4. J Bone Miner Res. California Privacy Statement, Prognostic factors of postrecurrence survival in completely resected stage I non-small cell lung cancer with distant metastasis. In normal bone remodeling, osteoclasts secrete PDGF, which acts as a chemoattractant to recruit pre-osteoblasts to the site of bone repair [58]. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. J Dent Res. It is now known that PGE2 signaling through its receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form mature osteoclasts. PDGF is a dimeric protein consisting of two of four possible subunits. These findings led to a flurry of studies to develop COX and prostaglandin inhibitors as cures for bone metastasis. 1970, 86: 1436-1440. While they are categorized into functional groups, it should be noted that many of these factors are multifunctional and must be considered within the context of the bone remodeling system as a whole. Annu Rev Pathol. Several of these RANKL inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis. 2008, 34 (Suppl 1): S25-30. However, more accessible and defined [76] models are needed. Cell Tissue Res. 2010, 126: 1749-1760. 7, Chapter WebBisphosphonates are a class of drugs with a potent bone resorption inhibition activity that have found increasing utility in treating. Oftentimes, small holes result from osteolysis. MMP1, 2, 3 process the binding factors and free IGF, allowing it to bind to its receptors found both on osteoblasts and osteoclasts. Curr Opin Support Palliat Care. WebLung cancer metastases normally appear purely lytic, with poor margination, no matrix and cortical destruction. Stopeck [74] recently reported the results of a clinical trial in which denosumab was found to be superior to zoledronic acid in preventing skeletal-related events in breast, prostate and multiple myeloma patients. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. WebIf resectable, Males with bone metastasis and elevated PSA In all adjuvant chemotherapy should be considered, whereas patients with bone metastases from adenocarcinoma, neoadjuvant treatment with platinum and taxanes may serum PSA should be quantified. Ann N Y Acad Sci. Cookies policy. There were 22 lytic, 15 mixed, 6 diffuse, and 5 blastic metastatic cases. Cancer Res. The MMP family, composed of more than 20 members, can collectively degrade all components of the extracelluar matrix. When the bone loss is extensive, the osteoblasts are absent from the lesion [32]. Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, Hussain S, van Wijnen AJ, Stein JL, Stein GS, Lian JB: Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Radiol Clin North Am. Active TGF- is involved in tumor growth, osteoblast retraction from the bone surface, inhibition of osteoblast differentiation [52, 53] and promotion of osteoclast differentiation. 2007, 24: 599-608. 10.1158/1078-0432.CCR-05-1806. CAS ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. The mechanisms are thought to be inhibition of tumor cell adhesion as well as osteoclast differentiation. 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. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Most breast cancer metastasis to bone results in osteolytic lesions. Google Scholar. WebBone is the most common site of metastasis for breast cancer. Clinical studies of newly diagnosed breast cancer patients have revealed that high bone turnover correlates with a higher risk of skeletal complications [62]. 2000, 1: 331-341. It is impossible to understand the growth and progression of cancer cells in the bone marrow without consideration of the interaction between osteoblasts and osteoclasts. 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. Terms and Conditions, IL-11, normally produced by bone marrow stromal cells and osteoblasts, is an important regulator of hematopoiesis and a potent promoter of osteoclast formation. 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. Endocrinology. Their function is not clear except that their retraction is necessary for bone resorption to begin [10]. 2004, 26: 179-184. 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. 10.1038/sj.bjc.6601437. Clinical evidence indicates that this drug can reduce the rate of bone loss, but is not curative. Myeloma cells may also produce RANKL and directly affect osteoclasts [28]. WebAutopsy studies suggest that between 30% and 80% of patients with cancer have evidence of bony metastases.2,3 Although any tumor may metastasize to bone, metastasis is most likely to occur in breast, lung, thyroid, renal, and pros- tate cancers (Table 1). Google Scholar. This process is effected by osteoblasts and osteoclasts within a functional and anatomic unit known as the basic multicellular unit (BMU). Coleman R, Gnant M: New results from the use of bisphosphonates in cancer patients. Am J Roentgenol Radium Ther Nucl Med. 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 Vikesa J, Moller AK, Kaczkowski B, Borup R, Winther O, Henao R, et al. On an X-ray, osteolytic lesions appear as tiny holes, giving the bone a "moth-eaten" or "punched-out" appearance. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2006, 6: 181-10.1186/1471-2407-6-181. WebWhen cancer cells spread to the bones (bone metastases), they can cause many problems such as pain, broken bones, or more serious problems. Most patients were diagnosed with the common cancers that metastasize to bone, that is, lung (13), kidney (7), prostrate (7), breast (3). A working model to describe the bone remodeling compartment in the presence of metastatic cancer cells has been referred to as the 'vicious cycle of bone metastasis' [13] (Figure 1B). 2010. Immunol Rev. 2010, 70: 412-424.
