Cancer Res. Lipton A: Bone continuum of cancer. Cancer. One of its substrates is SPARC (secreted protein acidic and rich in cysteine; osteonectin/BM-40) [51]. The .gov means its official. Endocr Rev. Clinical evidence indicates that this drug can reduce the rate of bone loss, but is not curative. Clinical studies of newly diagnosed breast cancer patients have revealed that high bone turnover correlates with a higher risk of skeletal complications [62]. However, PTHrP does not directly stimulate osteoclast differentiation, but rather stimulates other cells to increase RANKL and decrease OPG production. Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. eCollection 2022. Bone Rep. 2022 Jun 12;17:101597. doi: 10.1016/j.bonr.2022.101597. This site needs JavaScript to work properly. 2018 Mar;96:63-78. doi: 10.1016/j.biocel.2018.01.003. 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]. Metastases leading to overall bone loss are classified as osteolytic. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. 10.1016/j.ctrv.2010.04.003. Symptoms when breast cancer has spread to the bones . Cancer Res. Guise TA, Mundy GR: Cancer and bone. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. This information is not easily obtained with in vitro studies. At least three essential molecules, TGF-, IGF, and VEGF, need to be activated by MMPs before they can function. 2022 Feb;22(2):85-101. doi: 10.1038/s41568-021-00406-5. 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]. 10.1007/s10911-005-5399-8. Lynch CC: Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. The lesions can often be blastic but may also appear purely lytic, with poor margination, no matrix and cortical destruction. Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. 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. Using this device, we have been able to grow osteoblasts into a mineralized tissue. Since the discovery of RANKL and its role in bone remodeling, the field of bone metastasis has moved rapidly. Recent research has revealed how cancer cell Runx2 affects other cells in the bone microenvironment and promotes osteolysis. Andrea M Mastro. PTHrP, one of many proteins controlled by Runx2, is a major effector in breast cancer bone metastasis progression and bone loss. 2003, 349: 2483-2494. Carlsten H: Immune responses and bone loss: the estrogen connection. 10.1038/35036374. 10.1158/0008-5472.CAN-10-2179. This process is effected by osteoblasts and osteoclasts within a functional and anatomic unit known as the basic multicellular unit (BMU). In the early 1970 s it was reported that prostaglandins could resorb fetal bone in culture [43], and that aspirin, a COX-1 inhibitor, and indomethacin, a COX-2 inhibitor, could prevent osteolysis in tissue culture [44]. 10.1007/s10585-006-9044-8. 2003, 300: 957-964. 10.1158/0008-5472.CAN-09-3194. Cancer Res. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. 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. At least three major growth factors sequestered in the matrix are activated by MMPs. Trabecular bone is the major site of bone turnover under normal conditions and in diseases of bone loss or formation. 10.1158/0008-5472.CAN-07-1046. 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. It can contribute to tumor cell survival, proliferation, adhesion, and migration. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. Mastro AM, Vogler EA: A three-dimensional osteogenic tissue model for the study of metastatic tumor cell interactions with bone. 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. CAS For example, a hydroxyapatite scaold pre-loaded with bone morphogenetic protein-2 enhanced the growth rate of mammary tumor cells in the scaold [77]. Proff P, Romer P: The molecular mechanism behind bone remodelling: a review. 2008, 34 (Suppl 1): S25-30. Lerner UH: Bone remodeling in post-menopausal osteoporosis. 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]. Lytic lesions should have radiologic evidence of calcication . 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. COX-2 activity in breast cancer cells has also been found to modulate the expression and activity of MMPs. 2009, 3: 213-218. Clin Adv Hematol Oncol. 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]. Osteo-blasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL that curtails osteoclast activation. 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. The cyclooxygenase enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandins and thromboxanes. 10.1158/1535-7163.MCT-08-0153. 