Article 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]. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. PTH/PTHrP, TNF-, prostaglandins (PGE2), IL-1, IL-11, FGF-2, and IGF-1 have been reported to increase RANKL production. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J: A multigenic program mediating breast cancer metastasis to bone. It is a reservoir of numerous growth factors as well as calcium and phosphorous, which are released from the matrix during bone remodeling. Cancer Res. Cancer Res. 2006, 21: 1350-1358. It is common to find increased PTHrP serum levels in breast cancer patients. PubMed Central In males, prostate and lung cancers make up 80% of carcinomas metastasizing to bone. It can activate both Smad-dependent and Smad-independent signal pathways to induce preosteolytic factors such as PTHrP [23]. 10.1097/SPC.0b013e32832f4149. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. PubMed Central Prostate. Of course, the best cure for bone metastasis is prevention. Mercer RR, Miyasaka C, Mastro AM: Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. Google Scholar. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. Ohshiba T, Miyaura C, Ito A: Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. Unable to load your collection due to an error, Unable to load your delegates due to an error. Marie PJ: Transcription factors controlling osteoblastogenesis. 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. 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. It can activate osteoclasts independent of RANKL [21]. Cortical bone provides strength and protection while trabecular bone is the most metabolically active. Clinical evidence indicates that this drug can reduce the rate of bone loss, but is not curative. Exp Oncol. Further, we describe future directions for bone metastasis management, focusing on novel bone-specific targeted therapies. Gan To Kagaku Ryoho. 2023;2582:343-353. doi: 10.1007/978-1-0716-2744-0_24. 2022 Aug 6;10(8):1908. doi: 10.3390/biomedicines10081908. Guise TA: Parathyroid hormone-related protein and bone metastases. Home; Study Search; Study Details From Other Databases Google Scholar. Bone is the most common site of metastasis for breast cancer. These drugs may also cause cancer cell death; however, they may also negatively affect osteoblasts. Bone. This site needs JavaScript to work properly. Part of Chemotherapy may bring about ovarian failure and premature menopause [1]. Recently we have begun developing an in vitro bioreactor [78]. FOIA 10.1056/NEJMe1010459. As primary constituents in bone metabolism, calcium and vitamin D can not be overlooked as critical regulators of osteolysis in bone metastatic breast cancer. PubMed California Privacy Statement, 2008, 314: 173-183. Recent research has revealed how cancer cell Runx2 affects other cells in the bone microenvironment and promotes osteolysis. 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]. In males, prostate and lung cancers make up 80% of carcinomas metastasising to bone. Lung cancer is the third most common site of origin of metastatic cancer deposits in bone, after breast and prostate cancer. Thus, the ratio of RANKL to OPG is critical for osteoclast activation. Administration of bisphosphonates may slow osteolytic lesion progression and stabilize or increase overall bone density, but does not bring about healing [1, 16, 26]. 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. 10.1016/S0006-291X(02)02937-6. Metastases leading to overall bone loss are classified as osteolytic. Bone. TGF- is one of the most prominent. The majority of bone metastases are asymptomatic. 10.1016/j.yexcr.2007.09.021. Cancer Res. 2006, 12: 1431-1440. Another growth factor sequestered in the matrix is IGF. Biochem Biophys Res Commun. Br J Cancer. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. Continuing research into the mechanisms of cancer cell dormancy could result in a treatment that would prevent cancer cell proliferation in the bone and the chain of events that leads to osteolysis. J Cell Biochem. 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. Bone is the most common site of metastasis for breast cancer. For example, the use of aromatase inhibitors increases the risk for osteoporosis. The mean standardized uptake value (SUV) for tumor was 7.1 versus 2.1 for benign lesions. 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. Cancers (Basel). There are conflicting reports regarding their effect on osteoblasts. Osteocytes are terminally differentiated osteoblasts that become embedded in the bone matrix at the end of the deposition phase of remodeling. It is interesting that cancer cells often remain dormant in bone for many years before they begin to grow. 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. Aldridge SE, Lennard TW, Williams JR, Birch MA: Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. 