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. The main symptoms of breast cancer that has spread to bone are: Both RANKL and VEGF can induce osteoclast formation [48], and MMPs play a role in bone matrix degradation. 2022 Dec 2;11(12):2394. doi: 10.3390/antiox11122394. 2008, 7: 2807-2816. The dynamics of this system are interrupted when metastatic breast cancer cells are introduced, adding another layer of active molecules to the bone environment. Bone lining cells appear microscopically as relatively undifferentiated cells that line the bone. Metastases leading to overall bone loss are classified as osteolytic. PTHrP is expressed in the primary tumors of about 50% of patients and in more than 90% of breast cancer bone metastasis samples [18]. PMC 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). In people with breast and prostate cancer, the bone is often the first distant site of cancer spread. IL-8, a proinflammatory CXC chemokine, is secreted by monocytes, endothelial cells and osteoblasts. The https:// ensures that you are connecting to the Recent research has revealed how cancer cell Runx2 affects other cells in the bone microenvironment and promotes osteolysis. However, 15-20% of metastatic breast cancer lesions can be blastic or mixed. In reality the system is much more complex (Table 1). This process is effected by osteoblasts and osteoclasts within a functional and anatomic unit known as the basic multicellular unit (BMU). 2010, 115: 140-149. 2004, 21: 427-435. 2009, 7 (Suppl 7): S1-29. Bone metastasis can occur in any bone but more commonly occurs in the spine, pelvis and thigh. In this context, RANKL increases in the presence of inflammatory agents from infectious organisms, such as lipopolysaccharide, CpGpDNA and viral double-stranded DNA [41]. Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. 10.1196/annals.1365.035. 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. IGF, insulin-like growth factor; MCP-1, monocyte chemotactic protein-1; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor. While some of the growth factors produced by breast and prostate cancers may be different, ultimately they engage the bone re-modeling process. CA Cancer J Clin. 2009, 69: 4097-4100. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis. Cancer Treat Rev. MeSH 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. Keywords: Bone remodeling is often described as a cycle beginning with bone degradation and ending with bone deposition (Figure 1A). Clinical evidence indicates that this drug can reduce the rate of bone loss, but is not curative. 2009, 175: 1255-1269. There is evidence in both humans and animals that bone loss in osteolytic metastasis is partly due to the failure of the osteoblasts to produce new osteoid for the bone matrix. Induction of aberrant osteoclastogenesis is only part of the equation. Part of This site needs JavaScript to work properly. BMC Cancer. 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. 10.1038/clpt.2009.312. 2002, 13: 62-71. Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. In a recent comprehensive review article, Lynch [50] presents the case that they are 'master regulators' of the vicious cycle. Akech and colleagues [34] recently reported that Runx2 (Runt-related transcription factor 2) is produced by the highly metastatic prostate cancer cell PC-3, and positively correlates to the severity of osteolytic disease. 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. Cancer Res. There are two types of lesions: lytic lesions, which destroy bone material; and blastic lesions, which fill the bone with extra cells. 2003, 89: 2031-2037. Lerner UH: Bone remodeling in post-menopausal osteoporosis. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Kang and colleagues [20] found that expression of two MMP genes, MMP1 and ADAMTS1, discriminated between a subline of osteotropic metastatic MDA-MB-231 cells and the parental line. TGF- is well-known for its role in osteolytic bone metastasis. 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]. The role of lining cells. 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. IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. 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. 10.1210/en.142.12.5050. J Dent Res. 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. HHS Vulnerability Disclosure, Help PubMed Central Clin Oral Investig. In males, prostate and lung cancers make up 80% of carcinomas metastasizing to bone. While not directly responsible for osteolysis in metastatic breast cancer disease, there are physiological parameters that can amplify the degree of bone loss. In the final stages of metastatic osteolytic breast cancer disease, the cancer cells, fueled by growth factors released from the degraded matrix, expand unchecked. Several MMPs (MMP2, 3, 9) can release TGF- from the latent state, allowing it to become active. 