However, more accessible and defined [76] models are needed. In a study by Mercer and Mastro [59], osteoblasts treated with conditioned media from MDA-MB-231 breast cancer cells displayed disorganized F-actin fibrils and reduced focal adhesion plaques. Khosla S: Minireview: the OPG/RANKL/RANK system. Adv Drug Deliv Rev. Oncogene. In summary, all of these factors contribute to propagating the vicious cycle and increasing osteolysis (Figure 1B). 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. COX-2 inhibition also partially attenuated the ability of two breast cancer cell lines to degrade and invade extracellular matrix components such as laminin and collagen [47]. Troen BR: Molecular mechanisms underlying osteoclast formation and activation. Marie L, Braik D, Abdel-Razeq N, Abu-Fares H, Al-Thunaibat A, Abdel-Razeq H. Cancer Manag Res. Surprisingly, this treatment did not affect angiogenesis in the bone. IGF binding initiates production of M-CSF and RANKL by osteoblasts and c-fms and RANK by osteoclasts [54]. Breast Cancer Res. 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. Breast Cancer Research J Natl Compr Canc Netw. 3 2005, 310: 270-281. Clarke BL, Khosla S: Physiology of bone loss. 2001, 142: 5050-5055. 10.1056/NEJMoa030847. BMC Cancer. However, there is no guarantee that inhibition of osteolytic lesions would prevent the growth of cancer cells in the bone or their spread to other organs. The main symptoms of breast cancer that has spread to bone are: Bone metastases result in lesions or injury to the bone tissue. Cathepsin K is the major mediator of bone resorption, controlling the osteoclast portion of the vicious cycle. It is now generally accepted that the bone microenvironment is critical to the colonization and growth or dormancy of metastases. 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. Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis. Placental growth factor is a VEGF homologue that binds to the VEGF receptor VEGFR-1. 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. PubMed Ohshiba T, Miyaura C, Ito A: Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. For example, OPN is produced by many breast cancer cells and has a strong clinical correlation with poor prognosis and decreased survival [37]. This is a disease of clonal malignancy of terminally differentiated plasma cells that accumulate in the bone marrow. Doctors use imaging tests, such as x-rays, to figure out the types of . RANKL and other pro-osteoclastogenic cytokines are increased with a concomitant reduction in OPG, resulting in more osteoclast formation and bone degradation. Nevertheless, the inaccessibility, opacity and size of the skeleton make it difficult to study even in laboratory animals. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. 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. Kim HY, Bae SJ, Choi JW, Han S, Bae SH, Cheong JH, Jang H. Biomedicines. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL. The site is secure. Interestingly, many osteomimetic factors are regulated by the same transcription factor, Runx2, considered to be the major regulator of osteoblast commitment and differentiation [39]. 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. In the final stages of metastatic osteolytic breast cancer disease, the cancer cells, fueled by growth factors released from the degraded matrix, expand unchecked. 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. When a patient has a metastasis and no site of origin can be found (a metastasis of unknown origin) the most likely site is the lung or kidney. HHS Vulnerability Disclosure, Help The .gov means its official. Zambonin Zallone A, Teti A, Primavera MV: Resorption of vital or devitalized bone by isolated osteoclasts in vitro. official website and that any information you provide is encrypted 10.1097/COC.0b013e3181deb9e5. 10.1038/clpt.2009.312. 2008, Washington, DC: American Society for Bone and Mineral Research, 379-382. full_text. 2005, 24: 2543-2555. PTH/PTHrP, TNF-, prostaglandins (PGE2), IL-1, IL-11, FGF-2, and IGF-1 have been reported to increase RANKL production. 2005, 5 (Suppl): S46-53. More than 2 out of 3 breast and prostate cancers that . Bone metastasis significantly affects both quality of life and survival of the breast cancer patient. 10.1016/j.rcl.2010.02.014. Ann N Y Acad Sci. -. Federal government websites often end in .gov or .mil. Bone metastases from breast cancer are typically lytic, meaning that there is area of bone destruction at the site of metastasis. 2009, 13: 355-362. Radiol Clin North Am. Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. This feature accounts for the variable sensitivity and specificity of different imaging modalities. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. 10.1016/S1535-6108(03)00132-6. Metastases leading to overall bone loss are classified as osteolytic. Google Scholar. 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]. Nat Cell Biol. 2022 Nov 30;10:1088823. doi: 10.3389/fchem.2022.1088823. COX-2 activity in breast cancer cells has also been found to modulate the expression and activity of MMPs. 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. PloS one. MMP-9 is important in the cascade leading to activation of VEGFA. Careers. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. 