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. These approaches still rely on animals. 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. Ooi LL, Zheng Y, Stalgis-Bilinski K, Dunstan CR: The bone remodeling environment is a factor in breast cancer bone metastasis. A newly discovered molecule downstream of RANKL is extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147, a cell surface glycoprotein that is known to induce MMPs and VEGF [48]. However, more accessible and defined [76] models are needed. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. Metastatic breast cancer (also called stage IV or advanced breast cancer) is not a specific type of breast cancer. Another drug, teriparatide (Forteo), the amino-terminal 34 amino acids of parathyroid hormone, has been used for many years to treat osteoporosis. Cancer Cell. 1993 Jun 1;90(11):5021-5 Bone. This molecule is also produced by metastatic breast cancer cells [49]. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. 10.1038/sj.emboj.7600729. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. Further, we describe future directions for bone metastasis management, focusing on novel bone-specific targeted therapies. The blastic bone lesions are caused when the cancer cells release the fluids. 1970, 86: 1436-1440. Proteolytic cleavage of SPARC releases biologically active cleavage products that affect angiogenesis factors such as VEGF, platelet-derived growth factor (PDGF) and FGF-2. Pozzi S, Vallet S, Mukherjee S, Cirstea D, Vaghela N, Santo L, Rosen E, Ikeda H, Okawa Y, Kiziltepe T, Schoonmaker J, Xie W, Hideshima T, Weller E, Bouxsein ML, Munshi NC, Anderson KC, Raje N: High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Once bony metastases occur, cancer cure becomes impossible and in these cases radiation therapy, associated or not with systemic chemotherapy, may be . Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. In the next step, preosteoblasts are recruited from the mesenchymal stem cell population and differentiate into osteoblasts. 2008, 314: 173-183. statement and Google Scholar. 10.1038/sj.bjc.6602417. Federal government websites often end in .gov or .mil. 2. IGF binding proteins keep this molecule latent. Provided by the Springer Nature SharedIt content-sharing initiative. Cancer Res. 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. PubMed Central In the late 1980 s, PTHrP was linked to hypercalcemia in several cancers, providing evidence that PTHrP was involved in bone resorption. The lesions can often be blastic but may also appear purely lytic, with poor margination, no matrix and cortical destruction. 2003, 300: 957-964. 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. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. 2005, 5 (Suppl): S46-53. Shimo T, Okui T, Horie N, Yokozeki K, Takigawa M, Sasaki A. Several MMPs (MMP2, 3, 9) can release TGF- from the latent state, allowing it to become active. Eventually, bone remodeling ceases as both osteoblasts and osteoclasts are lost. For post-menopausal women, high bone turnover may be caused by estrogen deficiency. It inhibits the differentiation of osteoclasts by competitive binding with RANKL. Lung cancer is the third most common site of origin of metastatic cancer deposits in bone, after breast and prostate cancer. Dysfunctional Runx2 results in the developmental arrest of osteoblasts and inhibition of osteogenesis. 2 Of interest is that patients with blastic (versus osteolytic) bone metastases have been reported to have prolonged survival. Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. These molecules not only help support tumor cells, but also are osteoclastogenic. Other molecules made by multiple myeloma cells, such as IL-3, IL-7 and soluble frizzle-related protein-2, also inhibit osteoblast differentiation [27]. 10.1097/SPC.0b013e32832f4149. BMC Cancer. 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. 2022 Jul 20;14(14):3521. doi: 10.3390/cancers14143521. This remarkable process of bone degradation and formation is synchronized by direct cell contact and a variety of secreted factors (Table 1). It binds to two class III tyrosine kinase receptors, PDGFR and PDGFR, leading to activation of several signaling molecules. Bone remodeling is often described as a cycle beginning with bone degradation and ending with bone deposition (Figure 1A). N Engl J Med. 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. 10.1111/j.0105-2896.2005.00326.x. Both RANKL and VEGF can induce osteoclast formation [48], and MMPs play a role in bone matrix degradation. 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. Prostate. blastic (bone formation), or mixed lesions (Fig 2). An official website of the United States government. 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. 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. Breast Cancer Res. J Cell Biochem. Cancer Res. Myeloma cells produce factors that upregulate osteoblast production of M-CSF and RANKL and downregulate production of OPG. Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. Here we discuss some of the proposed mechanisms that contribute to metastatic breast cancer-induced bone loss. volume12, Articlenumber:215 (2010) Bookshelf Bone. Until recently they were the only FDA approved drugs for metastatic bone disease [71]. Chronic inflammation has long been considered a risk factor in cancer initiation [68]. 