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. 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. Ann N Y Acad Sci. Cancer Treat Rev. & Mastro, A.M. 10.1158/1078-0432.CCR-09-0426. Yang Y, Ren Y, Ramani VC, Nan L, Suva LJ, Sanderson RD: Heparanase enhances local and systemic osteolysis in multiple myeloma by upregulating the expression and secretion of RANKL. Nevertheless, they do not appear to function in the osteoclast resorption lacuna, probably due to the low pH in this compartment. While drugs that inhibit osteoclast differentiation or activity are vital to treating osteolysis, therapies designed to restore osteoblast number and function will be required to fully resolve osteolytic lesions. 2008, Washington, DC: American Society for Bone and Mineral Research, 379-382. full_text. 10.1023/A:1026526703898. 2006, 12: 1431-1440. It is required to drive mesenchymal cells to become osteoblasts. 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]. -, Proc Natl Acad Sci U S A. Radiotracer is taken up only by activated osteoblasts and as such, bone scans are quite often negative even with extensive skeletal involvement by myeloma [ 5 ]. Bookshelf 2010, 87: 401-406. 2010, 9: 122-10.1186/1476-4598-9-122. What initiates remodeling in the non-tumor-containing bone? Unable to load your collection due to an error, Unable to load your delegates due to an error. These findings led to a flurry of studies to develop COX and prostaglandin inhibitors as cures for bone metastasis. Springer Nature. The average survival after the diagnosis of a breast cancer metastasis to bone has dramatically . Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. 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]. Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. Mercer RR, Miyasaka C, Mastro AM: Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. Further stimulation results in large multinuclear cells capable of bone resorption. Cytokines such as IL-6, IL-8 and IL-11 secreted by breast cancer cells also promote osteoclast differentiation and bone resorption. Thus, bone loss is the result of excessive bone degradation and insufficient bone replacement. 2003, 38: 605-614. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. 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. 2006, 85: 596-607. 10.1007/s10585-004-1867-6. 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. 2010, 70: 6150-6160. 2008, 68: 7795-7802. However, once bone metastasis has occurred, the aim has been to break the osteolytic cycle by targeting osteoclasts. Bone. The ratio of RANKL to OPG determines the extent of the osteoclast activity and bone degradation. However, both bone degradation and deposition likely occur early in the metastatic process. 2023 BioMed Central Ltd unless otherwise stated. Unable to load your collection due to an error, Unable to load your delegates due to an error. 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]. The lesions can often be blastic but may also appear purely lytic, with poor margination, no matrix and cortical destruction. Mol Cancer Ther. 2007, 57: 43-66. Parathyroid hormone-related protein and bone metastases. Breast Cancer Research It was recently reported that mice deficient in vitamin D or calcium showed increased metastatic tumor growth and accelerated rates of bone resorption [66, 67]. However, cathepsin K is also produced by other cells in the bone microenvironment, such as macrophages and bone marrow stromal cells. 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. 2000, 373: 104-114. The majority of breast cancer metastases ultimately cause bone loss. Cancer. Current therapies consist of blocking osteoclast activity as a means of disrupting the vicious cycle. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. Carlsten H: Immune responses and bone loss: the estrogen connection. Google Scholar. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD: Role of IGF-I signaling in regulating osteoclastogenesis. Grey A: Teriparatide for bone loss in the jaw. The purpose of this study is to find a safe dose of: - Xentuzumab in combination with abemaciclib - Xentuzumab in combination with abemaciclib and hormonal therapies The study also tests whether these medicines make tumours shrink in participants with lung and breast cancer. Marie L, Braik D, Abdel-Razeq N, Abu-Fares H, Al-Thunaibat A, Abdel-Razeq H. Cancer Manag Res. Cancer Res. PubMed Central We also discuss known risk factors as well as detection and assessment of bone metastases. 