Breast cancer-derived factors facilitate osteolytic bone metastasis. Lerner UH: Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. Exp Cell Res. Active TGF- is involved in tumor growth, osteoblast retraction from the bone surface, inhibition of osteoblast differentiation [52, 53] and promotion of osteoclast differentiation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. For females, breast and lung are the most common primary sites ; nearly 80% of cancers that spread to the skeleton are from these locations. In this process, the older bone doesn't break down while the new bone forms. What initiates remodeling in the non-tumor-containing bone? 10.1177/154405910608500704. 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. 10.1016/j.ctrv.2008.03.008. PubMed Proteolytic cleavage of SPARC releases biologically active cleavage products that affect angiogenesis factors such as VEGF, platelet-derived growth factor (PDGF) and FGF-2. There is evidence that bisphosphonates also contribute to tumor cell death, especially in combination with chemotherapy [72]. Bone metastases are areas of cancer that develop when breast cancer cells travel to the bones. 10.1158/0008-5472.CAN-09-2758. Osteoblastic or blastic metastases cause an area of the bone to look denser or sclerotic. It has also been suggested that Runx2 is ectopically expressed in bone-destined metastatic breast cancer cells. However, both bone degradation and deposition likely occur early in the metastatic process. Clipboard, Search History, and several other advanced features are temporarily unavailable. At least three essential molecules, TGF-, IGF, and VEGF, need to be activated by MMPs before they can function. 2005, 10: 169-180. Privacy 10.1158/1078-0432.CCR-09-0426. Google Scholar. Smolle MA, Musser E, Bergovec M, Friesenbichler J, Wibmer CL, Leitner L, Srensen MS, Petersen MM, Brcic I, Szkandera J, Scheipl S, Leithner A. 2016 Apr 1;99(Pt B):206-211. doi: 10.1016/j.addr.2015.11.017. Endocrinology. Google Scholar. Osteocytes may act as mechanosensing cells and initiate the process when microfractures and loading are involved. Epidemiological studies have also correlated the increase in breast cancer rates with decreasing sunlight exposure. Accessibility 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. 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]. PubMed Using this device, we have been able to grow osteoblasts into a mineralized tissue. 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. Once osteoblasts finish bone deposition, they undergo apoptosis, remain in the matrix as osteocytes or revert to thin bone-lining cells. Bookshelf It promotes growth and survival of tumor cells [61], and is also involved in osteoclast differentiation. 10.1016/S0006-291X(02)02937-6. 10.1158/0008-5472.CAN-07-1046. Symptoms when breast cancer has spread to the bones . Edited by: Rosen CL. eCollection 2022. 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. 2005, 24: 2543-2555. Khosla S: Minireview: the OPG/RANKL/RANK system. eCollection 2022 Dec. Edwards CM, Clements ME, Vecchi LA 3rd, Johnson JA, Johnson RW. 1993 Jun 1;90(11):5021-5 2010, 70: 6537-6547. Cite this article. 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]. 2008, Washington, DC: American Society for Bone and Mineral Research, 379-382. full_text. 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. Even in adults it is estimated that about 10% of the bone is renewed each year [7]. RANKL and other pro-osteoclastogenic cytokines are increased with a concomitant reduction in OPG, resulting in more osteoclast formation and bone degradation. The majority of breast cancer metastases ultimately cause bone loss. J Dent Res. 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. While ductal carcinoma in situ detected early is 98% curable, bone metastases are basically incurable [2]. Bone remodeling is often described as a cycle beginning with bone degradation and ending with bone deposition (Figure 1A). quiz S30, CAS In reality the system is much more complex (Table 1). This article is part of a review series on New pathways of metastasis, edited by Lewis Chodosh. 10.1196/annals.1365.035. 2001, 37: 106-113. PGs produced from this arachidonic acid conversion are both autocrine and paracrine factors that help to govern physiologic homeostasis. Metastatic breast cancer cells or their conditioned media increase osteoblast apoptosis, and suppress osteoblast differentiation and expression of proteins required for new bone matrix formation. Cookies policy. Cytokines such as IL-6, IL-8 and IL-11 secreted by breast cancer cells also promote osteoclast differentiation and bone resorption. 2009, 11: R56-10.1186/bcr2345. The lesions can often be blastic but may also appear purely lytic, with poor margination, no matrix and cortical destruction. blastic (bone formation), or mixed lesions (Fig 2). Denosumab (Prolia), the latest drug to enter the field, is a monoclonal antibody to RANKL. Dysfunctional Runx2 results in the developmental arrest of osteoblasts and inhibition of osteogenesis. DMS is a senior research technician with many years experience in the bone field. prostate = blastic/sclerotic . This loss is more precipitous in women, due to the decrease in estrogen at menopause [3]. Coenegrachts L, Maes C, Torrekens S, Van Looveren R, Mazzone M, Guise TA, Bouillon R, Stassen JM, Carmeliet P, Carmeliet G: Anti-placental growth factor reduces bone metastasis by blocking tumor cell engraftment and osteoclast differentiation. These drugs may also cause cancer cell death; however, they may also negatively affect osteoblasts. break). 