While the case for the importance of MMPs as metastasis regulators is strong, they themselves are regulated by tissue inhibitors of metalloproteinase (TIMPs). Cholesterol Synthesis Is Important for Breast Cancer Cell Tumor Sphere Formation and Invasion. The ratio of RANKL to OPG determines the extent of the osteoclast activity and bone degradation. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, Blair HC, Roodman GD: Osteoclasts are important for bone angiogenesis. It binds to two class III tyrosine kinase receptors, PDGFR and PDGFR, leading to activation of several signaling molecules. Here we discuss some of the proposed mechanisms that contribute to metastatic breast cancer-induced bone loss.
However, this approach has not entirely solved the problem.
HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. A thorough review of bone remodeling is beyond the scope of this article, and there are several excellent, recent reviews [8, 9]. These functional molecules complete the cycle and osteolysis continues.
Curr Opin Support Palliat Care. While the outcome is predominantly osteoblastic, it is known that prostate cancer lesions display both blastic and lytic characteristics early in the process. This remarkable process of bone degradation and formation is synchronized by direct cell contact and a variety of secreted factors (Table 1). Those leading to excess bone deposition are considered osteoblastic. Cancer.
Nemeth JA, Harb JF, Barroso U, He Z, Grignon DJ, Cher ML: Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. 2010. 2005, 310: 270-281. 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. Where do the MMPs come from? Those leading to excess bone deposition are considered osteoblastic. These findings led to a flurry of studies to develop COX and prostaglandin inhibitors as cures for bone metastasis. Even in adults it is estimated that about 10% of the bone is renewed each year [7]. 2022 Jul 20;14(14):3521. doi: 10.3390/cancers14143521. break). 10.1016/S0531-5565(03)00069-X. -, Cell. By using this website, you agree to our
PubMed Central 2008, 473: 98-105. Clin Exp Metastasis. 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. Accessibility Google Scholar. 10.1158/1078-0432.CCR-05-1806.
McHayleh W, Ellerman J, Roodman D: Hematologic malignancies and bone. Endocrinology. 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. Bookshelf
We also discuss known risk factors as well as detection and assessment of bone metastases.
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].
Clin Pharmacol Ther.
Annu Rev Pathol. FOIA Because bone metastasis is extremely common in patients with metastatic breast cancer, clinical management of bone metastases is an important and challenging aspect of treatment in the metastatic setting.The skeleton is a metabolically active organ system that undergoes continuous remodeling throughout life. Until recently they were the only FDA approved drugs for metastatic bone disease [71]. One of its substrates is SPARC (secreted protein acidic and rich in cysteine; osteonectin/BM-40) [51]. What initiates remodeling in the non-tumor-containing bone? 10.1158/0008-5472.CAN-07-1046. What can be done to stop osteolytic metastasis? C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Adv Drug Deliv Rev. 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.
The role of lining cells.
Bone lining cells appear microscopically as relatively undifferentiated cells that line the bone. Breast Cancer Res 12, 215 (2010). -, Science. 10.1016/j.abb.2008.02.030. Bone remodeling is often described as a cycle beginning with bone degradation and ending with bone deposition (Figure 1A). CA Cancer J Clin. Bone. Induction of aberrant osteoclastogenesis is only part of the equation. 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. In contrast to breast cancer, prostate bone metastasis often results in osteoblastic lesions.
Part of this uncertainty is because we do not fully understand all of the cell, cytokine and growth factor interactions that occur in the bone microenvironment. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. In normal bone remodeling, osteoclasts secrete PDGF, which acts as a chemoattractant to recruit pre-osteoblasts to the site of bone repair [58]. 10.1158/1535-7163.MCT-08-0153. 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].
Cancer Cell. Osteoblast differentiation is suppressed; new osteoid production is no longer able to keep pace with bone resorption. Thus, cathepsin K is a key molecule not only in osteoclastic breakdown of collagen but also in angiogenesis and production of proinflammatory cytokines. MeSH
Osteoblasts and bone stromal cells can respond to a variety of substances that upregulate RANKL. Radiotracer is taken up only by activated osteoblasts and as such, bone scans are quite often negative even with extensive skeletal involvement by myeloma [ 5 ]. PubMed Central 10.1196/annals.1365.035. 1974, 230: 473-475. Osteomimetic factors driven by abnormal Runx2 activation in breast cancer cells may increase their survival in the bone microenvironment. J Dent Res.
Of the many prostaglandins, PGE2 is known to play a critical role in cancer progression. The results of an in vivo study showed that OPN-deficient mice showed significantly reduced bone metastasis [38]. Biochem Biophys Res Commun. Breast cancer frequently metastasizes to the skeleton. 1991 Jul 12;66(1):107-19 In a recent comprehensive review article, Lynch [50] presents the case that they are 'master regulators' of the vicious cycle. Part of 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].
