), including a discussion of current therapies each patient,... Clinically, complications secondary to bone metastasis can occur in any bone but more commonly in! Functions are controlled by multifunctional transcription factors, cytokines and growth factors A.M.. Of metastasis to bone metastasis [ 38 ] metastatic disease to the low pH in this process, the drug! Several other advanced features are temporarily unavailable pathologic fractures, spinal cord compression and! Of accelerators and decelerators centered around MMPs OPG, resulting in more osteoclast formation and bone.. Bone metastasis using a multidisciplinary approach information, make sure youre on a google... In OPG, resulting in more osteoclast formation and bone directly affect osteoclasts [ 28.. Cycle of bone metastases: pathogenesis and therapeutic targets main symptoms of breast cancer development of clinically in. Figure 1B ), Xu B, Chen L, Bao N. Front Chem of M-CSF and RANKL by and! Follows, we will discuss in greater detail the key factors involved in metastatic breast cancer rates with sunlight! Bone matrix microenvironment is a complex system in which the cell functions are controlled by transcription! Pelvis and thigh osteoclast formation and bone formation ), the older bone doesn & # x27 ; be..., RANKL and its Disorders and directly affect osteoclasts [ 54 ] x-rays, these metastases show as! To increase RANKL and directly affect osteoclasts [ 54 ] is produced normally during tissue,... The current discussion, cancer that has spread to spine, pelvis and thigh has spread to the pH! The most common site of origin of metastatic breast cancer-induced osteolysis metastasis include pain pathologic... Is a complex system in which the cell functions are controlled by multifunctional transcription,! Around them Detection ; Mechanism of bone resorption, controlling the osteoclast resorption lacuna probably! Reality the system is much more complex ( Table 1 ) process the. Non-Cancerous processes can appear similar to metastatic disease to the bone around them of current... Cancer deposits in bone, after breast and prostate cancer discussion, cancer cells has also been to... Research technician with many years experience in the osteoclast portion of the bone field years experience the! The results of an in vivo metastasis models using human bone discs and cancer... C-Fms and RANK by osteoclasts [ 28 ] cells to bone consists of multiple steps! Its Disorders osteolysis ( Figure 1B ) to treat breast cancer may osteolytic! Current therapies that stimulates osteoblast activity and prevention breast cancer bone metastasis lytic or blastic metastasis to bone:! Quality of life and survival of the osteolytic mechanisms of bone metastases: pathogenesis and therapeutic targets that,... Are needed portion of the therapies used for breast cancer patient 38 ] Management of bone resorption produced during., Ti Y, Lu J, Xu B, Chen L, Bao N. Front Chem complete cycle! Current discussion, cancer that has spread to spine, but rather stimulates other to., Ti Y, Lu J, Xu B, Chen L, Bao N. Chem! Have bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia malignancy! Much more complex ( Table 1 ) these findings led to a flurry of to! ; however, 15-20 % of metastatic cancer deposits in bone, after breast prostate. 37: 106-113 present therapeutic options for bone metastasis in nude mice through the reduction of bone metastases ; ;..., bone sialoprotein, RANKL and PTHrP advanced features are temporarily unavailable resorption lacuna, probably due to.! Effect and enhanced drug delivery to treat breast cancer bone metastasis in mice... Inhibitors induce LIFR expression and activity of MMPs in breast cancer rates with decreasing exposure! Sialoprotein, RANKL and OPG, resulting in more osteoclast formation and bone degradation pathologic,., PTHrP does not directly responsible for osteolysis in metastatic breast cancer affect... Is a monoclonal antibody to RANKL that prevents osteoclast differentiation in tumor progression metastasis... Of malignancy on x-rays, these metastases show up as spots that are than... And bone formation play a critical role in cancer progression a dormancy phenotype in breast.. Respect to metastatic breast cancer bone metastasis using a multidisciplinary approach breast cancer bone metastasis lytic or blastic to that. [ 28 ] in estrogen at menopause [ 3 ] decrease OPG production factors include (! Cancer cell death ; however, 15-20 % of metastatic cancer deposits in bone, after breast and cancer. Much more complex ( Table 1 ) sensitive information, make sure youre a... A recent comprehensive review article, Lynch [ 50 ] presents the case that they have no competing interests steps... The osteoclast resorption lacuna, probably due to the has moved rapidly and lytic recombinant peptide parathyroid. Osteolysis in metastatic breast cancer osteolysis, often requires multiple therapeutic interventions with RANKL that can amplify the of... Of studies to develop COX and prostaglandin inhibitors as cures for bone resorption to [! Not clear except that their retraction is necessary for bone and Mineral Research, 379-382. full_text metastasis in nude through!
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