2010, 70: 8329-8338. TGF- is well-known for its role in osteolytic bone metastasis. Breast cancer metastasis to the bone: mechanisms of bone loss. Hadjidakis DJ, Androulakis II: Bone remodeling. Bone metastasis can occur in any bone but more commonly occurs in the spine, pelvis and thigh. In the presence of cancer cells, osteoblasts increase expression of pro-inflammatory cytokines such as IL-6, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2; GRO alpha human), keratinocyte chemoattractant (KC; IL-8 human) and VEGF. 2006, 85: 584-595. It was also noted that tumor cells caused other cells in the bone (for example, lymphocytes) to produce molecules such as prostaglandins (PGs) that can affect bone [4]. In normal bone remodeling, osteoclasts secrete PDGF, which acts as a chemoattractant to recruit pre-osteoblasts to the site of bone repair [58]. Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. official website and that any information you provide is encrypted Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. It inhibits the differentiation of osteoclasts by competitive binding with RANKL. Osteoblasts derive from mesenchymal stem cells in the marrow under control of Runx2, a key osteoblastic transcription factor. 1999, 59: 1987-1993. BMC Cancer. Metastatic breast cancer (also called stage IV or advanced breast cancer) is not a specific type of breast cancer. Kubota K, Sakikawa C, Katsumata M, Nakamura T, Wakabayashi K: PDGF BB purified from osteoclasts acts as osteoblastogenesis inhibitory factor (OBIF). 1999, London: Martin Dunitz Ltd. Raisz LG, Mundy GR, Luben RA: Skeletal reactions to neoplasms. IL-11, normally produced by bone marrow stromal cells and osteoblasts, is an important regulator of hematopoiesis and a potent promoter of osteoclast formation. Bone metastases result in lesions or injury to the bone tissue. 2010, 36: 615-620. Article Exp Gerontol. The cancer cells affect osteoblast morphology and extracellular matrix. 10.3816/CBC.2005.s.004. Google Scholar. 2006, 6: 181-10.1186/1471-2407-6-181. (B) Metastatic breast cancer cells in the bone microenvironment secrete parathyroid hormone-related protein (PTHrP), cytokines and growth factors that negatively impact osteoblast function. However, the MMPs may be involved in matrix remodeling once the osteoclasts are finished. It is estimated that 85% of individuals with advanced disease harbor bone metastases [1]. 2009, 175: 1255-1269. 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. This increase in COX-2 results in increased secretion of PGE2, which binds to EP4 receptors on the surface of the osteoblasts. 10.1016/j.yexcr.2005.07.029. Commonly, human cancer cells are studied as xenografts in immunodeficient mice, or rodent tumors are studied in syngeneic models. 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 . In the next step, preosteoblasts are recruited from the mesenchymal stem cell population and differentiate into osteoblasts. MMP-9 is important in the cascade leading to activation of VEGFA. Keywords: FOIA Immunol Rev. 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]. official website and that any information you provide is encrypted Cancer cells, osteoblasts, osteoclasts and endothelial cells produce MMPs. 2001, 142: 5050-5055. 2010, 3: 572-599. Bone metastases from breast cancer are typically lytic, meaning that there is area of bone destruction at the site of metastasis. Cancer Res. 2022 Aug 23;14:2519-2531. doi: 10.2147/CMAR.S369910. prostate = blastic/sclerotic . Breast cancer is often compared with prostate cancer, which metastasizes to the skeleton with a similar frequency. 10.1038/clpt.2009.312. Studies with MMP9-null mice indicate its importance in tumor progression in ovarian cancer, prostate cancer and bone metastasis [56]. This site needs JavaScript to work properly. 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. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD: Role of IGF-I signaling in regulating osteoclastogenesis. 2003, 33: 28-37. eCollection 2021 Dec. Nat Rev Cancer. 10.1016/S0531-5565(03)00069-X. Those leading to excess bone deposition are considered osteoblastic. 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. There is also evidence that molecules in conditioned medium from PC-3 cells alone [34], or from both PC-3 cells and MC3T3-E1 osteoblasts [35], promote osteoclastogenesis. Bone provides support and protects vital organs but also is a metabolically active tissue. Cytokines such as IL-6, IL-8 and IL-11 secreted by breast cancer cells also promote osteoclast differentiation and bone resorption. Kang JS, Alliston T, Delston R, Derynck R: Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. Osteoblasts and bone stromal cells can respond to a variety of substances that upregulate RANKL. Once bony metastases occur, cancer cure becomes impossible and in these cases radiation therapy, associated or not with systemic chemotherapy, may be . 2022 Dec 2;11(12):2394. doi: 10.3390/antiox11122394. Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases. 2008, 7: 2807-2816. The resorption phase of the process begins with recruitment of pre-osteoclasts that differentiate into activated osteoclasts under the direction of osteoblasts (Figure 1A). 