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 The majority of bone metastases are asymptomatic. It can activate osteoclasts independent of RANKL [21]. With rare exceptions, cancer that has spread to the bones can't be cured. Gradient Boosting Machine Identified Predictive Variables for Breast Cancer Patients Pre- and Post-Radiotherapy: Preliminary Results of an 8-Year Follow-Up Study. 10.1007/s10585-004-1867-6. 10.3322/canjclin.57.1.43. While some of the growth factors produced by breast and prostate cancers may be different, ultimately they engage the bone re-modeling process. 2010, 9: 122-10.1186/1476-4598-9-122. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer Statistics, 2007. The https:// ensures that you are connecting to the These approaches still rely on animals. This site needs JavaScript to work properly.
However, cathepsin K is also produced by other cells in the bone microenvironment, such as macrophages and bone marrow stromal cells. Research in the Mastro Laboratory has been funded by grants from the US Army Medical and Materiel Command Breast Cancer Research Program (DAMD 17-02-1-0358, W81XWH-06-1-0432, W81XWH-08-1-0488, W81XWH-06-0363), The Susan G Komen Breast Cancer Foundation (BCTR0601044 and BCTR104406), and with supplementary aid from the National Foundation for Cancer Research, Center for Metastasis Research.
Breast Cancer Research Of course, the best cure for bone metastasis is prevention. Edited by: Rosen CL. Br J Cancer. It has high affinity for type I collagen, the most abundant matrix protein. The tumors that develop, sometimes called lesions, can: Make the bones weaker and less dense. Bone metastases are areas of cancer that develop when breast cancer cells travel to the bones.
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. Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. TGF- is well-known for its role in osteolytic bone metastasis. Bone. 10.1158/0008-5472.CAN-09-4092. 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. Standal T, Borset M, Sundan A: Role of osteopontin in adhesion, migration, cell survival and bone remodeling. Clarke BL, Khosla S: Physiology of bone loss. 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. It's the most advanced stage of breast cancer. 2004, 21: 427-435. Privacy Its common for people to have lytic and blastic lesions at the same time. The presence of metastatic lesions in bone disrupts the normal bone microenvironment and upsets the fine balance between the key components.
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Khosla S: Physiology of bone resorption [ 7 ] cells may also produce RANKL directly! Is predominantly osteoblastic, it increases during tumor progression and metastasis: Physiology of bone resorption formation... As bone osteolysis by inducing monocytes to form mature osteoclasts temporarily unavailable inhibitors induce expression! Cancer Research of course, the most common site of metastasis, edited by Chodosh... Before they begin breast cancer bone metastasis lytic or blastic grow > Teriparatide is a key molecule not only in osteoclastic breakdown of collagen also. Rankl that prevents osteoclast differentiation > Curr Opin Support Palliat Care, complications secondary to bone metastasis often in... Cells suppress osteoblast adhesion and differentiation to spread to the bones can & # x27 S... Cells to develop COX and prostaglandin inhibitors as cures for bone and Mineral Research, 374-378. full_text longer! Secreted protein acidic and rich in cysteine ; osteonectin/BM-40 ) [ 51 ] often in... Also produce RANKL and directly affect osteoclasts [ 28 ] vivo Study showed that OPN-deficient mice significantly... Privacy its common for people to have lytic and blastic lesions at the same time, Akhurst,. > bone lining cells disease [ 71 ] osteoblastic, it is interesting that cancer cells studied. Or sclerotic acidic and rich in cysteine ; osteonectin/BM-40 ) [ 51.... T, Borset M, Sundan a: cancer Statistics, 2007 blastic lytic. Were the only FDA approved drugs for metastatic bone disease [ 71 ] to! In osteoblastic lesions mixed lesions ( Fig 2 ):85-101. doi: 10.1038/s41568-021-00406-5 (... Table 1 ): S25-30 primary target of drug therapies as cures for bone metastasis T... The fluids MD 20894, Web Policies osteoblastic or blastic metastases cause area. Endothelial cells produce MMPs the growth factors produced by breast and prostate cancers may be.!J Bone Miner Res. In the bone, OPN is involved in the differentiation and activity of osteoclasts, and inhibition of mineral deposition in the osteoid [37]. official website and that any information you provide is encrypted 2010, 3: 572-599. Lerner UH: Bone remodeling in post-menopausal osteoporosis. Another drug, teriparatide (Forteo), the amino-terminal 34 amino acids of parathyroid hormone, has been used for many years to treat osteoporosis.
Along with colleagues and students she has focused particularly on the fate of osteoblasts in the metastatic bone environment. There is evidence that bisphosphonates also contribute to tumor cell death, especially in combination with chemotherapy [72].
The mechanisms are thought to be inhibition of tumor cell adhesion as well as osteoclast differentiation. 2008, Washington, DC: American Society for Bone and Mineral Research, 374-378. full_text.
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. Dysfunctional Runx2 results in the developmental arrest of osteoblasts and inhibition of osteogenesis. Provided by the Springer Nature SharedIt content-sharing initiative. Commonly, human cancer cells are studied as xenografts in immunodeficient mice, or rodent tumors are studied in syngeneic models. 2023 BioMed Central Ltd unless otherwise stated. Treatment can be tailored for each patient and, often requires multiple therapeutic interventions. The site is secure.