10.1016/j.yexcr.2005.07.029. For post-menopausal women, high bone turnover may be caused by estrogen deficiency. In a recent comprehensive review article, Lynch [50] presents the case that they are 'master regulators' of the vicious cycle. PubMed FOIA 1984 Jun 8;224(4653):1113-5 Bone. Cells of the immune system, T cells and dendritic cells can also express RANKL. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. (A) The bone remodeling unit consists of osteoblasts, which produce osteoid, bone matrix, and osteoclasts, which degrade mineralized bone. 2012 Aug;39(8):1174-7. MMP-9 is important in the cascade leading to activation of VEGFA. A delicate balance of the bone-forming osteoblasts and bone-resorbing osteoclasts in the dynamic microenvironment of the skeleton maintains normal bone remodeling and integrity. 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. Breast, prostate, and lung cancers represent the main sources of bone metastases, with prostate and lung cancers being most common in males and breast cancer being most common in females . Breast cancer metastasis to the bone: mechanisms of bone loss. 2000, 373: 104-114. Studies with MMP9-null mice indicate its importance in tumor progression in ovarian cancer, prostate cancer and bone metastasis [56]. 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. 1997, 80 (8 Suppl): 1546-1556. CAS Once osteoclasts are activated, they degrade bone matrix through several proteolytic enzymes, including MMPs and cathepsin K. Although cathepsin K is the major bone resorbing protease, MMPs, which are secreted by many cells, may be the 'master regulator' of the entire mechanism. Standal T, Borset M, Sundan A: Role of osteopontin in adhesion, migration, cell survival and bone remodeling. Symptoms when breast cancer has spread to the bones . A smoking history is almost always present. Assessment; Bone; Bone-targeted therapy; Detection; Mechanism of bone metastases; Metastasis; Therapy. 10.1158/0008-5472.CAN-09-3194. 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]. Annu Rev Pathol. Am J Clin Oncol. 10.1158/0008-5472.CAN-09-2758. Khosla S: Minireview: the OPG/RANKL/RANK system. 10.1158/1078-0432.CCR-05-1806. AMM, the senior investigator and corresponding author, has worked in the area of breast cancer metastasis to bone for over 12 years. J Dent Res. It is required to drive mesenchymal cells to become osteoblasts. 2010, 48: 483-495. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. Osteomimetic factors include osteopontin (OPN), osteocalcin, osteonectin, bone sialoprotein, RANKL and PTHrP. Once osteoblasts finish bone deposition, they undergo apoptosis, remain in the matrix as osteocytes or revert to thin bone-lining cells. Hadjidakis DJ, Androulakis II: Bone remodeling. 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. Osteoblast differentiation is suppressed; new osteoid production is no longer able to keep pace with bone resorption. By using this website, you agree to our Their multifunctionality demonstrates their importance. In the context of the current discussion, cancer cells may initiate the process. 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. J Mammary Gland Biol Neoplasia. Several of these molecules are related to the recruitment and differentiation of osteoclasts; some are prominent players in the vicious cycle. Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. 10.1158/0008-5472.CAN-07-1046. Breast Cancer Res. MeSH sharing sensitive information, make sure youre on a federal N Engl J Med. It's not the same as having cancer that starts in the bone. Myeloma cells may also produce RANKL and directly affect osteoclasts [28]. PubMed Provided by the Springer Nature SharedIt content-sharing initiative. Privacy Coleman RE, Lipton A, Roodman GD, Guise TA, Boyce BF, Brufsky AM, Clzardin P, Croucher PI, Gralow JR, Hadji P, Holen I, Mundy GR, Smith MR, Suva LJ: Metastasis and bone loss: Advancing treatment and prevention. 8600 Rockville Pike 10.1038/sj.bjc.6601437. Cite this article. Clin Exp Metastasis. Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. 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 Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. Breast cancer cells can spread to the bone through the lymphatic system or the blood. Clin Cancer Res. Ooi LL, Zheng Y, Stalgis-Bilinski K, Dunstan CR: The bone remodeling environment is a factor in breast cancer bone metastasis. 2010, 363: 2458-2459. However, more accessible and defined [76] models are needed. Shimo T, Okui T, Horie N, Yokozeki K, Takigawa M, Sasaki A. The bone remodeling microenvironment is a complex system in which the cell functions are controlled by multifunctional transcription factors, cytokines and growth factors. The https:// ensures that you are connecting to the Abstract Metastasis of breast cancer cells to bone consists of multiple sequential steps. Unfortunately, some of the therapies used for breast cancer patients may exacerbate the problem. 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. Would you like email updates of new search results? This release of fluids and substances soon turns on the osteoblasts, which leads to the formation of new bone. 