Abstract
Cancer of any type often can be described by an arrest, alteration or disruption in the normal development of a tissue or organ, and understanding of the normal counterpart’s development can aid in understanding the malignant state. This is certainly true for osteosarcoma and the normal developmental pathways that guide osteoblast development that are changed in the genesis of osteogenic sarcoma. A carefully regulated crescendo–decrescendo expression of RUNX2 accompanies the transition from mesenchymal stem cell to immature osteoblast to mature osteoblast. This pivotal role is controlled by several pathways, including bone morphogenic protein (BMP), Wnt/β-catenin, fibroblast growth factor (FGF), and protein kinase C (PKC). The HIPPO pathway and its downstream target YAP help to regulate proliferation of immature osteoblasts and their maturation into non-proliferating mature osteoblasts. This pathway also helps regulate expression of the mature osteoblast protein osteocalcin. YAP also regulates expression of MT1-MMP, a membrane-bound matrix metalloprotease responsible for remodeling the extracellular matrix surrounding the osteoblasts. YAP, in turn, can be regulated by the ERBB family protein Her-4. Osteosarcoma may be thought of as a cell held at the immature osteoblast stage, retaining some of the characteristics of that developmental stage. Disruptions of several of these pathways have been described in osteosarcoma, including BMP, Wnt/b-catenin, RUNX2, HIPPO/YAP, and Her-4. Further, PKC can be activated by several receptor tyrosine kinases implicated in osteosarcoma, including the ERBB family (EGFR, Her-2 and Her-4 in osteosarcoma), IGF1R, FGF, and others. Understanding these functions may aid in the understanding the mechanisms underpinning clinical observations in osteosarcoma, including both the lytic and blastic phenotypes of tumors, the invasiveness of the disease, and the tendency for treated tumors to ossify rather than shrink. Through a better understanding of the relationship between normal osteoblast development and osteosarcoma, we may gain insights into novel therapeutic avenues and improved outcomes.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Tang N, Song W-X, Luo J, Luo X, Chen J, Sharff K, Bi Y, He B-C, Huang J-Y, Zhu G-H, Su Y-X, Jiang W, Tang M, He Y, Wang Y, Chen L, Zuo G-W, Shen J, Pan X, Reid R, Luu H, Haydon R, He T-C (2009) BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signalling. J Cell Mol Med 13(8B):2448–2464. doi:10.1111/j.1582-4934.2008.00569.x
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147. doi:10.1126/science.284.5411.143
Harding WG, Courville CB (1934) Bone formation in metastases of osteogenic sarcoma: report of case with metastases to the brain. Am J Cancer 21(4):787–794. doi:10.1158/ajc.1934.787
Phillips C (1935) Osteogenic sarcoma: its pathologic characteristics. Radiology 24(6):728–734. doi:10.1148/24.6.728
Berman SD, Calo E, Landman AS, Danielian PS, Miller ES, West JC, Fonhoue BD, Caron A, Bronson R, Bouxsein ML, Mukherjee S, Lees JA (2008) Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage. Proc Natl Acad Sci 105(33):11851–11856. doi:10.1073/pnas.0805462105
Komori T, Kishimoto T (1998) Cbfa1 in bone development. Curr Opin Genet Dev 8(4):494–499
Blyth K, Cameron E, Neil J (2005) The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer 5(5):376–387
Kundu M, Javed A, Jeon J, Horner A, Shum L, Eckhaus M, Muenke M, Lian J, Yang Y, Nuckolls G, Stein G, Liu P (2002) Cbfbeta interacts with Runx2 and has a critical role in bone development. Nat Genet 32(4):639–644
McLarren KW, Theriault FM, Stifani S (2001) Association with the nuclear matrix and interaction with Groucho and RUNX proteins regulate the transcription repression activity of the basic helix loop helix factor Hes1. J Biol Chem 276(2):1578–1584. doi:10.1074/jbc.M007629200
Lian J, Stein J, Stein G, van Wijnen A, Montecino M, Javed A, Gutierrez S, Shen J, Zaidi S, Drissi H (2003) Runx2/Cbfa1 functions: diverse regulation of gene transcription by chromatin remodeling and co-regulatory protein interactions. Connect Tissue Res 44(Suppl 1):141–148
Otto F, Lubbert M, Stock M (2003) Upstream and downstream targets of RUNX proteins. J Cell Biochem 89(1):9–18
Thiede M, Smock S, Petersen D, Grasser W, Thompson D, Nishimoto S (1994) Presence of messenger ribonucleic acid encoding osteocalcin, a marker of bone turnover, in bone marrow megakaryocytes and peripheral blood platelets. Endocrinology 135(3):929–937. doi:10.1210/en.135.3.929