2010, 87: 401-406. Endocrinology. Purpose: This is a study in adult patients with different types of cancer. It is estimated that osteolytic lesions occur in 60 to 95% of myeloma patients [1, 27]. VEGF also forms a complex with the extracellular matrix [31, 55]. MeSH PubMed Google Scholar. The MMPs are considered to be important in the bone metastatic process. 2006, 21: 1350-1358. Rucci N, Teti A: Osteomimicry: how tumor cells try to deceive the bone. MMPs are involved in the bone remodeling process after osteoclasts are finished. In many cases, osteolytic and osteoblastic changes occur simulta-neously.28 Up to half of all bone metastases from breast cancer tend to show osteolytic changes.5,7,29-31 However, because all types of bone metastases show . These molecules bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. 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. 10.1210/endo-86-6-1436. Ooi LL, Zheng Y, Stalgis-Bilinski K, Dunstan CR: The bone remodeling environment is a factor in breast cancer bone metastasis. Y-CC is a senior graduate student completing work on the studies of selenium in breast cancer metastasis. Google Scholar. Gan To Kagaku Ryoho. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. 10.1007/s10585-004-1867-6. There is evidence that bisphosphonates also contribute to tumor cell death, especially in combination with chemotherapy [72]. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. 2009, 15: 5829-5839. IL-8, a proinflammatory CXC chemokine, is secreted by monocytes, endothelial cells and osteoblasts. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. SPARC cleavage also coincides with an increase in inflammatory cytokines such as IL-6 and IL-8 [51]. 10.1158/0008-5472.CAN-09-4092. 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. Several MMPs (MMP2, 3, 9) can release TGF- from the latent state, allowing it to become active. Clin Exp Metastasis. 2010, 3: 572-599. sharing sensitive information, make sure youre on a federal IL-11, normally produced by bone marrow stromal cells and osteoblasts, is an important regulator of hematopoiesis and a potent promoter of osteoclast formation. However, breast cancer cells are unable to progress in bone unless they destroy bone with the assistance of bone-resorbing osteoclasts. Recently we have begun developing an in vitro bioreactor [78]. At higher doses they may in fact prevent osteoblast differentiation [30]. 2008, 7: 2807-2816. Clin Orthop Relat Res. The majority of breast cancer metastases ultimately cause bone loss. Arch Biochem Biophys. statement and volume12, Articlenumber:215 (2010) Thus, in the course of the osteolytic process, the osteoblasts are unable to fulfill their role as bone building cells. FOIA Lipton A: Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA: Molecular biology of bone metastasis. 2009, 3: 213-218. Guise TA, Mundy GR: Cancer and bone. 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. eCollection 2022 Dec. Edwards CM, Clements ME, Vecchi LA 3rd, Johnson JA, Johnson RW. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. Ooi LL, Zhou H, Kalak R, Zheng Y, Conigrave AD, Seibel MJ, Dunstan CR: Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis. 10.2741/S110. (B) Metastatic breast cancer cells in the bone microenvironment secrete parathyroid hormone-related protein (PTHrP), cytokines and growth factors that negatively impact osteoblast function. The skeleton is constantly undergoing remodeling. 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]. 2010. Federal government websites often end in .gov or .mil. 2010, 70: 8329-8338. While the outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics early in the process. 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 Kubota K, Sakikawa C, Katsumata M, Nakamura T, Wakabayashi K: PDGF BB purified from osteoclasts acts as osteoblastogenesis inhibitory factor (OBIF). In doing so, cancer cells are equipped to home, adhere, survive and proliferate in the bone microenvironment. However, PTHrP does not directly stimulate osteoclast differentiation, but rather stimulates other cells to increase RANKL and decrease OPG production. government site. Epub 2021 Jul 10. CAS Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE: Bone resorption predicts for skeletal complications in metastatic bone disease. 1974, 230: 473-475. The https:// ensures that you are connecting to the Clezardin P, Teti A: Bone metastasis: pathogenesis and therapeutic implications. Bone metastases are areas of cancer that develop when breast cancer cells travel to the bones. This process is effected by osteoblasts and osteoclasts within a functional and anatomic unit known as the basic multicellular unit (BMU). 2006, 85: 596-607. Osteoblasts and bone stromal cells can respond to a variety of substances that upregulate RANKL. EMBO J. 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. Juarez P, Guise TA: TGF-beta in cancer and bone: Implications for treatment of bone metastases. There are many suspected factors, such as microfractures, loss of mechanical loading, hormones, cytokines, calcium levels and inflammation. The MMP family, composed of more than 20 members, can collectively degrade all components of the extracelluar matrix. However, the process is described in brief in order to further consider the mechanisms of osteolytic metastasis. Further stimulation results in large multinuclear cells capable of bone resorption. The majority of breast cancer metastases ultimately cause bone loss. Biochem Biophys Res Commun. 10.1182/blood-2009-08-237628. Due to this, the bones get harder and cause the condition called sclerosis. 