1991 Jul 12;66(1):107-19 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. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer Statistics, 2007. Before 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. In addition, production of inflammatory cytokines (that is, IL-6, TNF-, M-CSF, IL-1) is suppressed by estrogen [64]. 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. Administration of bisphosphonates may slow osteolytic lesion progression and stabilize or increase overall bone density, but does not bring about healing [1, 16, 26]. Front Biosci (Schol Ed). In a recent comprehensive review article, Lynch [50] presents the case that they are 'master regulators' of the vicious cycle. In addition, its expression is enhanced in the presence of TGF- [20]. In doing so, cancer cells are equipped to home, adhere, survive and proliferate in the bone microenvironment. The resorption phase of the process begins with recruitment of pre-osteoclasts that differentiate into activated osteoclasts under the direction of osteoblasts (Figure 1A). -, Science. More than half of people who develop stage IV breast cancer have bone metastasis. 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. Breast cancer metastasis to the bone: mechanisms of bone loss. It can contribute to tumor cell survival, proliferation, adhesion, and migration. Bone provides support and protects vital organs but also is a metabolically active tissue. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies. sharing sensitive information, make sure youre on a federal 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]. It should be noted that in addition to obvious members of the vicious cycle, other factors are produced during the process, including inflammatory cytokines, which significantly affect tumor cell survival, cell differentiation, and angiogenesis. While the outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics early in the process. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. Clin Exp Metastasis. 1974, 230: 473-475. In the context of the current discussion, cancer cells may initiate the process. 10.3322/canjclin.57.1.43. Cancer. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Clin Orthop Relat Res. Bethesda, MD 20894, Web Policies 10.1158/0008-5472.CAN-08-1078. Stopeck A: Denosumab findings in metastatic breast cancer. 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. J Biomol Tech. Ann N Y Acad Sci. PubMed Before government site. Am J Clin Oncol. Bone lining cells appear microscopically as relatively undifferentiated cells that line the bone. Feng X, McDonald JM: Disorders of bone remodeling. Endocrinology. The role of PTHrP in bone metabolism is not fully understood, but it is known to cause upregulation of RANKL and downregulation of OPG [19], thus enhancing osteoclast function leading to bone degradation. On x-rays, these metastases show up as spots that are whiter than the bone around them. Mol Cancer Ther. For example, OPN is produced by many breast cancer cells and has a strong clinical correlation with poor prognosis and decreased survival [37]. These findings led to a flurry of studies to develop COX and prostaglandin inhibitors as cures for bone metastasis. It is now known that PGE2 signaling through its receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form mature osteoclasts. Trabecular bone is the major site of bone turnover under normal conditions and in diseases of bone loss or formation. IGF binding proteins keep this molecule latent. Biochem Biophys Res Commun. 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. Estrogen profoundly affects bone remodeling by suppressing production of RANKL while increasing production of OPG. However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. Article Ganapathy and colleagues [24] found that TGF- antagonists are able to reduce bone metastasis and the number and activity of differentiated osteoclasts [24]. At least three major growth factors sequestered in the matrix are activated by MMPs. The cancer cells affect osteoblast morphology and extracellular matrix. The other 20% of primary disease sites in both sexes are: kidney, thyroid, gastrointestinal tract and other locations. Prostate. There are 5 tumors notorious for their capacity to spread to bone that include Breast, Lung, Thyroid, Renal Cell and Prostate (a popular memory aid is BLT Kosher Pickle.) Of the bisphosphonates, zoledronic acid is the most potent. In advanced disease, bone formation is essentially absent, and the processes of bone resorption and formation become uncoupled. Thus, the ratio of RANKL to OPG is critical for osteoclast activation. 2003, 3: 537-549. 2003, 89: 2031-2037. 2002, 13: 62-71. 2000, 1: 331-341. Verbruggen ASK, McCarthy EC, Dwyer RM, McNamara LM. Clin Breast Cancer. Metastasis of breast cancer cells to bone consists of multiple sequential steps. Identification of a stimulator or protector of osteoblasts would be a major improvement in treatment for osteolytic breast cancer as well as other diseases of bone loss. N Engl J Med. Kang JS, Alliston T, Delston R, Derynck R: Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. 10.1158/1535-7163.MCT-08-0153. 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