Morrison N, Shine J, Fragonas J, Verkest V, McMenemy M, Eisman J (1989) 1,25-dihydroxyvitamin D-responsive element and glucocorticoid repression in the osteocalcin gene. Science 246(4934):1158–1161. doi:10.1126/science.2588000
Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura K, Chung U, Kawaguchi H (2006) Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum 54(8):2462–2470
Bergwitz C, Prochnau A, Mayr B, Kramer F, Rittierodt M, Berten H, Hausamen J, Brabant G (2001) Identification of novel CBFA1/RUNX2 mutations causing cleidocranial dysplasia. J Inherit Metab Dis 24(6):648–656
Galindo M, Pratap J, Young DW, Hovhannisyan H, Im H-J, Choi J-Y, Lian JB, Stein JL, Stein GS, van Wijnen AJ (2005) The bone-specific expression of Runx2 OSCILLATES DURING THE CELL CYCLE TO SUPPORT a G1-related antiproliferative function in osteoblasts. J Biol Chem 280(21):20274–20285. doi:10.1074/jbc.M413665200
Thomas DM, Johnson SA, Sims NA, Trivett MK, Slavin JL, Rubin BP, Waring P, McArthur GA, Walkley CR, Holloway AJ, Diyagama D, Grim JE, Clurman BE, Bowtell DDL, Lee J-S, Gutierrez GM, Piscopo DM, Carty SA, Hinds PW (2004) Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. J Cell Biol 167(5):925–934. doi:10.1083/jcb.200409187
Lee J, Thomas D, Gutierrez G, Carty S, Yanagawa S, Hinds P (2006) HES1 cooperates with pRb to activate RUNX2-dependent transcription. J Bone Miner Res 21(6):921–933
Monroe D, Hawse J, Subramaniam M, Spelsberg T (2010) Retinoblastoma binding protein-1 (RBP1) is a Runx2 coactivator and promotes osteoblastic differentiation. BMC Musculoskelet Disord 11:104
Ozaki T, Wu D, Sugimoto H, Nagase H, Nakagawara A (2013) Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage. Cell Death Dis 4:e610. doi:10.1038/cddis.2013.127
Park HR, Won Jung W, Bertoni F et al (2004) Molecular analysis of p53, MDM2 and H-ras genes in low-grade central osteosarcoma. Pathology Research and Practice 200(6):439–445
Martin J, Zielenska M, Stein G, van Wijnen A, Squire J (2011) The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma 2011:282745
Watanabe T, Oyama T, Asada M, Harada D, Ito Y, Inagawa M, Suzuki Y, Sugano S, K-i K, Karsenty G, Komori T, Kitagawa M, Asahara H (2013) MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development. PLoS Genet 9(1):e1003132. doi:10.1371/journal.pgen.1003132
Wang CY, Yang SF, Wang Z, Tan JM, Xing SM, Chen DC, Xu SM, Yuan W (2013) PCAF acetylates Runx2 and promotes osteoblast differentiation. J Bone Miner Metab 31(4):381–389. doi:10.1007/s00774-013-0428-y
Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J, Nanes MS (2000) Inhibition of osteoblast differentiation by tumor necrosis factor-{alpha}. Endocrinology 141(11):3956–3964. doi:10.1210/en.141.11.3956
Li Y, Li A, Strait K, Zhang H, Nanes M, Weitzmann M (2007) Endogenous TNFalpha lowers maximum peak bone mass and inhibits osteoblastic Smad activation through NF-kappaB. J Bone Miner Res 22(5):646–655
Olfa G, Christophe C, Philippe L, Romain S, Khaled H, Pierre H, Odile B, Jean-Christophe D (2010) RUNX2 regulates the effects of TNFalpha on proliferation and apoptosis in SaOs-2 cells. Bone 46(4):901–910
Li X, McGee-Lawrence M, Decker M, Westendorf J (2010) The Ewing’s sarcoma fusion protein, EWS-FLI, binds Runx2 and blocks osteoblast differentiation. J Cell Biochem 111(4):933–943
Zhu J, Shimizu E, Zhang X, Partridge N, Qin L (2011) EGFR signaling suppresses osteoblast differentiation and inhibits expression of master osteoblastic transcription factors Runx2 and Osterix. J Cell Biochem 112(7):1749–1760. doi:10.1002/jcb.23094
van der Deen M, Akech J, Lapointe D, Gupta S, Young D, Montecino M, Galindo M, Lian J, Stein J, Stein G, van Wijnen A (2012) Genomic promoter occupancy of runt-related transcription factor RUNX2 in osteosarcoma cells identifies genes involved in cell adhesion and motility. J Biol Chem 287(7):4503–4517. doi:10.1074/jbc.M111.287771
Rao T, Kühl M (2010) An updated overview on Wnt signaling pathways: a prelude for more. Circ Res 106(12):1798–1806. doi:10.1161/CIRCRESAHA.110.219840
Rodda S, McMahon A (2006) Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133(16):3231–3244. doi:10.1242/dev.02480
Maeda K, Takahashi N, Kobayashi Y (2013) Roles of Wnt signals in bone resorption during physiological and pathological states. J Mol Med (Berlin, Germany) 91(1):15–23. doi:10.1007/s00109-012-0974-0