10.1006/bbrc.2001.5127. 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. 10.1038/onc.2009.389. 2009, 13: 355-362. MMP1, 2, 3 process the binding factors and free IGF, allowing it to bind to its receptors found both on osteoblasts and osteoclasts. Gradient Boosting Machine Identified Predictive Variables for Breast Cancer Patients Pre- and Post-Radiotherapy: Preliminary Results of an 8-Year Follow-Up Study. Mastro AM, Vogler EA: A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. Cancer. Pratap and colleagues [40] found that Runx2 responds to TGF- stimulation by activating the expression of Indian hedgehog (IHH), which further increases the level of PTHrP. 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. The .gov means its official. Article Assessment; Bone; Bone-targeted therapy; Detection; Mechanism of bone metastases; Metastasis; Therapy. Other cells of the osteoblastic lineage include bone lining cells and osteocytes. 10.1056/NEJMe1010459. Osteoblasts derive from mesenchymal stem cells in the marrow under control of Runx2, a key osteoblastic transcription factor. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. In addition, other cells not specific for bone but likely to be found in the bone (macrophages, neutrophils and T lymphocytes) produce MMPs. Endocr Rev. Bone Rep. 2022 Jun 12;17:101597. doi: 10.1016/j.bonr.2022.101597. Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. 10.1038/sj.bjc.6601437. Aldridge SE, Lennard TW, Williams JR, Birch MA: Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. However, the MMPs may be involved in matrix remodeling once the osteoclasts are finished. 10.1007/s10911-005-5399-8. The MMP family, composed of more than 20 members, can collectively degrade all components of the extracelluar matrix. 10.1177/154405910608500703. government site. Osteoblast differentiation is suppressed; new osteoid production is no longer able to keep pace with bone resorption. Here we discuss some of the proposed mechanisms that contribute to metastatic breast cancer-induced bone loss. Bone metastases in breast cancer may be osteolytic, osteoblastic, or mixed blastic and lytic. Clinical studies of newly diagnosed breast cancer patients have revealed that high bone turnover correlates with a higher risk of skeletal complications [62]. Ann N Y Acad Sci. HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. An Open Label, Phase Ib, Dose-escalation Study Evaluating the Safety and Tolerability of Xentuzumab and Abemaciclib in Patients With Locally Advanced or Metastatic Solid Tumours and in Combination With Endocrine Therapy in Patients With Locally Advanced o. 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. Bone metastases result in lesions or injury to the bone tissue. An official website of the United States government. The osteoclasts work as part of the bone remodeling compartment, underneath a canopy of bone lining cells. This area has been likened to an extracellular lysosome [11]. 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. PubMed Surprisingly, this treatment did not affect angiogenesis in the bone. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. Due to this, the bones get harder and cause the condition called sclerosis. Exp Cell Res. Cancer Res. Primarily they spread to spine, but lung cancer is known to metastasize to the . However, breast cancer cells are unable to progress in bone unless they destroy bone with the assistance of bone-resorbing osteoclasts. All three doctors say that new, progressive pain in your bones or joints is the most common symptom of metastatic breast cancer in bones. Google Scholar. Cathepsin K is believed to be the major protease in this capacity. 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 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. What can be done to stop osteolytic metastasis? 2003, 300: 957-964. 2012 Aug;39(8):1174-7. Its common for people to have lytic and blastic lesions at the same time. As seen in the images here, multiple, confluent sclerotic, blastic bony lesions are typical of metastatic breast cancer. 2006, 21: 1350-1358. 10.1016/S8756-3282(03)00086-3. 2005, 24: 2543-2555. Mol Cancer Ther. There are many suspected factors, such as microfractures, loss of mechanical loading, hormones, cytokines, calcium levels and inflammation. 10.3390/ph3030572. 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. It is estimated that osteolytic lesions occur in 60 to 95% of myeloma patients [1, 27]. 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.