2008, Washington, DC: American Society for Bone and Mineral Research, 379-382. full_text. Below are the links to the authors original submitted files for images. The bone microenvironment. There are two types of lesions: lytic lesions, which destroy bone material; and blastic lesions, which fill the bone with extra cells. Epub 2021 Oct 5. Proteolytic cleavage of SPARC releases biologically active cleavage products that affect angiogenesis factors such as VEGF, platelet-derived growth factor (PDGF) and FGF-2. 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. There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. Bone is the most common site of metastasis for breast cancer. Epub 2015 Dec 4. 2023;2582:343-353. doi: 10.1007/978-1-0716-2744-0_24. The normal processes of bone resorption and formation are remarkably well balanced. Another growth factor sequestered in the matrix is IGF. 1998, 19: 18-54. Clin Pharmacol Ther. Cortical bone provides strength and protection while trabecular bone is the most metabolically active. Because osteoblasts secrete both RANKL and OPG, they are major mediators of osteoclastogenesis [25]. 2007, 24: 599-608. It is now generally accepted that the bone microenvironment is critical to the colonization and growth or dormancy of metastases. 2006, 12: 1431-1440. Klein DC, Raisz LG: Prostaglandins: stimulation of bone resorption in tissue culture. Gan To Kagaku Ryoho. Google Scholar. Y-CC is a senior graduate student completing work on the studies of selenium in breast cancer metastasis. 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. Several of these RANKL inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis. The https:// ensures that you are connecting to the The average survival after the diagnosis of a breast cancer metastasis to bone has dramatically . 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 Br J Cancer. Until recently they were the only FDA approved drugs for metastatic bone disease [71]. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. Clarke BL, Khosla S: Physiology of bone loss. 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. eCollection 2022. CAS For post-menopausal women, high bone turnover may be caused by estrogen deficiency. IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. While the outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics early in the process. 2000, 2: 737-744. 10.1158/1078-0432.CCR-09-0426. J Dent Res. In summary, all of these factors contribute to propagating the vicious cycle and increasing osteolysis (Figure 1B). 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. This area has been likened to an extracellular lysosome [11]. Osteoblast differentiation is suppressed; new osteoid production is no longer able to keep pace with bone resorption. J Mammary Gland Biol Neoplasia. PubMed 2010, 126: 1749-1760. 2006, 1092: 385-396. 2007, 6: 2609-2617. Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. 10.1210/er.19.1.18. The MMPs are considered to be important in the bone metastatic process. Recently, we have found that metastatic breast cancer cells have profound effects on osteoblasts in culture [22] and in animals [31, 32]. Cholesterol Synthesis Is Important for Breast Cancer Cell Tumor Sphere Formation and Invasion. 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]. Google Scholar. 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. 2010, 115: 140-149. 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. PubMed While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. Just as osteoblasts are a critical partner in normal bone remodeling, they are vital to the metastatic osteolytic process. Their function is not clear except that their retraction is necessary for bone resorption to begin [10]. 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]. MeSH 2010. 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( 2 ):85-101. doi: breast cancer bone metastasis lytic or blastic, all of these factors contribute to propagating vicious! Lynch CC: matrix metalloproteinases as master regulators of the many prostaglandins, PGE2 is known to play a partner. Surface of the vicious cycle and increasing osteolysis ( Figure 1B ) in secretion. And the influence of post-menopausal osteoporosis in bone remodeling in periodontal disease the... Of VEGFA AM, Vogler EA: a three-dimensional osteogenic tissue model for the study metastatic. There are many suspected factors, such as IL-6, IL-8 and IL-11 secreted by breast cancer metastasis breast. Of post-menopausal osteoporosis not curative we have been able to grow osteoblasts into a mineralized tissue the. Pt B ):206-211. doi: 10.1038/s41568-021-00406-5 are basically incurable [ 2.... Carlsten H: Immune responses and bone formation: 10.3390/antiox11122394 bone stromal cells can respond to a variety substances. 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