Wan Y, Lu C, Cao J, Zhou R, Yao Y, Yu J, Zhang L, Zhao H, Li H, Zhao J, Zhu X, He L, Liu Y, Yao Z, Yang X, Guo X (2013) Osteoblastic Wnts differentially regulate bone remodeling and the maintenance of bone marrow mesenchymal stem cells. Bone 55(1):258–267. doi:10.1016/j.bone.2012.12.052
Sonomoto K, Yamaoka K, Oshita K, Fukuyo S, Zhang X, Nakano K, Okada Y, Tanaka Y (2012) Interleukin-1β induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt-5a/receptor tyrosine kinase-like orphan receptor 2 pathway. Arthritis Rheum 64(10):3355–3363. doi:10.1002/art.34555
Włodarski K, Galus R, Brodzikowska A, Włodarski P (2013) Sclerostin, an osteocytes-derived bone-forming inhibitor. Pol Orthop Traumatol 78:151–154
Yu L, van der Valk M, Cao J, Han C-YE, Juan T, Bass M, Deshpande C, Damore M, Stanton R, Babij P (2011) Sclerostin expression is induced by BMPs in human Saos-2 osteosarcoma cells but not via direct effects on the sclerostin gene promoter or ECR5 element. Bone 49(6):1131–1140. doi:10.1016/j.bone.2011.08.016
Hart M, Concordet J, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R, Polakis P (1999) The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol 9(4):207–210. doi:10.1016/S0960-9822(99)80091-8
Lin C, Guo Y, Ghaffar S, McQueen P, Pourmorady J, Christ A, Rooney K, Ji T, Eskander R, Zi X, Hoang B (2013) Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma. Sarcoma 2013:147541. doi:10.1155/2013/147541
Loeser R (2013) Osteoarthritis year in review 2013: biology. Osteoarthritis Cartilage. doi:10.1016/j.joca.2013.05.020
Ruan J, Trotter T, Nan L, Luo R, Javed A, Sanderson R, Suva L, Yang Y (2013) Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease. Bone. doi:10.1016/j.bone.2013.07.024
Steensma M, Tyler W, Shaber A, Goldring S, Ross F, Williams B, Healey J, Purdue P (2013) Targeting the giant cell tumor stromal cell: functional characterization and a novel therapeutic strategy. PLoS One 8(7):e69101. doi:10.1371/journal.pone.0069101
Ornitz D, Marie P (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16(12):1446–1465. doi:10.1101/gad.990702
Hanneken A (2001) Structural characterization of the circulating soluble FGF receptors reveals multiple isoforms generated by secretion and ectodomain shedding. FEBS Lett 489(2–3):176–181. doi:10.1016/S0014-5793(00)02409-1
Jang J-H (2002) Identification and characterization of soluble isoform of fibroblast growth factor receptor 3 in human SaOS-2 osteosarcoma cells. Biochem Biophys Res Commun 292(2):378–382. doi:10.1006/bbrc.2002.6668
Ezzat S, Zheng L, Yu S, Asa S (2001) A soluble dominant negative fibroblast growth factor receptor 4 isoform in human MCF-7 breast cancer cells. Biochem Biophys Res Commun 287(1):60–65. doi:10.1006/bbrc.2001.5546
Celli G, LaRochelle W, Mackem S, Sharp R, Merlino G (1998) Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning. EMBO J 17(6):1642–1655. doi:10.1093/emboj/17.6.1642
Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L (1994) Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J 13(14):3296–3301
Valta M, Hentunen T, Qu Q, Valve E, Harjula A, Seppänen J, Väänänen H, Härkönen P (2006) Regulation of osteoblast differentiation: a novel function for fibroblast growth factor 8. Endocrinology 147(5):2171–2182. doi:10.1210/en.2005-1502
Biver E, Soubrier A-S, Thouverey C, Cortet B, Broux O, Caverzasio J, Hardouin P (2012) Fibroblast growth factor 2 inhibits up-regulation of bone morphogenic proteins and their receptors during osteoblastic differentiation of human mesenchymal stem cells. Biochem Biophys Res Commun 427(4):737–742. doi:10.1016/j.bbrc.2012.09.129
Choi K-Y, Kim H-J, Lee M-H, Kwon T-G, Nah H-D, Furuichi T, Komori T, Nam S-H, Kim Y-J, Kim H-J, Ryoo H-M (2005) Runx2 regulates FGF2-induced Bmp2 expression during cranial bone development. Dev Dyn 233(1):115–121. doi:10.1002/dvdy.20323
Bodo M, Lilli C, Bellucci C, Carinci P, Calvitti M, Pezzetti F, Stabellini G, Bellocchio S, Balducci C, Carinci F, Baroni T (2002) Basic fibroblast growth factor autocrine loop controls human osteosarcoma phenotyping and differentiation. Mol Med 8(7):393–404
Birkedal-Hansen H, Moore W, Bodden M, Windsor L, Birkedal-Hansen B, DeCarlo A, Engler J (1993) Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4(2):197–250. doi:10.1177/10454411930040020401
Bjørnland K, Flatmark K, Pettersen S, Aaasen A, Fodstad O, Maelandsmo G (2005) Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res 127(2):151–156. doi:10.1016/j.jss.2004.12.016