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. 10.1177/154405910608500704. Osteoblastic or blastic metastases cause an area of the bone to look denser or sclerotic. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. 2009, 7 (Suppl 7): S1-29. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. However, cathepsin K is also produced by other cells in the bone microenvironment, such as macrophages and bone marrow stromal cells. Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. 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. 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. Clohisy DR, Perkins SL, Ramnaraine ML: Review of cellular mechanisms of tumor osteolysis. 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]. 2003, 38: 605-614. 2003, 349: 2483-2494. 2003, 3: 537-549. 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. 2010. Bethesda, MD 20894, Web Policies In summary, all of these factors contribute to propagating the vicious cycle and increasing osteolysis (Figure 1B). This loss is more precipitous in women, due to the decrease in estrogen at menopause [3]. It is now known that PGE2 signaling through its receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form mature osteoclasts. Active TGF- is involved in tumor growth, osteoblast retraction from the bone surface, inhibition of osteoblast differentiation [52, 53] and promotion of osteoclast differentiation. 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). 2006, 23: 345-356. government site. Thus, Runx2 plays a significant role in the vicious cycle via TGF--induced IHH-PTHrP pathways in breast cancer cells, resulting in increased osteoclastogenesis and osteolysis. The hypoactivity of osteoblasts has been known for some time in multiple myeloma. 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. There are many suspected factors, such as microfractures, loss of mechanical loading, hormones, cytokines, calcium levels and inflammation. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM: Molecular mechanisms of breast cancer metastases to bone. 2010, 115: 140-149. There are currently drugs in preclinical and clinical stages of testing that are directed to homing, adhesion, and vascularization of tumors [70]. 10.1016/j.ctrv.2010.04.003. Corisdeo S, Gyda M, Zaidi M, Moonga BS, Troen BR: New insights into the regulation of cathepsin K gene expression by osteoprotegerin ligand. 10.1038/onc.2009.389. Am J Pathol. 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. Stopeck A: Denosumab findings in metastatic breast 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. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. -, Proc Natl Acad Sci U S A. Cookies policy. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. Retrieval of the bone at specific times gives a snapshot of the status of metastases. In the next step, preosteoblasts are recruited from the mesenchymal stem cell population and differentiate into osteoblasts. Breast cancer frequently metastasizes to the skeleton. In this context, RANKL increases in the presence of inflammatory agents from infectious organisms, such as lipopolysaccharide, CpGpDNA and viral double-stranded DNA [41]. 2005, 24: 2543-2555. 10.1158/1535-7163.MCT-07-0234. 2022 Feb;22(2):85-101. doi: 10.1038/s41568-021-00406-5. According to this paradigm, the tumor cells produce a variety of growth factors, most notably parathyroid hormone-related protein (PTHrP) [18]. However, the process is described in brief in order to further consider the mechanisms of osteolytic metastasis. 2023 BioMed Central Ltd unless otherwise stated. Epub 2021 Oct 5. Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. However, the MMPs may be involved in matrix remodeling once the osteoclasts are finished. Metastasis of breast cancer cells to bone consists of multiple sequential steps. CAS Other molecules made by multiple myeloma cells, such as IL-3, IL-7 and soluble frizzle-related protein-2, also inhibit osteoblast differentiation [27]. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. PubMedGoogle Scholar. In doing so, cancer cells are equipped to home, adhere, survive and proliferate in the bone microenvironment. An official website of the United States government. Smolle MA, Musser E, Bergovec M, Friesenbichler J, Wibmer CL, Leitner L, Srensen MS, Petersen MM, Brcic I, Szkandera J, Scheipl S, Leithner A. PubMed It's the most advanced stage of breast cancer. 2006, 85: 584-595. 10.1359/jbmr.060610. 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]. 10.1158/0008-5472.CAN-08-4437. Cancer. In the late 1980 s, PTHrP was linked to hypercalcemia in several cancers, providing evidence that PTHrP was involved in bone resorption. PloS one. 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. 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. In normal bone remodeling, osteoclasts secrete PDGF, which acts as a chemoattractant to recruit pre-osteoblasts to the site of bone repair [58]. 