2005, 10: 169-180. In addition, production of inflammatory cytokines (that is, IL-6, TNF-, M-CSF, IL-1) is suppressed by estrogen [64]. 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. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. 10.1007/s00784-009-0268-2. 2012 Aug;39(8):1174-7. The cancer cells affect osteoblast morphology and extracellular matrix. 10.1097/COC.0b013e3181deb9e5. There are many excellent reviews describing this paradigm [1417] from its inception in the 1990 s. The minimal essential components are osteoblasts, osteoclasts, tumor cells and the mineralized bone matrix. 2008, 473: 98-105. Clipboard, Search History, and several other advanced features are temporarily unavailable. It has high affinity for type I collagen, the most abundant matrix protein. PDGF can function as a mitogen for cells of mesenchymal origin and possesses chemoattractant properties, making it an important factor in cell proliferation and migration. Placental growth factor is a VEGF homologue that binds to the VEGF receptor VEGFR-1. Endocr Rev. The majority of bone metastases are asymptomatic. Cancer Res. Privacy Kinder M, Chislock E, Bussard KM, Shuman L, Mastro AM: Metastatic breast cancer induces an osteoblast inflammatory response. It is estimated that osteolytic lesions occur in 60 to 95% of myeloma patients [1, 27]. At least three major growth factors sequestered in the matrix are activated by MMPs. In fact, a new drug, denosumab (Prolia), a fully human monoclonal antibody to RANKL, has been approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal women with high risk of osteoporotic fractures, and is under priority review for patients with bone metastases. In males, prostate and lung cancers make up 80% of carcinomas metastasising to bone. Ohshiba T, Miyaura C, Ito A: Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. However, once bone metastasis has occurred, the aim has been to break the osteolytic cycle by targeting osteoclasts. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. Primarily they spread to spine, but lung cancer is known to metastasize to the . 60% of breast CA is blastic 90% of prostate CA is blastic cortical metastasis are common in lung cancer lesions distal to elbow and knee are usually from lung or renal primary studies Workup for older patient with single bone lesion and unknown primary includes imaging plain radiographs CT of chest / abdomen / pelvis technetium bone scan labs Aldridge SE, Lennard TW, Williams JR, Birch MA: Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. Studies with MMP9-null mice indicate its importance in tumor progression in ovarian cancer, prostate cancer and bone metastasis [56]. 2009, 3: 213-218. spinal cord compression) palpable mass deformity pathological fracture hypercalcemia bone marrow aplasia 10.1016/j.ctrv.2008.03.008. Using this device, we have been able to grow osteoblasts into a mineralized tissue. 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 Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis. Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. Several of these RANKL inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis. Epub 2018 Jan 5. Often, bone metastases have both lytic and blastic features. Purpose: This is a study in adult patients with different types of cancer. It promotes growth and survival of tumor cells [61], and is also involved in osteoclast differentiation. Bone is the most common site of metastasis for breast cancer. 2005, 24: 2543-2555. Disclaimer, National Library of Medicine Its common for people to have lytic and blastic lesions at the same time. Metastatic bone lesions are the predominant malignancy to effect bone, with 15 times the occurrence rate of the next most common bone malignancy. J Natl Compr Canc Netw. 1973, 28: 316-321. 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. As might be expected from the nature of the osteolytic process, that is, the degradation of bone, the microenvironment contains many proteases. 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. Hadjidakis DJ, Androulakis II: Bone remodeling. Cancer. Google Scholar. However, the process is described in brief in order to further consider the mechanisms of osteolytic metastasis. There are conflicting reports regarding their effect on osteoblasts. 2009, 15: 5829-5839. 2000, 373: 104-114. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. The .gov means its official. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. Due to this, the bones get harder and cause the condition called sclerosis. Google Scholar. Bethesda, MD 20894, Web Policies 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. This information is not easily obtained with in vitro studies. Clipboard, Search History, and several other advanced features are temporarily unavailable. Troen BR: Molecular mechanisms underlying osteoclast formation and activation. . N Engl J Med. CAS 2009, 13: 355-362. Klein DC, Raisz LG: Prostaglandins: stimulation of bone resorption in tissue culture. Rucci N, Teti A: Osteomimicry: how tumor cells try to deceive the bone. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. Recently we have begun developing an in vitro bioreactor [78]. official website and that any information you provide is encrypted Cancer Res. These molecules cause osteoblasts not only to form new bone but also to release RANKL and other osteoclastic mediators. 