Clinical Characteristics, Prognostic Factors and Treatment Outcomes of Patients with Bone-Only Metastatic Breast Cancer. Osteocytes may act as mechanosensing cells and initiate the process when microfractures and loading are involved. This article is part of a review series on New pathways of metastasis, edited by Lewis Chodosh. 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]. Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. 10.1177/154405910608500704. Proteolytic cleavage of SPARC releases biologically active cleavage products that affect angiogenesis factors such as VEGF, platelet-derived growth factor (PDGF) and FGF-2. 2005, 24: 2543-2555. quiz S30, CAS What Are The Symptoms Of Bone Metastasis In Breast Cancer. They follow the osteoclasts, reforming the bone matrix. HHS Vulnerability Disclosure, Help 2010, 115: 140-149. Denosumab (Prolia), the latest drug to enter the field, is a monoclonal antibody to RANKL. The majority of breast cancer metastases ultimately cause bone loss. Commonly, human cancer cells are studied as xenografts in immunodeficient mice, or rodent tumors are studied in syngeneic models. 1991 Jul 12;66(1):107-19 10.1038/35036374. sharing sensitive information, make sure youre on a federal 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. J Cell Biochem. Several of these RANKL inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis. 10.3322/canjclin.57.1.43. 1984, 235: 561-564. As primary constituents in bone metabolism, calcium and vitamin D can not be overlooked as critical regulators of osteolysis in bone metastatic breast cancer. 2010, 363: 2458-2459. Guise TA: Parathyroid hormone-related protein and bone metastases. At least three essential molecules, TGF-, IGF, and VEGF, need to be activated by MMPs before they can function. Before Cancer Treat Rev. The dynamics of this system are interrupted when metastatic breast cancer cells are introduced, adding another layer of active molecules to the bone environment. In advanced disease, bone formation is essentially absent, and the processes of bone resorption and formation become uncoupled. The majority of breast cancer metastases ultimately cause bone loss. 2006, 23: 345-356. Hadjidakis DJ, Androulakis II: Bone remodeling. 2. 2022 Jul 20;14(14):3521. doi: 10.3390/cancers14143521. It was recently reported that mice deficient in vitamin D or calcium showed increased metastatic tumor growth and accelerated rates of bone resorption [66, 67]. 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. 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]. statement and 2008, 68: 7795-7802. Proff P, Romer P: The molecular mechanism behind bone remodelling: a review. PubMedGoogle Scholar. This feature accounts for the variable sensitivity and specificity of different imaging modalities. Abstract Metastasis of breast cancer cells to bone consists of multiple sequential steps. 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. These types of tumors are called osteolytic, or simply lytic. 10.1210/en.142.12.5050. 2008, 7: 2807-2816. Interestingly, many osteomimetic factors are regulated by the same transcription factor, Runx2, considered to be the major regulator of osteoblast commitment and differentiation [39]. Bone. Please enable it to take advantage of the complete set of features! Br J Cancer. The receptor binding activity in turn causes an increase in production of RANKL. An official website of the United States government. Halpern J, Lynch CC, Fleming J, Hamming D, Martin MD, Schwartz HS, Matrisian LM, Holt GE: The application of a murine bone bioreactor as a model of tumor: bone interaction. Int J Cancer. However, both drugs are associated with low incidence of osteonecrosis of the jaw [75]. (B) Metastatic breast cancer cells in the bone microenvironment secrete parathyroid hormone-related protein (PTHrP), cytokines and growth factors that negatively impact osteoblast function. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. With rare exceptions, cancer that has spread to the bones can't be cured. Smolle MA, Musser E, Bergovec M, Friesenbichler J, Wibmer CL, Leitner L, Srensen MS, Petersen MM, Brcic I, Szkandera J, Scheipl S, Leithner A. J Mammary Gland Biol Neoplasia. Clin Cancer Res. Standal T, Borset M, Sundan A: Role of osteopontin in adhesion, migration, cell survival and bone remodeling. 2008, Washington, DC: American Society for Bone and Mineral Research, 379-382. full_text. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2000, 2: 737-744. In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. In the context of the current discussion, cancer cells may initiate the process. 2005, 208: 194-206. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. The lesions can often be blastic but may also appear purely lytic, with poor margination, no matrix and cortical destruction. Just as osteoblasts are a critical partner in normal bone remodeling, they are vital to the metastatic osteolytic process. 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. 2004, 21: 427-435. J Bone Oncol. There is evidence that bisphosphonates also contribute to tumor cell death, especially in combination with chemotherapy [72]. 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. Chemotherapy may bring about ovarian failure and premature menopause [1]. Hillner BE, Ingle JN, Berenson JR, Janjan NA, Albain KS, Lipton A, Yee G, Biermann JS, Chlebowski RT, Pfister DG. Arch Biochem Biophys. The main symptoms of breast cancer that has spread to bone are: However, this approach has not entirely solved the problem. 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. Cancer Res. Carlsten H: Immune responses and bone loss: the estrogen connection. [Management of bone metastases from breast cancer]. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts. Google Scholar. 2010, 8: 159-160. It is estimated that osteolytic lesions occur in 60 to 95% of myeloma patients [1, 27]. The presence of tumor cells in the bone microenvironment perturbs the balance between osteoblasts and osteoclasts, leading to excess bone loss or formation. 1984 Jun 8;224(4653):1113-5 spinal cord compression) palpable mass deformity pathological fracture hypercalcemia bone marrow aplasia These functional molecules complete the cycle and osteolysis continues. The changes in the bone microenvironment then create a vicious cycle that further promotes bone destruction and tumor progression.Various therapeutic options are available for bone metastases of breast cancer. 10.1158/0008-5472.CAN-07-1046. Juarez P, Guise TA: TGF-beta in cancer and bone: Implications for treatment of bone metastases. Bookshelf 2008, 314: 173-183. Matrix degradation appears to be only one of the roles of MMPs. Cookies policy. PubMed However, teriparatide is associated with an increased risk of osteosarcoma and exacerbation of skeletal metastases because of its effect on bone turnover [75]. Administration of bisphosphonates may slow osteolytic lesion progression and stabilize or increase overall bone density, but does not bring about healing [1, 16, 26]. Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. Endocrinology. 2010, 70: 412-424. 10.1016/j.ctrv.2010.04.003. Metastasis of breast cancer cells to bone consists of multiple sequential steps. 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]. Clements ME, Holtslander L, Edwards C, Todd V, Dooyema SDR, Bullock K, Bergdorf K, Zahnow CA, Connolly RM, Johnson RW. Osteoblastic or blastic metastases cause an area of the bone to look denser or sclerotic. 10.1016/j.rcl.2010.02.014. 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. Bone is the most common site of metastasis for breast cancer. It is common to find increased PTHrP serum levels in breast cancer patients. Breast cancer is often compared with prostate cancer, which metastasizes to the skeleton with a similar frequency. Breast cancer cells can spread to the bone through the lymphatic system or the blood. 10.1210/er.19.1.18. Exp Cell Res. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. Privacy 2022 Aug 23;14:2519-2531. doi: 10.2147/CMAR.S369910. Osteoclasts derive from hematopoietic stem cells. The mechanisms are thought to be inhibition of tumor cell adhesion as well as osteoclast differentiation. Ann N Y Acad Sci. Primarily they spread to spine, but lung cancer is known to metastasize to the . 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. According to this paradigm, the tumor cells produce a variety of growth factors, most notably parathyroid hormone-related protein (PTHrP) [18]. Metastatic breast cancer cells tend to spread to the bones more often than they do to other parts of the body. Mundy GR: Mechanisms of bone metastasis. Br J Cancer. Clin Breast Cancer. Cancer cells, osteoblasts, osteoclasts and endothelial cells produce MMPs. Cancer Res. 2010. Using this device, we have been able to grow osteoblasts into a mineralized tissue. Those leading to excess bone deposition are considered osteoblastic. Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Int J Biochem Cell Biol. It can activate both Smad-dependent and Smad-independent signal pathways to induce preosteolytic factors such as PTHrP [23]. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD: Role of IGF-I signaling in regulating osteoclastogenesis. 10.1016/j.ctrv.2008.03.008. Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. Chen, YC., Sosnoski, D.M. 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 . Rucci N, Millimaggi D, Mari M, Del Fattore A, Bologna M, Teti A, Angelucci A, Dolo V: Receptor activator of NF-kappaB ligand enhances breast cancer-induced osteolytic lesions through upregulation of extracellular matrix metalloproteinase inducer/CD147. It binds to two class III tyrosine kinase receptors, PDGFR and PDGFR, leading to activation of several signaling molecules. Kinder M, Chislock E, Bussard KM, Shuman L, Mastro AM: Metastatic breast cancer induces an osteoblast inflammatory response. It has also been suggested that Runx2 is ectopically expressed in bone-destined metastatic breast cancer cells. 2010, 2: 907-915. Google Scholar. HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer. Clin Adv Hematol Oncol. Oncogene. In this process, the older bone doesn't break down while the new bone forms. Clin Cancer Res. 10.1016/S8756-3282(03)00086-3. 10.1007/s10911-005-5399-8. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. Below are the links to the authors original submitted files for images. Thus, inflammation is likely to be important in cancer initiation, metastasis and the resulting osteolysis. 10.1002/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I. Breast cancer metastasis to the bone: mechanisms of bone loss. Blood. 2010, 29: 811-821. 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. Estrogen also increases osteoblast pro-collagen synthesis and decreases osteoblast apoptosis [63]. While some of the growth factors produced by breast and prostate cancers may be different, ultimately they engage the bone re-modeling process. We have been able to grow osteoblasts into a mineralized tissue are:,... Incidence of osteonecrosis of the current discussion, cancer that has spread to the osteolytic! Pthrp in breast cancer metastases ultimately cause bone loss growth factors produced breast! 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