10.1016/j.ctrv.2008.03.008. 10.1177/154405910608500703. Mouse Models of Tumor Bone Metastasis and Invasion for Studying CCN Proteins. PubMed More than half of people who develop stage IV breast cancer have bone metastasis. 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. 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]. 10.1210/en.142.12.5050. We present therapeutic options for bone metastasis using a multidisciplinary approach. In addition, other cells not specific for bone but likely to be found in the bone (macrophages, neutrophils and T lymphocytes) produce MMPs. Bone Rep. 2022 Jun 12;17:101597. doi: 10.1016/j.bonr.2022.101597. 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). 2009, 11: R56-10.1186/bcr2345. Clohisy DR, Perkins SL, Ramnaraine ML: Review of cellular mechanisms of tumor osteolysis. 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. quiz S30, CAS Several groups have developed in vivo models in which bone or bone substitutes are implanted in animals. Sanchez-Fernandez MA, Gallois A, Riedl T, Jurdic P, Hoflack B: Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling. Oncogene. It is estimated that 85% of individuals with advanced disease harbor bone metastases [1]. In addition, pre-clinical trials with agents that target cathepsin K, certain matrix metalloproteinases (MMPs), and transforming growth factor (TGF)- are underway. Marie PJ: Transcription factors controlling osteoblastogenesis. Just as osteoblasts are a critical partner in normal bone remodeling, they are vital to the metastatic osteolytic process. 2006, 23: 345-356. 1984, 235: 561-564. MeSH This loss is more precipitous in women, due to the decrease in estrogen at menopause [3]. Disclaimer, National Library of Medicine 2001, 285: 335-339. This site needs JavaScript to work properly. Thus, bone loss is the result of excessive bone degradation and insufficient bone replacement. Several of these RANKL inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. Terms and Conditions, Induction of aberrant osteoclastogenesis is only part of the equation. Accessibility 1973, 28: 316-321. 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. However, cathepsin K is also produced by other cells in the bone microenvironment, such as macrophages and bone marrow stromal cells. PubMed Central When treated with neutralizing antibody to PDGF, the osteoblasts assumed normal morphology. Estrogen has also been shown to promote osteoclast apoptosis and inhibit activation of mature osteoclasts. Mol Cancer Ther. PubMed Feng X, McDonald JM: Disorders of bone remodeling. 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]. Both RANKL and VEGF can induce osteoclast formation [48], and MMPs play a role in bone matrix degradation. In males, prostate and lung cancers make up 80% of carcinomas metastasising to bone. We are in the process of adding osteoclasts to the system to create a rudimentary in vitro bone remodeling unit. This molecule is also produced by metastatic breast cancer cells [49]. Breast cancer had the highest . While the case for the importance of MMPs as metastasis regulators is strong, they themselves are regulated by tissue inhibitors of metalloproteinase (TIMPs). 2010, 126: 1749-1760. Exp Gerontol. 1999, 59: 1987-1993. . Eur J Cancer. 2003, 3: 537-549. Clinical studies of newly diagnosed breast cancer patients have revealed that high bone turnover correlates with a higher risk of skeletal complications [62]. While breast cancer metastases can have blastic and lytic lesions, myeloma bone lesions are purely osteolytic due to increased osteoclast activity and suppressed osteoblast activity . 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. While not directly responsible for osteolysis in metastatic breast cancer disease, there are physiological parameters that can amplify the degree of bone loss. Kinder M, Chislock E, Bussard KM, Shuman L, Mastro AM: Metastatic breast cancer induces an osteoblast inflammatory response. Edited by: Rosen CL. 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. Their multifunctionality demonstrates their importance. 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. These drugs may also cause cancer cell death; however, they may also negatively affect osteoblasts. TGF- is one of the most prominent. All in all, PTHrP is an important mediator between breast cancer cells and cells of the bone microenvironment and, as such, is a major contributor to the bone degradation process. Provided by the Springer Nature SharedIt content-sharing initiative. However, both bone degradation and deposition likely occur early in the metastatic process. Bone. As pointed out by Lynch, the spatial and temporal expression of these molecules is of utmost importance. It's not the same as having cancer that starts in the bone. 10.1016/S8756-3282(03)00086-3. Endocrinology. In reality the system is much more complex (Table 1). 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]. Cancer Res. Primarily they spread to spine, but lung cancer is known to metastasize to the . Cells of the monocyte-macrophage lineage are stimulated to form osteoclast progenitor cells. Cancer Res. Article Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. 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 . 2010, 36: 615-620. Once osteoclasts are activated, they degrade bone matrix through several proteolytic enzymes, including MMPs and cathepsin K. 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