Liao C-L, Lai K-C, Huang A-C, Yang J-S, Lin J-J, Wu S-H, Gibson Wood W, Lin J-G, Chung J-G (2012) Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the matrix metalloproteinase-2/-9, protein kinase B (PKB) and PKC signaling pathways. Food Chem Toxicol 50(5):1734–1740. doi:10.1016/j.fct.2012.02.033
Lu K-H, Yang H-W, Su C-W, Lue K-H, Yang S-F, Hsieh Y-S (2013) Phyllanthus urinaria suppresses human osteosarcoma cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways. Food Chem Toxicol 52:193–199. doi:10.1016/j.fct.2012.11.019
Himelstein B, Asada N, Carlton M, Collins M (1998) Matrix metalloproteinase-9 (MMP-9) expression in childhood osseous osteosarcoma. Med Pediatr Oncol 31(6):471–474. doi:10.1002/(SICI)1096-911X(199812)31:6<471::AID-MPO2>3.0.CO;2-M
Okada Y, Naka K, Kawamura K, Matsumoto T, Nakanishi I, Fujimoto N, Sato H, Seiki M (1995) Localization of matrix metalloproteinase 9 (92-kilodalton gelatinase/type IV collagenase = gelatinase B) in osteoclasts: implications for bone resorption. Lab Invest 72(3):311–322
Kim S-M, Lee H, Park Y-S, Lee Y, Seo S (2012) ERK5 regulates invasiveness of osteosarcoma by inducing MMP-9. J Orthop Res 30(7):1040–1044. doi:10.1002/jor.22025
Chan K, Wong H, Jin G, Liu B, Cao R, Cao Y, Lehti K, Tryggvason K, Zhou Z (2012) MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling and calvarial osteogenesis. Dev Cell 22(6):1176–1190. doi:10.1016/j.devcel.2012.04.014
Tang Y, Rowe R, Botvinick E, Kurup A, Putnam A, Seiki M, Weaver V, Keller E, Goldstein S, Dai J, Begun D, Saunders T, Weiss S (2013) MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis. Dev Cell 25(4):402–416. doi:10.1016/j.devcel.2013.04.011
Husmann K, Arlt M, Muff R, Langsam B, Bertz J, Born W, Fuchs B (2013) Matrix Metalloproteinase 1 promotes tumor formation and lung metastasis in an intratibial injection osteosarcoma mouse model. Biochim Biophys Acta 1832(2):347–354. doi:10.1016/j.bbadis.2012.11.006
Zhang W, Shen X, Wan C, Zhao Q, Zhang L, Zhou Q, Deng L (2012) Effects of insulin and insulin-like growth factor 1 on osteoblast proliferation and differentiation: differential signalling via Akt and ERK. Cell Biochem Funct 30(4):297–302. doi:10.1002/cbf.2801
Taniguchi C, Emanuelli B, Kahn C (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7(2):85–96. doi:10.1038/nrm1837
Wang Y-H, Han X-D, Qiu Y, Xiong J, Yu Y, Wang B, Zhu Z-Z, Qian B-P, Chen Y-X, Wang S-F, Shi H-F, Sun X (2012) Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma. J Surg Oncol 105(3):235–243. doi:10.1002/jso.22077
Luk F, Yu Y, Walsh W, Yang J-L (2011) IGF1R-targeted therapy and its enhancement of doxorubicin chemosensitivity in human osteosarcoma cell lines. Cancer Invest 29(8):521–532. doi:10.3109/07357907.2011.606252
Kurmasheva R, Dudkin L, Billups C, Debelenko L, Morton C, Houghton P (2009) The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res 69(19):7662–7671. doi:10.1158/0008-5472.CAN-09-1693
Miyazono K, Maeda S, Imamura T (2005) BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16(3):251–263. doi:10.1016/j.cytogfr.2005.01.009
Noël D, Gazit D, Bouquet C, Apparailly F, Bony C, Plence P, Millet V, Turgeman G, Perricaudet M, Sany J, Jorgensen C (2004) Short-term BMP-2 expression is sufficient for in vivo osteochondral differentiation of mesenchymal stem cells. Stem Cells 22(1):74–85. doi:10.1634/stemcells.22-1-74
Gu K, Zhang L, Jin T, Rutherford R (2004) Identification of potential modifiers of Runx2/Cbfa1 activity in C2C12 cells in response to bone morphogenetic protein-7. Cells Tissues Organs 176(1–3):28–40. doi:10.1159/000075025
Fakhry A, Ratisoontorn C, Vedhachalam C, Salhab I, Koyama E, Leboy P, Pacifici M, Kirschner R, Nah H-D (2005) Effects of FGF-2/-9 in calvarial bone cell cultures: differentiation stage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential. Bone 36(2):254–266. doi:10.1016/j.bone.2004.10.003
Hughes-Fulford M, Li C-F (2011) The role of FGF-2 and BMP-2 in regulation of gene induction, cell proliferation and mineralization. J Orthop Surg Res 6:8. doi:10.1186/1749-799X-6-8
Zhang R, Oyajobi B, Harris S, Chen D, Tsao C, Deng H-W, Zhao M (2013) Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone 52(1):145–156. doi:10.1016/j.bone.2012.09.029
Lind M, Eriksen E, Bünger C (1996) Bone morphogenetic protein-2 but not bone morphogenetic protein-4 and -6 stimulates chemotactic migration of human osteoblasts, human marrow osteoblasts, and U2-OS cells. Bone 18(1):53–57
Nakashima K, de Crombrugghe B (2003) Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet 19(8):458–466. doi:10.1016/S0168-9525(03)00176-8