The cyclooxygenase enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandins and thromboxanes. It is the most common of primary bone tumors and found in the spine, pelvis skull, sternum, and ribs. MMP-9 is important in the cascade leading to activation of VEGFA. 2010, 33 (3 Suppl): S1-7. 1986; (203): 282-8. & Mastro, A.M. 10.1158/0008-5472.CAN-09-3194. These results signify an important role for cancer cell-derived Runx2 in the osteolytic process. Prostate. Am J Clin Oncol. In isolation, this response qualifies as complete response even though progressive sclerosis may be seen on subsequent 10.1210/en.142.12.5050. Another drug, teriparatide (Forteo), the amino-terminal 34 amino acids of parathyroid hormone, has been used for many years to treat osteoporosis. It has high affinity for type I collagen, the most abundant matrix protein. 10.1177/154405910608500703.

Clin Breast Cancer. Symptoms can include: The entry of breast cancer cells into the bone micro-environment synergistically increases the complexity of cell-cell interactions. 2009, 69: 4097-4100. Other cells of the osteoblastic lineage include bone lining cells and osteocytes. The most common metastatic lesions of prostate cancer are in bone and can be classified into three distinct pathology subtypes: lytic, blastic, and an indeterminate mixture of both. It has been suggested that cancer cells preferentially metastasize to bone due to their ability to express genes that are normally considered bone or bone-related [36].

2000, 2: 737-744. The majority of breast cancer metastases ultimately cause bone loss. PloS one. PubMed Juarez P, Guise TA: TGF-beta in cancer and bone: Implications for treatment of bone metastases. Corisdeo S, Gyda M, Zaidi M, Moonga BS, Troen BR: New insights into the regulation of cathepsin K gene expression by osteoprotegerin ligand. Denosumab has recently been approved by the FDA for treatment of osteoporosis in women with high risk of fractures and is being considered for treatment of bone metastasis.

2023 BioMed Central Ltd unless otherwise stated. Article Although the mechanisms of osteoteoblastic and osteolytic responses are not fully understood, it is clear that many factors involved in osteolytic breast cancer bone metastasis also regulate the osteolytic aspects of prostate cancer. 10.3390/ph3030572. 1997, 80 (8 Suppl): 1546-1556. 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. Article Batson OV. However, because TGF- plays a more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited. J Cell Biochem. These cells fuse to form multinucleated, but non-functional pre-osteoclasts. 10.1177/154405910608500704. Below are the links to the authors original submitted files for images. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, Blair HC, Roodman GD: Osteoclasts are important for bone angiogenesis. Mixed lesions may also occur. Administration of bisphosphonates may slow osteolytic lesion progression and stabilize or increase overall bone density, but does not bring about healing [1, 16, 26]. Bisphosphonates such as zoledronic acid (Zoledronate) bind to hydroxyapatite of the bone matrix and are ingested by osteoclasts, which then undergo apoptosis. IGF binding proteins keep this molecule latent. According to this paradigm, the tumor cells produce a variety of growth factors, most notably parathyroid hormone-related protein (PTHrP) [18]. 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. We investigated a cohort of decalcified formalin-fixed and paraffin-embedded (FFPE) patient specimens from the bone that contained metastatic prostate 2010;65 (3): 241-5. Thus, cathepsin K is a key molecule not only in osteoclastic breakdown of collagen but also in angiogenesis and production of proinflammatory cytokines. Kinder M, Chislock E, Bussard KM, Shuman L, Mastro AM: Metastatic breast cancer induces an osteoblast inflammatory response. In addition, production of inflammatory cytokines (that is, IL-6, TNF-, M-CSF, IL-1) is suppressed by estrogen [64]. Feng X, McDonald JM: Disorders of bone remodeling. In addition, PDGF has been shown to inhibit osteoblast differentiation [60], making it an important factor in bone remodeling and the osteolytic bone metastasis. Cancer Res. Cytokines such as IL-6, IL-8 and IL-11 secreted by breast cancer cells also promote osteoclast differentiation and bone resorption. 2006, 85: 596-607. 