2022 Feb;22(2):85-101. doi: 10.1038/s41568-021-00406-5. PubMed Exp Oncol. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL. What can be done to stop osteolytic metastasis? IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. Oncogene. Google Scholar. Bone is the most common site of metastasis for breast cancer. 8600 Rockville Pike These molecules bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. and transmitted securely. 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 . Breast cancer is often compared with prostate cancer, which metastasizes to the skeleton with a similar frequency. TGF- is one of the most prominent. Guise [18] demonstrated that increasing the expression of PTHrP in cancer cells enhanced osteolytic lesions in vivo, while decreasing the expression reduced the number and size of lesions. 10.1158/0008-5472.CAN-09-4092. Orr and colleagues [5] have determined MMPs sufficient to resorb bone in vitro and to contribute to the process in vivo. Of the bisphosphonates, zoledronic acid is the most potent. Breast cancer had the highest . By using this website, you agree to our For example, the use of aromatase inhibitors increases the risk for osteoporosis. Article Clinical evidence indicates that this drug can reduce the rate of bone loss, but is not curative. Drugs of the bisphosphonate family have been used for many years as the standard of care. McHayleh W, Ellerman J, Roodman D: Hematologic malignancies and bone. 2003, 38: 605-614. Guise TA, Mundy GR: Cancer and bone. Bethesda, MD 20894, Web Policies eCollection 2022. Bone metastases may cause pain, may make the bones more susceptible to fractures, and may cause increased levels of calcium in the blood. The presence of metastatic lesions in bone disrupts the normal bone microenvironment and upsets the fine balance between the key components. 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). Blood. -, Cell. In the process, growth factors stored in the matrix, such as transforming growth factor (TGF)-, vascular endothelial growth factor (VEGF), insulin-like growth factors (IGFs), bone morphogenic proteins and fibroblast-derived factors, as well as calcium, are released into the bone microenvironment. PubMed Central However, this approach has not entirely solved the problem. 2010, [Epub ahead of print]. At higher doses they may in fact prevent osteoblast differentiation [30]. (A) The bone remodeling unit consists of osteoblasts, which produce osteoid, bone matrix, and osteoclasts, which degrade mineralized bone. Elazar V, Adwan H, Bauerle T, Rohekar K, Golomb G, Berger MR: Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis. 10.1158/1078-0432.CCR-05-1806. The receptor binding activity in turn causes an increase in production of RANKL. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. The site is secure. and transmitted securely. Int J Cancer. Clements ME, Holtslander L, Edwards C, Todd V, Dooyema SDR, Bullock K, Bergdorf K, Zahnow CA, Connolly RM, Johnson RW. RANKL and other pro-osteoclastogenic cytokines are increased with a concomitant reduction in OPG, resulting in more osteoclast formation and bone degradation. 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]. There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. 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. This area has been likened to an extracellular lysosome [11]. Article Osteoclasts derive from mononuclear myeloid precursors that fuse to form pre-osteoclasts. 2001, 285: 335-339. Article 2010, 70: 412-424. PubMed Cancer Res. MMPs are involved in the bone remodeling process after osteoclasts are finished. RANKL clearly holds the key to the osteolytic process. PubMed Central In reality the system is much more complex (Table 1). [Management of bone metastases from breast cancer]. Temporal and spatial changes in bone mineral content and mechanical properties during breast-cancer bone metastases. 2008, Washington, DC: American Society for Bone and Mineral Research, 374-378. full_text. PDGF is a dimeric protein consisting of two of four possible subunits. Bone. Unable to load your collection due to an error, Unable to load your delegates due to an error. They follow the osteoclasts, reforming the bone matrix. 2005, 92: 1531-1537. Current therapeutic targets are indicated in green. break). The mechanisms are thought to be inhibition of tumor cell adhesion as well as osteoclast differentiation. -, Cancer Metastasis Rev. 1974, 230: 473-475. 2003, 3: 537-549. The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. It can contribute to tumor cell survival, proliferation, adhesion, and migration. Bone lining cells appear microscopically as relatively undifferentiated cells that line the bone. Biochem Biophys Res Commun. 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. 2009, 7 (Suppl 7): S1-29. Carlsten H: Immune responses and bone loss: the estrogen connection. 2008, 7: 2807-2816. 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]. Google Scholar. 2000, 1: 331-341. Evidence from an intratibial bone metastasis model indicates that when highly aggressive metastatic MDA-MB-231 cells express dysfunctional Runx2 or small hair-pin RNA for Runx2, both osteoclastogenesis and osteolytic lesions decrease [40]. In addition, PDGF has been shown to inhibit osteoblast differentiation [60], making it an important factor in bone remodeling and the osteolytic bone metastasis. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. PubMed Central They activate latent molecules released from the matrix. 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. Bisphosphonates binding to hydroxyapatite are ingested by osteoclasts and cause their apoptosis. Abstract Metastasis of breast cancer cells to bone consists of multiple sequential steps. Epidemiological studies have also correlated the increase in breast cancer rates with decreasing sunlight exposure. Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. 10.1177/154405910608500703. Exp Cell Res. The bone microenvironment. Those leading to excess bone deposition are considered osteoblastic. Clin Cancer Res. Breast cancer frequently metastasizes to the skeleton. Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. 10.1158/0008-5472.CAN-10-2179. The https:// ensures that you are connecting to the Please enable it to take advantage of the complete set of features! Bone is the most common site of metastasis for breast cancer. Bussard KM, Venzon DJ, Mastro AM: Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast 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. 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. 2006, 21: 1350-1358. 2010, 70: 6537-6547. 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. 10.1177/154405910608500704. This is a disease of clonal malignancy of terminally differentiated plasma cells that accumulate in the bone marrow. Osteoclasts derive from hematopoietic stem cells. Cells of the monocyte-macrophage lineage are stimulated to form osteoclast progenitor cells. Gradient Boosting Machine Identified Predictive Variables for Breast Cancer Patients Pre- and Post-Radiotherapy: Preliminary Results of an 8-Year Follow-Up Study. The main symptoms of breast cancer that has spread to bone are: In the young adult, bone mass reaches its peak, but with increasing age there is a slow loss of mass. 1999, London: Martin Dunitz Ltd. Raisz LG, Mundy GR, Luben RA: Skeletal reactions to neoplasms. 2022 Dec 2;11(12):2394. doi: 10.3390/antiox11122394. 2006, 85: 584-595. PubMed 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. Since the discovery of RANKL and its role in bone remodeling, the field of bone metastasis has moved rapidly. 2004, 26: 179-184. Bone metastases in breast cancer may be osteolytic, osteoblastic, or mixed blastic and lytic. Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. 10.1056/NEJMe1010459. Thus, inflammation is likely to be important in cancer initiation, metastasis and the resulting osteolysis. 10.1016/j.ctrv.2010.04.003. These functional molecules complete the cycle and osteolysis continues. Survival Prediction in Patients Treated Surgically for Metastases of the Appendicular Skeleton-An External Validation of 2013-SPRING Model. Osteomimetic factors include osteopontin (OPN), osteocalcin, osteonectin, bone sialoprotein, RANKL and PTHrP. 10.1038/onc.2009.389. 2006, 6: 181-10.1186/1471-2407-6-181. The role of lining cells. 1991 Jul 12;66(1):107-19 PloS one. Matrix degradation appears to be only one of the roles of MMPs. Their function is not clear except that their retraction is necessary for bone resorption to begin [10]. PubMed Biochem Biophys Res Commun. Federal government websites often end in .gov or .mil. 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]. 10.1158/1078-0432.CCR-09-0426. PubMed PGE2 is associated with inflammation, cell growth, tumor development and metastasis [42]. Clarke BL, Khosla S: Physiology of bone loss. 10.1007/s10911-005-5399-8. 10.1016/j.rcl.2010.02.014. 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). 10.1016/S0006-291X(02)02937-6. Cancer Res. It can activate both Smad-dependent and Smad-independent signal pathways to induce preosteolytic factors such as PTHrP [23]. Symptoms can arise in a number of scenarios 1,3,6: local bone pain soft tissue mass resulting in: direct compression of adjacent structures by extraosseous soft tissue mass (e.g. 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. Breast Cancer Res 12, 215 (2010). 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]. 1998, 19: 18-54. Google Scholar. Exp Cell Res. Interestingly, many osteomimetic factors are regulated by the same transcription factor, Runx2, considered to be the major regulator of osteoblast commitment and differentiation [39]. We present therapeutic options for bone metastasis using a multidisciplinary approach. Cancer. The https:// ensures that you are connecting to the Current therapies consist of blocking osteoclast activity as a means of disrupting the vicious cycle. 2022 Aug 23;14:2519-2531. doi: 10.2147/CMAR.S369910. -, Science. PTH/PTHrP, TNF-, prostaglandins (PGE2), IL-1, IL-11, FGF-2, and IGF-1 have been reported to increase RANKL production. 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. Search History, and MMPs play a role in bone disrupts the normal bone microenvironment and the... Deposition ( Figure 1A ) on novel bone-specific targeted therapies clinic -- antitumor activity and bone metastasis using a approach... Undergo apoptosis the clinic -- antitumor activity and prevention of metastasis to bone metastasis significantly affects both quality of and. 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