Cao Y, Zhou Z, de Crombrugghe B, Nakashima K, Guan H, Duan X, Jia S-F, Kleinerman E (2005) Osterix, a transcription factor for osteoblast differentiation, mediates antitumor activity in murine osteosarcoma. Cancer Res 65(4):1124–1128. doi:10.1158/0008-5472.CAN-04-2128
Salinas-Souza C, De Oliveira R, Alves M, Garcia Filho R, Petrilli A, Toledo S (2013) The metastatic behavior of osteosarcoma by gene expression and cytogenetic analyses. Hum Pathol. doi:10.1016/j.humpath.2013.04.013
Horvai A, Roy R, Borys D, O’Donnell R (2012) Regulators of skeletal development: a cluster analysis of 206 bone tumors reveals diagnostically useful markers. Mod Pathol 25(11):1452–1461. doi:10.1038/modpathol.2012.110
Bourgeois P, Stoetzel C, Bolcato-Bellemin A, Mattei M, Perrin-Schmitt F (1996) The human H-twist gene is located at 7p21 and encodes a B-HLH protein that is 96 % similar to its murine M-twist counterpart. Mamm Genome 7(12):915–917. doi:10.1007/s003359900269
Martin T, Goyal A, Watkins G, Jiang W (2005) Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 12(6):488–496. doi:10.1245/ASO.2005.04.010
Puisieux A, Valsesia-Wittmann S, Ansieau S (2006) A twist for survival and cancer progression. Br J Cancer 94(1):13–17. doi:10.1038/sj.bjc.6602876
Wu K-J, Yang M-H (2011) Epithelial-mesenchymal transition and cancer stemness: the Twist1-Bmi1 connection. Biosci Rep 31(6):449–455. doi:10.1042/BSR20100114
Isenmann S, Arthur A, Zannettino A, Turner J, Shi S, Glackin C, Gronthos S (2009) TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment. Stem Cells (Dayton, Ohio) 27(10):2457–2468. doi:10.1002/stem.181
Hayashi M, Nimura K, Kashiwagi K, Harada T, Takaoka K, Kato H, Tamai K, Kaneda Y (2007) Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling. J Cell Sci 120(Pt 8):1350–1357. doi:10.1242/jcs.000067
Yousfi M, Lasmoles F, Marie P (2002) TWIST inactivation reduces CBFA1/RUNX2 expression and DNA binding to the osteocalcin promoter in osteoblasts. Biochem Biophys Res Commun 297(3):641–644. doi:10.1016/S0006-291X(02)02260-X
Wu J, Liao Q, He H, Zhong D, Yin K (2012) TWIST interacts with β-catenin signaling on osteosarcoma cell survival against cisplatin. Mol Carcinog. doi:10.1002/mc.21991
Lee M, Lowe G, Strong D, Wergedal J, Glackin C (1999) TWIST, a basic helix-loop-helix transcription factor, can regulate the human osteogenic lineage. J Cell Biochem 75(4):566–577. doi:10.1002/(SICI)1097-4644(19991215)75:4<566::AID-JCB3>3.0.CO;2-0
Miraoui H, Severe N, Vaudin P, Pagès J-C, Marie P (2010) Molecular silencing of Twist1 enhances osteogenic differentiation of murine mesenchymal stem cells: implication of FGFR2 signaling. J Cell Biochem 110(5):1147–1154. doi:10.1002/jcb.22628
Danciu T, Li Y, Koh A, Xiao G, McCauley L, Franceschi R (2012) The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts. J Cell Biochem 113(1):70–79. doi:10.1002/jcb.23329
Entz-Werle N, Lavaux T, Metzger N, Stoetzel C, Lasthaus C, Marec P, Kalifa C, Brugieres L, Pacquement H, Schmitt C, Tabone M-D, Gentet J-C, Lutz P, Babin A, Oudet P, Gaub M, Perrin-Schmitt F (2007) Involvement of MET/TWIST/APC combination or the potential role of ossification factors in pediatric high-grade osteosarcoma oncogenesis. Neoplasia (New York, NY) 9(8):678–688
Yang D-C, Yang M-H, Tsai C-C, Huang T-F, Chen Y-H, Hung S-C (2011) Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST. PLoS One 6(9):e23965. doi:10.1371/journal.pone.0023965
Pan D (2010) The hippo signaling pathway in development and cancer. Dev Cell 19(4):491–505. doi:10.1016/j.devcel.2010.09.011
Stanger BZ (2008) Organ size determination and the limits of regulation. Cell Cycle 7(3):318–324
Halder G, Johnson RL (2011) Hippo signaling: growth control and beyond. Development 138(1):9–22. doi:10.1242/dev.045500
Lian I, Kim J, Okazawa H, Zhao J, Zhao B, Yu J, Chinnaiyan A, Israel MA, Goldstein LS, Abujarour R, Ding S, Guan KL (2010) The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev 24(11):1106–1118. doi:10.1101/gad.1903310
Grusche FA, Degoutin JL, Richardson HE, Harvey KF (2011) The Salvador/Warts/Hippo pathway controls regenerative tissue growth in Drosophila melanogaster. Dev Biol 350(2):255–266. doi:10.1016/j.ydbio.2010.11.020
Cao X, Pfaff SL, Gage FH (2008) YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev 22(23):3320–3334. doi:10.1101/gad.1726608
Wu S, Huang J, Dong J, Pan D (2003) hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114(4):445–456
Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G (2003) Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol 5(10):914–920. doi:10.1038/ncb1050
Harvey KF, Pfleger CM, Hariharan IK (2003) The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114(4):457–467
Pantalacci S, Tapon N, Leopold P (2003) The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5(10):921–927. doi:10.1038/ncb1051
Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber D, Hariharan IK (2002) salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110(4):467–478
Praskova M, Xia F, Avruch J (2008) MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol 18(5):311–321. doi:10.1016/j.cub.2008.02.006
Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH (2005) The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24(12):2076–2086. doi:10.1038/sj.onc.1208445
Huang J, Wu S, Barrera J, Matthews K, Pan D (2005) The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122(3):421–434. doi:10.1016/j.cell.2005.06.007
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21(21):2747–2761. doi:10.1101/gad.1602907
Zhao B, Tumaneng K, Guan KL (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol 13(8):877–883. doi:10.1038/ncb2303
Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA (2002) “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298(5593):597–600. doi:10.1126/science.1072530
Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI (2003) NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev 17(9):1090–1100. doi:10.1101/gad.1054603
Okada T, Lopez-Lago M, Giancotti FG (2005) Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J Cell Biol 171(2):361–371. doi:10.1083/jcb.200503165
Yu FX, Guan KL (2013) The Hippo pathway: regulators and regulations. Genes Dev 27(4):355–371. doi:10.1101/gad.210773.112
Zhang L, Ren F, Zhang Q, Chen Y, Wang B, Jiang J (2008) The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev Cell 14(3):377–387. doi:10.1016/j.devcel.2008.01.006
Ferrigno O, Lallemand F, Verrecchia F, L’Hoste S, Camonis J, Atfi A, Mauviel A (2002) Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21(32):4879–4884. doi:10.1038/sj.onc.1205623
Ge L, Smail M, Meng W, Shyr Y, Ye F, Fan KH, Li X, Zhou HM, Bhowmick NA (2011) Yes-associated protein expression in head and neck squamous cell carcinoma nodal metastasis. PLoS One 6(11):e27529. doi:10.1371/journal.pone.0027529
Komuro A, Nagai M, Navin NE, Sudol M (2003) WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem 278(35):33334–33341
Stein GS, Lian JB, Stein JL, van Wijnen AJ, Choi JY, Pratap J, Zaidi SK (2003) Temporal and spatial parameters of skeletal gene expression: targeting RUNX factors and their coregulatory proteins to subnuclear domains. Connect Tissue Res 44(Suppl 1):149–153
Geryk-Hall M, Yang Y, Hughes DPM (2010) Driven to death: inhibition of farnesylation increases Ras activity in osteosarcoma and promotes growth arrest and cell death. Mol Cancer Ther 9(5):1111–1119. doi:10.1158/1535-7163.mct-09-0833
Zhao B, Lei QY, Guan KL (2008) The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol 20(6):638–646. doi:10.1016/j.ceb.2008.10.001
Song H, Kim H, Lee K, Lee DH, Kim TS, Song JY, Lee D, Choi D, Ko CY, Kim HS, Shin HI, Choi J, Park H, Park C, Jeong D, Lim DS (2012) Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. EMBO J 31(5):1147–1159. doi:10.1038/emboj.2011.480
Nissen-Meyer LS, Jemtland R, Gautvik VT, Pedersen ME, Paro R, Fortunati D, Pierroz DD, Stadelmann VA, Reppe S, Reinholt FP, Del Fattore A, Rucci N, Teti A, Ferrari S, Gautvik KM (2007) Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice. J Cell Sci 120(Pt 16):2785–2795. doi:10.1242/jcs.003855
Bhattaram P, Penzo-Mendez A, Sock E, Colmenares C, Kaneko KJ, Vassilev A, Depamphilis ML, Wegner M, Lefebvre V (2010) Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors. Nat Commun 1:9. doi:10.1038/ncomms1008
Yu FX, Zhang Y, Park HW, Jewell JL, Chen Q, Deng Y, Pan D, Taylor SS, Lai ZC, Guan KL (2013) Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev 27(11):1223–1232. doi:10.1101/gad.219402.113
Kim M, Kim M, Lee S, Kuninaka S, Saya H, Lee H, Lee S, Lim DS (2013) cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. EMBO J 32(11):1543–1555. doi:10.1038/emboj.2013.102
Wang W, Huang J, Chen J (2011) Angiomotin-like proteins associate with and negatively regulate YAP1. J Biol Chem 286(6):4364–4370. doi:10.1074/jbc.C110.205401
Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N, Hirahara S, Stephenson RO, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki EM, Nojima H, Rossant J, Nakao K, Niwa H, Sasaki H (2009) The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 16(3):398–410. doi:10.1016/j.devcel.2009.02.003