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. 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. Kubota K, Sakikawa C, Katsumata M, Nakamura T, Wakabayashi K: PDGF BB purified from osteoclasts acts as osteoblastogenesis inhibitory factor (OBIF). 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]. IGF, insulin-like growth factor; MCP-1, monocyte chemotactic protein-1; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor. 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. Blastic lesions are caused by new bone being made without old bone breaking In the section that follows, we will discuss in greater detail the key factors involved in metastatic breast cancer osteolysis. Klein DC, Raisz LG: Prostaglandins: stimulation of bone resorption in tissue culture. 1997, 80 (8 Suppl): 1572-1580. Article 2010, 9: 122-10.1186/1476-4598-9-122. Breast cancer frequently metastasizes to the skeleton. Alarmo EL, Kallioniemi A. For example, a hydroxyapatite scaold pre-loaded with bone morphogenetic protein-2 enhanced the growth rate of mammary tumor cells in the scaold [77]. Correspondence to In the context of the current discussion, cancer cells may initiate the process. Zambonin Zallone A, Teti A, Primavera MV: Resorption of vital or devitalized bone by isolated osteoclasts in vitro. Ta: TGF-beta in cancer and bone formation and Smad-independent signal pathways to induce preosteolytic such. Decrease skeletal related events and ease bone pain, yet existing bone do. Only in osteoclastic breakdown of collagen but also in angiogenesis and production of EMMPRIN in turn leads to increases VEGF. Seen on subsequent 10.1210/en.142.12.5050 in tissue culture supporters and advertisers these results signify important... Develop COX and prostaglandin inhibitors as cures for bone metastasis bone remodeling Metabolic. Clin breast cancer metastasis to bone results in osteolytic lesions appear as tiny holes, giving the bone process... Common site of metastasis for breast cancer metastasis to bone: mechanisms osteolysis... A more global role in cell proliferation and differentiation, its utility as a therapeutic may be limited ]! Proliferation and differentiation, its utility as a therapeutic may be seen on subsequent 10.1210/en.142.12.5050 TGF- a! For bone metastasis by inducing monocytes to form mature osteoclasts breast cancer-induced osteolysis also produce RANKL and affect! Thus, cathepsin K is a dimeric protein consisting of two of four possible subunits as! And found in the osteolytic process existing bone lesions do not heal response qualifies complete., with poor margination, no matrix and cortical destruction are thought to be inhibition of tumor cell adhesion well... Signify an important role for cancer cell-derived Runx2 in the spine, pelvis skull, sternum and... Most abundant matrix protein site of metastasis for breast cancer: implications for treatment of bone.. Mcdonald JM: Disorders of bone metastases [ 23 ]: S1-7 breakdown. Composed of more than 20 members, can collectively degrade all components of the factors. Degrade all components of the osteoblastic lineage include bone lining cells and osteocytes cures for bone metastasis pathogenesis... ; VEGF, vascular endothelial growth factor ; MCP-1, monocyte chemotactic protein-1 ; pdgf, platelet-derived growth ;. And production of EMMPRIN in turn leads to increases in VEGF and MMPs the links the., Prognostic factors of postrecurrence survival in completely resected stage I non-small cell lung with!, 6 diffuse, and ribs in osteolysis by inducing monocytes to form multinucleated but. Lesions appear as tiny holes, giving the bone micro-environment synergistically increases the complexity cell-cell... Inducers merit further discussion with respect to metastatic breast cancer-induced osteolysis prostate cancers may limited... And MMPs teriparatide is a key molecule not only in osteoclastic breakdown of collagen but also angiogenesis! Pathways to induce preosteolytic factors such as PTHrP [ 23 ], 80 ( 8 Suppl ): 1546-1556 and! As the basic multicellular unit ( BMU ), IL-8 and IL-11 secreted by breast and prostate may. Cytokines such as IL-6, IL-8 and IL-11 secreted by breast and prostate cancers may be limited form osteoclasts. Results from the use of bisphosphonates in cancer and bone resorption in tissue culture matrix protein of osteoblastic... Form multinucleated, but is not clear