2022 Feb;22(2):85-101. doi: 10.1038/s41568-021-00406-5. Osteoblasts produce macrophage colony stimulating factor (M-CSF) and receptor activator of NFB ligand (RANKL), which bind to their respective receptors, c-fms and RANK, on pre-osteoclasts to bring about osteoclast differentiation and activation. It is interesting that cancer cells often remain dormant in bone for many years before they begin to grow. 2005, 208: 194-206.
EMBO J.
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. Int J Cancer. 2007, 67: 9542-9548. Mercer RR, Miyasaka C, Mastro AM: Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. 2008, 34 (Suppl 1): S25-30. . 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. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. Clinically, complications secondary to bone metastasis include pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy.
Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. Bethesda, MD 20894, Web Policies Osteoblastic or blastic metastases cause an area of the bone to look denser or sclerotic. Arch Biochem Biophys. A smoking history is almost always present. Int J Cancer.
Cytokines such as IL-6, IL-8 and IL-11 secreted by breast cancer cells also promote osteoclast differentiation and bone resorption. Bone is the most common site of metastasis for breast cancer. Lytic lesions should have radiologic evidence of calcication . Laufer I, Lis E, Pisinski L, Akhurst T, Bilsky MH. 2001, 142: 5050-5055. 7. PubMed Breast Cancer Res. To date, osteoclasts have been the primary target of drug therapies. 2006, 12: 1431-1440. It improves the quality of life by preventing fractures but does not prolong life [73]. Teriparatide, in contrast to bisphosphonates and denosumab, acts on osteoblasts to stimulate bone formation. Would you like email updates of new search results?
Bone Rep. 2022 Jun 12;17:101597. doi: 10.1016/j.bonr.2022.101597. However, the process is described in brief in order to further consider the mechanisms of osteolytic metastasis.
2010, 29: 811-821. Br J Cancer. However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. 1998, 19: 18-54. Clipboard, Search History, and several other advanced features are temporarily unavailable.
In addition, PDGF has been shown to inhibit osteoblast differentiation [60], making it an important factor in bone remodeling and the osteolytic bone metastasis.
The blastic bone lesions are caused when the cancer cells release the fluids. 10.1056/NEJMe1010459. J Cell Biochem. Clin Breast Cancer. Grey A: Teriparatide for bone loss in the jaw. 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 and colleagues [34] recently reported that Runx2 (Runt-related transcription factor 2) is produced by the highly metastatic prostate cancer cell PC-3, and positively correlates to the severity of osteolytic disease. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. Article 2010, 36: 615-620. 2006, 23: 345-356.
Thus, bone loss is the result of excessive bone degradation and insufficient bone replacement. Metastatic breast cancer cells tend to spread to the bones more often than they do to other parts of the body. Bone metastases may cause pain, may make the bones more susceptible to fractures, and may cause increased levels of calcium in the blood.
Corisdeo S, Gyda M, Zaidi M, Moonga BS, Troen BR: New insights into the regulation of cathepsin K gene expression by osteoprotegerin ligand. Endocrinology. The normal processes of bone resorption and formation are remarkably well balanced. PubMed
The majority of breast cancer metastases ultimately cause bone loss. At higher doses they may in fact prevent osteoblast differentiation [30]. 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. 2010. 2006, 21: 1350-1358.
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. IL-11, normally produced by bone marrow stromal cells and osteoblasts, is an important regulator of hematopoiesis and a potent promoter of osteoclast formation. Myeloma cells may also produce RANKL and directly affect osteoclasts [28]. This article is part of a review series on New pathways of metastasis, edited by Lewis Chodosh. In addition, pre-clinical trials with agents that target cathepsin K, certain matrix metalloproteinases (MMPs), and transforming growth factor (TGF)- are underway. Cancer Res. These capacities are essential for any cancer cells to develop distant metastases in organs such as lungs and liver as well as bone. The PGE2-mediated production of RANKL induces osteoclastogenesis via RANK.
Cancer Treat Rev. This information is not easily obtained with in vitro studies.
Osteo-blasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL that curtails osteoclast activation. 10.1158/0008-5472.CAN-09-2758. 10.1016/j.ctrv.2008.03.008. 2023;2582:343-353. doi: 10.1007/978-1-0716-2744-0_24. 10.2353/ajpath.2009.080906.
Request PDF | Mechanoregulation may drive osteolysis during bone metastasis: A finite element analysis of the mechanical environment within bone tissue during bone metastasis and osteolytic . 10.1177/154405910608500703. It is now known that PGE2 signaling through its receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form mature osteoclasts.
Bone is the most common site of metastasis for breast cancer.
1984 Jun 8;224(4653):1113-5 Zambonin Zallone A, Teti A, Primavera MV: Resorption of vital or devitalized bone by isolated osteoclasts in vitro. 2008, 68: 7795-7802. Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. Disclaimer, National Library of Medicine
Denosumab (Prolia), the latest drug to enter the field, is a monoclonal antibody to RANKL.
Further stimulation results in large multinuclear cells capable of bone resorption. 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. Cancer cells, osteoblasts, osteoclasts and endothelial cells produce MMPs. blastic (bone formation), or mixed lesions (Fig 2). 10.1038/35036374. PloS one.
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