Leung CY, Zernicka-Goetz M (2013) Angiomotin prevents pluripotent lineage differentiation in mouse embryos via Hippo pathway-dependent and -independent mechanisms. Nat Commun 4:2251. doi:10.1038/ncomms3251
Tschop K, Conery AR, Litovchick L, Decaprio JA, Settleman J, Harlow E, Dyson N (2011) A kinase shRNA screen links LATS2 and the pRB tumor suppressor. Genes Dev 25(8):814–830. doi:10.1101/gad.2000211
Aylon Y, Michael D, Shmueli A, Yabuta N, Nojima H, Oren M (2006) A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev 20(19):2687–2700. doi:10.1101/gad.1447006
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA (2006) Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A 103(33):12405–12410. doi:10.1073/pnas.0605579103
McClatchey AI, Saotome I, Mercer K, Crowley D, Gusella JF, Bronson RT, Jacks T (1998) Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev 12(8):1121–1133
St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T (1999) Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 21(2):182–186. doi:10.1038/5965
Bothos J, Tuttle RL, Ottey M, Luca FC, Halazonetis TD (2005) Human LATS1 is a mitotic exit network kinase. Cancer Res 65(15):6568–6575. doi:10.1158/0008-5472.CAN-05-0862
Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N (2010) Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell 18(2):300–308. doi:10.1016/j.devcel.2009.12.011
Gharanei S, Brini AT, Vaiyapuri S, Alholle A, Dallol A, Arrigoni E, Kishida T, Hiruma T, Avigad S, Grimer R, Maher ER, Latif F (2013) RASSF2 methylation is a strong prognostic marker in younger age patients with Ewing sarcoma. Epigenetics 8(9)
Richter AM, Walesch SK, Wurl P, Taubert H, Dammann RH (2012) The tumor suppressor RASSF10 is upregulated upon contact inhibition and frequently epigenetically silenced in cancer. Oncogenesis 1:e18. doi:10.1038/oncsis.2012.18
Hsu JH, Lawlor ER (2011) BMI-1 suppresses contact inhibition and stabilizes YAP in Ewing sarcoma. Oncogene 30(17):2077–2085. doi:10.1038/onc.2010.571
Wu Z, Min L, Chen D, Hao D, Duan Y, Qiu G, Wang Y (2011) Overexpression of BMI-1 promotes cell growth and resistance to cisplatin treatment in osteosarcoma. PLoS One 6(2):e14648
Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL (2012) Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26(1):54–68. doi:10.1101/gad.173435.111
Keely PJ (2013) Proteolytic remodeling of the ECM and the geometric control of stem cell fate. Dev Cell 25(4):325–326. doi:10.1016/j.devcel.2013.05.012
Kim JE, Finlay GJ, Baguley BC (2013) The role of the hippo pathway in melanocytes and melanoma. Front Oncol 3:123. doi:10.3389/fonc.2013.00123
De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110. doi:10.1038/nrc3447
Wang Y, Shang Y (2013) Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res 319(2):160–169. doi:10.1016/j.yexcr.2012.07.019
Yang N, Morrison CD, Liu P, Miecznikowski J, Bshara W, Han S, Zhu Q, Omilian AR, Li X, Zhang J (2012) TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin. Cell Cycle 11(15):2922–2930. doi:10.4161/cc.21386
Hergovich A (2012) YAP-Hippo signalling downstream of leukemia inhibitory factor receptor: implications for breast cancer. Breast Cancer Res 14(6):326. doi:10.1186/bcr3349
Irvine KD (2012) Integration of intercellular signaling through the Hippo pathway. Semin Cell Dev Biol 23(7):812–817. doi:10.1016/j.semcdb.2012.04.006
Polakis P (2012) Wnt signaling in cancer. Cold Spring Harb Perspect Biol 4(5). doi:10.1101/cshperspect.a008052
Louvi A, Artavanis-Tsakonas S (2012) Notch and disease: a growing field. Semin Cell Dev Biol 23(4):473–480. doi:10.1016/j.semcdb.2012.02.005
Tumaneng K, Schlegelmilch K, Russell RC, Yimlamai D, Basnet H, Mahadevan N, Fitamant J, Bardeesy N, Camargo FD, Guan KL (2012) YAP mediates crosstalk between the Hippo and PI(3)K-TOR pathways by suppressing PTEN via miR-29. Nat Cell Biol 14(12):1322–1329. doi:10.1038/ncb2615
Konsavage WM Jr, Kyler SL, Rennoll SA, Jin G, Yochum GS (2012) Wnt/beta-catenin signaling regulates Yes-associated protein (YAP) gene expression in colorectal carcinoma cells. J Biol Chem 287(15):11730–11739. doi:10.1074/jbc.M111.327767
Fujii M (2012) Exploration of a new drug that targets YAP. J Biochem 152(3):209–211. doi:10.1093/jb/mvs072
Bao Y, Nakagawa K, Yang Z, Ikeda M, Withanage K, Ishigami-Yuasa M, Okuno Y, Hata S, Nishina H, Hata Y (2011) A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription. J Biochem 150(2):199–208. doi:10.1093/jb/mvr063