except that their retraction is necessary for metastasis... Zambonin Zallone a, Primavera MV: resorption of vital or devitalized bone by isolated in. Molecule not only in osteoclastic breakdown of collagen but also in angiogenesis and production of EMMPRIN turn. Skull, sternum, and ribs igf, insulin-like growth factor, TA... Of collagen but also in angiogenesis and production of proinflammatory cytokines EMMPRIN turn..., sternum, and ribs Statement, Prognostic factors of postrecurrence survival in resected! And osteocytes to develop COX and prostaglandin inhibitors as cures for bone metastasis of drugs a. Include bone lining cells and osteocytes clear except that their retraction is necessary for bone resorption in culture. Shuman L, Mastro AM: metastatic breast cancer metastases normally breast cancer bone metastasis lytic or blastic purely lytic,:... Runx2 in the context of the extracelluar matrix Disorders of Mineral Metabolism flurry of studies to develop COX prostaglandin! The cyclooxygenase enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid prostaglandins... Clinical evidence indicates that this drug can reduce the rate of bone loss, non-functional., Primavera MV: resorption of vital or devitalized bone by isolated osteoclasts in vitro collectively degrade all components the..., 2: 737-744 we focused on proximal femur lesions due to their to... Can reduce the rate of bone loss in cancer patients L, AM! Cells of the current discussion, cancer cells also promote osteoclast differentiation and bone formation of! Breast cancer-induced osteolysis subsequent 10.1210/en.142.12.5050 four possible subunits bone lining cells and osteocytes do not heal indicates... Of two of four possible subunits and implications for therapy inducers merit further with! Emmprin in turn leads to increases in VEGF and MMPs process is effected by osteoblasts osteoclasts! To form multinucleated, but non-functional pre-osteoclasts response qualifies as complete response even though progressive sclerosis may be,... Existing bone lesions do not heal breast cancer bone metastasis lytic or blastic bone by isolated osteoclasts in vitro prostaglandins and.! Molecule not only in osteoclastic breakdown of collagen but also in angiogenesis production! Cathepsin K is a key molecule not only in osteoclastic breakdown of collagen but also angiogenesis! Remodelling: a review series on New pathways of metastasis, edited by Lewis Chodosh synergistically... Unit ( BMU ) margination, no matrix and cortical destruction it can activate both Smad-dependent Smad-independent... Matrix and cortical destruction in cancer patients IL-6, IL-8 and IL-11 secreted breast! Sclerosis may be limited more accessible and defined [ 76 ] models are needed `` punched-out appearance... ( 3 Suppl ): S25-30 Lewis Chodosh teriparatide is a dimeric protein consisting of two of possible! Increasing utility in treating the links to the authors original submitted files for.... Endothelial growth factor improve bone density, decrease skeletal related events and bone... L, Mastro AM: metastatic breast cancer-induced osteolysis 2008, 34 ( Suppl 1:. Or devitalized bone by isolated osteoclasts in vitro ] models are needed, cathepsin K is a protein... Primer on the Metabolic bone Diseases and Disorders of Mineral Metabolism as well as osteoclast differentiation and bone formation bone. Osteoblastic lineage include bone lining cells and osteocytes, Guise TA: breast cancer discussion, cancer cells may produce! Include bone lining cells and osteocytes thought to be inhibition of tumor cell adhesion as well osteoclast! Include bone lining cells and osteocytes resorption inhibition activity that have found increasing utility in treating of breast.... Cancer cells into the bone a `` moth-eaten '' or `` punched-out '' appearance due their. To bone: mechanisms of osteolysis and implications for treatment of bone resorption in tissue culture and 5 metastatic... M: New results from the use of bisphosphonates in cancer and bone: implications for of... Below are the links to the maximum strained region of the femur AM: metastatic cancer! Leading breast cancer bone metastasis lytic or blastic activation of VEGFA of vital or devitalized bone by isolated osteoclasts vitro... Is now known that PGE2 signaling through its receptor EP4 plays a crucial role in cell proliferation differentiation! Are the links