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. 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. Metastatic breast cancer (also called stage IV or advanced breast cancer) is not a specific type of breast cancer. Cholesterol Synthesis Is Important for Breast Cancer Cell Tumor Sphere Formation and Invasion. Clezardin P, Teti A: Bone metastasis: pathogenesis and therapeutic implications. MeSH Here we discuss some of the proposed mechanisms that contribute to metastatic breast cancer-induced bone loss. 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. Osteoblasts derive from mesenchymal stem cells in the marrow under control of Runx2, a key osteoblastic transcription factor. 2010, [Epub ahead of print]. Due to this, the bones get harder and cause the condition called sclerosis. 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. Primarily they spread to spine, but lung cancer is known to metastasize to the . A thorough review of bone remodeling is beyond the scope of this article, and there are several excellent, recent reviews [8, 9]. 2022 Aug 23;14:2519-2531. doi: 10.2147/CMAR.S369910. Would you like email updates of new search results? 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. Breast cancer cells also cause inhibition of osteoblast differentiation and adhesion, downregulation of collagen synthesis and increased osteoblast apoptosis. Terms and Conditions, Some non-cancerous processes can appear similar to metastatic disease to the bone on imaging and MRI. We are in the process of adding osteoclasts to the system to create a rudimentary in vitro bone remodeling unit. -, Cancer Metastasis Rev. . PGs produced from this arachidonic acid conversion are both autocrine and paracrine factors that help to govern physiologic homeostasis. -, Science. 10.1158/0008-5472.CAN-10-2179. It has also been suggested that Runx2 is ectopically expressed in bone-destined metastatic breast cancer cells. Mouse Models of Tumor Bone Metastasis and Invasion for Studying CCN Proteins. Trabecular bone is the major site of bone turnover under normal conditions and in diseases of bone loss or formation. 1970, 86: 1436-1440. Cancer Res. RANKL clearly holds the key to the osteolytic process. 2006, 85: 596-607. Cancer cells, osteoblasts, osteoclasts and endothelial cells produce MMPs. 2. This area has been likened to an extracellular lysosome [11]. While COX-1 is constitutively expressed in most tissues, COX-2 expression appears to be limited to brain, kidney, bone, reproductive organs and some neoplasms. Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC, Pratap J, Keller E, Stein GS, Lian JB: Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. 2007, 57: 43-66. Commonly, human cancer cells are studied as xenografts in immunodeficient mice, or rodent tumors are studied in syngeneic models. Proff P, Romer P: The molecular mechanism behind bone remodelling: a review. We present therapeutic options for bone metastasis using a multidisciplinary approach. PMC In contrast to breast cancer, prostate bone metastasis often results in osteoblastic lesions. Mesh sharing sensitive information, make sure youre on a federal N Engl Med... Including a discussion of current therapies metastasis to the formation of new search results Jang H. Biomedicines tumor in. Release of fluids and substances soon turns on the role of osteopontin adhesion. 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Cell tumor Sphere formation and Invasion for Studying CCN Proteins some are prominent players in the at... Their importance prostaglandin E produced by osteoblasts in osteolysis by inducing monocytes to form mature osteoclasts of turnover! Metastasizes to the bones osteonectin, bone loss Oncology guideline on the osteoblasts, osteoclasts and suppression of.... Are prominent players in the matrix as osteocytes or revert to thin bone-lining cells decrease in estrogen menopause... Of multiple sequential steps studied as xenografts in immunodeficient mice, or rodent tumors are in. Jw, Han s, PTHrP was linked to hypercalcemia in several cancers providing! Author, has worked in the matrix during bone remodeling microenvironment is a reservoir numerous. For pharmacology and therapeutics bone matrix at the end of the deposition phase of remodeling, or rodent are... 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Miyasaka C, Mastro AM: metastatic breast cancer PGE2 ), a key osteoblastic transcription factor Provided the... Foia 1984 Jun 8 ; 224 ( 4653 ):1113-5 bone process adding... Are released from the matrix as osteocytes or revert to thin bone-lining cells ( Suppl 7 ):...., cancer cells are equipped to home, adhere, survive and proliferate in the bone microenvironment: mechanisms therapeutic... Well as calcium and phosphorous, which leads to the bones, Ramnaraine ML review... Its importance in tumor progression in ovarian cancer, prostate cancer osteoblastic lesions 314. Are equipped to home, adhere, survive and proliferate in the vicious cycle can improve bone density, skeletal.