Casalini P, Iorio MV, Galmozzi E, Menard S (2004) Role of HER receptors family in development and differentiation. J Cell Physiol 200(3):343–350. doi:10.1002/jcp.20007
Muraoka-Cook RS, Sandahl M, Husted C, Hunter D, Miraglia L, Feng SM, Elenius K, Earp HS 3rd (2006) The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells. Mol Biol Cell 17(9):4118–4129. doi:10.1091/mbc.E06-02-0101
Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM (2005) WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res 65(15):6764–6772. doi:10.1158/0008-5472.CAN-05-1150
Junttila T, Sundvall M, Maatta J, Elenius K (2000) Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants. Trends Cardiovasc Med 10(7):304–310
Veikkolainen V, Vaparanta K, Halkilahti K, Iljin K, Sundvall M, Elenius K (2011) Function of ERBB4 is determined by alternative splicing. Cell Cycle 10(16):2647–2657
Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7(7):505–516. doi:10.1038/nrm1962
Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G (2006) Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 127(1):185–197. doi:10.1016/j.cell.2006.07.037
Muraoka-Cook RS, Sandahl MA, Strunk KE, Miraglia LC, Husted C, Hunter DM, Elenius K, Chodosh LA, Earp HS 3rd (2009) ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo. Mol Cell Biol 29(18):4935–4948. doi:10.1128/MCB.01705-08
Huang Z, Wang Y, Nayak PS, Dammann CE, Sanchez-Esteban J (2012) Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions. J Biol Chem 287(22):18091–18102. doi:10.1074/jbc.M111.313163
Vaskovsky A, Lupowitz Z, Erlich S, Pinkas-Kramarski R (2000) ErbB-4 activation promotes neurite outgrowth in PC12 cells. J Neurochem 74(3):979–987
Schneider MR, Sibilia M, Erben RG (2009) The EGFR network in bone biology and pathology. Trends Endocrinol Metabol 20(10):517–524, http://dx.doi.org/10.1016/j.tem.2009.06.008
Hong W, Guan KL (2012) The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol 23(7):785–793. doi:10.1016/j.semcdb.2012.05.004
Hollmen M, Elenius K (2010) Potential of ErbB4 antibodies for cancer therapy. Future Oncol 6(1):37–53. doi:10.2217/fon.09.144
Rokavec M, Justenhoven C, Schroth W, Istrate MA, Haas S, Fischer HP, Vollmert C, Illig T, Hamann U, Ko YD, Glavac D, Brauch H (2007) A novel polymorphism in the promoter region of ERBB4 is associated with breast and colorectal cancer risk. Clin Cancer Res 13(24):7506–7514. doi:10.1158/1078-0432.CCR-07-0457
Junttila TT, Sundvall M, Lundin M, Lundin J, Tanner M, Harkonen P, Joensuu H, Isola J, Elenius K (2005) Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells. Cancer Res 65(4):1384–1393
Xu S, Kitayama J, Yamashita H, Souma D, Nagawa H (2008) Nuclear translocation of HER4/c-erbB-4 is significantly correlated with prognosis of esophageal squamous cell carcinoma. J Surg Oncol 97(1):44–50
Hughes DP, Thomas DG, Giordano TJ, Baker LH, McDonagh KT (2004) Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res 64(6):2047–2053
Hughes DPM, Thomas DG, Giordano TJ, McDonagh KT, Baker LH (2006) Essential erbB family phosphorylation in osteosarcoma as a target for CI-1033 inhibition. Pediatr Blood Cancer 46(5):614–623
Hua Y, Gorshkov K, Yang Y, Wang W, Zhang N, Hughes D (2012) Slow down to stay alive: HER4 protects against cellular stress and confers chemoresistance in neuroblastoma. Cancer 118(20):5140–5154
Kang HG, Jenabi JM, Zhang J, Keshelava N, Shimada H, May WA, Ng T, Reynolds CP, Triche TJ, Sorensen PH (2007) E-cadherin cell-cell adhesion in ewing tumor cells mediates suppression of anoikis through activation of the ErbB4 tyrosine kinase. Cancer Res 67(7):3094–3105. doi:10.1158/0008-5472.CAN-06-3259
Merimsky O, Kollender Y, Issakov J, Inbar M, Flusser G, Benayahu D, Meller I, Bickels J (2003) Induction chemotherapy for bone sarcoma in adults: correlation of results with erbB-4 expression. Oncol Rep 10(5):1593–1599
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Mortus, J.R., Zhang, Y., Hughes, D.P.M. (2014). Developmental Pathways Hijacked by Osteosarcoma. In: Kleinerman, M.D., E. (eds) Current Advances in Osteosarcoma. Advances in Experimental Medicine and Biology, vol 804. Springer, Cham. https://doi.org/10.1007/978-3-319-04843-7_5
Download citation
DOI: https://doi.org/10.1007/978-3-319-04843-7_5
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-04842-0
Online ISBN: 978-3-319-04843-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)