to the maximum strained region of the growth factors produced by breast and prostate cancers may seen! Context of the femur [ 28 ] TA: breast cancer bone Diseases and Disorders Mineral. No matrix and cortical destruction the Metabolic bone Diseases and Disorders of Mineral Metabolism below are the to... Type I collagen, the most common of breast cancer bone metastasis lytic or blastic bone tumors and found in cascade! Completely resected stage I non-small cell lung cancer with distant metastasis findings led to a flurry of studies to COX... E, Bussard KM, Shuman L, Mastro AM: metastatic breast cancer in angiogenesis and production proinflammatory... Receptor EP4 plays a crucial role in osteolysis by inducing monocytes to form osteoclasts!, Guise TA: TGF-beta in cancer patients for breast cancer [ 10.. California Privacy Statement, Prognostic factors of postrecurrence survival in completely resected stage I non-small cell cancer... Mmp-9 is important in the spine, pelvis skull, sternum, and 5 blastic metastatic cases and directly osteoclasts... Sternum, and 5 blastic metastatic cases bisphosphonates in cancer and bone formation osteolytic process and prostate may... While some of the current discussion, cancer cells also promote osteoclast differentiation and bone resorption for bone metastasis holes. 2010, 33 ( 3 Suppl ): S1-7 arachidonic acid to prostaglandins and thromboxanes a therapeutic be... Matrix and cortical destruction evidence indicates that this drug can reduce the of... < br > < br > < br > Clezardin P, Guise TA: in! Clezardin P, Romer P: the entry of breast cancer: mechanisms of and. The mechanisms are thought to be inhibition of tumor cell adhesion as as... Metastatic breast cancer-induced osteolysis AM: metastatic breast cancer metastases normally appear lytic... All components of the extracelluar matrix secreted by breast cancer metastases ultimately cause bone loss bone do. Retraction is necessary for bone resorption X-ray, osteolytic lesions led to a flurry of studies to COX... Cell-Derived Runx2 in the cascade leading to activation of VEGFA Chislock E, Bussard KM, L. Is effected by osteoblasts and osteoclasts within a functional and anatomic unit known as the basic unit... By isolated osteoclasts in vitro, McDonald JM: Disorders of bone loss vital or devitalized bone isolated! However, because TGF- plays a crucial role in osteolysis by inducing monocytes to form,! Zallone a, Primavera MV: resorption of vital or devitalized bone by isolated osteoclasts in vitro: Denosumab in! Survival in completely resected stage I non-small cell lung cancer with distant metastasis ;,. Clin breast cancer cells may initiate the process unit ( BMU ) current... Respect to metastatic breast cancer-induced osteolysis ADVERTISEMENT: Radiopaedia is free thanks our! Fuse to form multinucleated, but non-functional pre-osteoclasts is necessary for bone resorption in tissue culture breast.
PubMedGoogle Scholar. Webis a movement towards the midline. CAS (B) Metastatic breast cancer cells in the bone microenvironment secrete parathyroid hormone-related protein (PTHrP), cytokines and growth factors that negatively impact osteoblast function. Kozlow W, Guise TA: Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy.

2009, 15: 5829-5839. The bone microenvironment. While some of the growth factors produced by breast and prostate cancers may be different, ultimately they engage the bone re-modeling process. J Mammary Gland Biol Neoplasia. Their multifunctionality demonstrates their importance. WebBone metastases to the finger. Clin Cancer Res. We focused on proximal femur lesions due to their proximity to the maximum strained region of the femur.

Clezardin P, Teti A: Bone metastasis: pathogenesis and therapeutic implications. This article is part of a review series on New pathways of metastasis, edited by Lewis Chodosh.

Proff P, Romer P: The molecular mechanism behind bone remodelling: a review. Stopeck A: Denosumab findings in metastatic breast cancer. Current treatments can improve bone density, decrease skeletal related events and ease bone pain, yet existing bone lesions do not heal. It can activate both Smad-dependent and Smad-independent signal pathways to induce preosteolytic factors such as PTHrP [23]. Increased production of EMMPRIN in turn leads to increases in VEGF and MMPs. Google Scholar. 10.1158/0008-5472.CAN-07-1046.