Serglycin Induces Osteoclastogenesis and Promotes Tumor Growth in Giant Cell Tumor of Bone

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Sep 24

PMID 34556636

Citations 9

Authors

Yunfei He

Dongdong Cheng

Cheng Lian

Yingjie Liu

Wenqian Luo

Yuan Wang

Chengxin Ma

Qiuyao Wu

Pu Tian

Dasa He

Zhenchang Jia

Xianzhe Lv

Xue Zhang

Zhen Pan

Jinxi Lu

Yansen Xiao

Peiyuan Zhang

Yajun Liang

QingCheng Yang

Guohong Hu

Affiliations

Soon will be listed here.

Abstract

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

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References

Elliott J, Miller C, Pohajdak B, Talbot D, Helgason C, Bleackley R . Induction of a proteoglycan core protein mRNA in mouse T lymphocytes. Mol Immunol. 1993; 30(8):749-54. DOI: 10.1016/0161-5890(93)90146-3. View

Hinoi E, Ochi H, Takarada T, Nakatani E, Iezaki T, Nakajima H . Positive regulation of osteoclastic differentiation by growth differentiation factor 15 upregulated in osteocytic cells under hypoxia. J Bone Miner Res. 2011; 27(4):938-49. DOI: 10.1002/jbmr.1538. View

Chandran M, Zeng W . Severe Oral Mucosal Ulceration Associated with Oral Bisphosphonate Use: The Importance of Imparting Proper Instructions on Medication Administration and Intake. Case Rep Med. 2021; 2021:6620489. PMC: 7969094. DOI: 10.1155/2021/6620489. View

Zhang Z, Deng Y, Zheng G, Jia X, Xiong Y, Luo K . SRGN-TGFβ2 regulatory loop confers invasion and metastasis in triple-negative breast cancer. Oncogenesis. 2017; 6(7):e360. PMC: 5541705. DOI: 10.1038/oncsis.2017.53. View

Van der Heijden L, Dijkstra P, van de Sande M, Kroep J, Nout R, van Rijswijk C . The clinical approach toward giant cell tumor of bone. Oncologist. 2014; 19(5):550-61. PMC: 4012970. DOI: 10.1634/theoncologist.2013-0432. View

Alberghini M, Kliskey K, Krenacs T, Picci P, Kindblom L, Forsyth R . Morphological and immunophenotypic features of primary and metastatic giant cell tumour of bone. Virchows Arch. 2009; 456(1):97-103. DOI: 10.1007/s00428-009-0863-2. View

Matsumoto Y, Okada Y, Fukushi J, Kamura S, Fujiwara T, Iida K . Role of the VEGF-Flt-1-FAK pathway in the pathogenesis of osteoclastic bone destruction of giant cell tumors of bone. J Orthop Surg Res. 2010; 5:85. PMC: 2993664. DOI: 10.1186/1749-799X-5-85. View

Theocharis A, Seidel C, Borset M, Dobra K, Baykov V, Labropoulou V . Serglycin constitutively secreted by myeloma plasma cells is a potent inhibitor of bone mineralization in vitro. J Biol Chem. 2006; 281(46):35116-28. DOI: 10.1074/jbc.M601061200. View

Kang Y, Siegel P, Shu W, Drobnjak M, Kakonen S, Cordon-Cardo C . A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003; 3(6):537-49. DOI: 10.1016/s1535-6108(03)00132-6. View

10.

Si J, Wang C, Zhang D, Wang B, Zhou Y . Osteopontin in Bone Metabolism and Bone Diseases. Med Sci Monit. 2020; 26:e919159. PMC: 7003659. DOI: 10.12659/MSM.919159. View

11.

Niemann C, Kjeldsen L, Ralfkiaer E, Jensen M, Borregaard N . Serglycin proteoglycan in hematologic malignancies: a marker of acute myeloid leukemia. Leukemia. 2007; 21(12):2406-10. DOI: 10.1038/sj.leu.2404975. View

12.

Hayashida K, Kawabata Y, Kato I, Kamiishi T, Matsuo K, Takeyama M . Clinical and pathological analysis of giant cell tumor of bone with denosumab treatment and local recurrence. J Orthop Sci. 2020; 27(1):215-221. DOI: 10.1016/j.jos.2020.11.005. View

13.

Scotto di Carlo F, Divisato G, Iacoangeli M, Esposito T, Gianfrancesco F . The identification of H3F3A mutation in giant cell tumour of the clivus and the histological diagnostic algorithm of other clival lesions permit the differential diagnosis in this location. BMC Cancer. 2018; 18(1):358. PMC: 5880014. DOI: 10.1186/s12885-018-4291-z. View

14.

Guo J, Chiu C, Wang M, Li F, Chen J . Proteoglycan serglycin promotes non-small cell lung cancer cell migration through the interaction of its glycosaminoglycans with CD44. J Biomed Sci. 2020; 27(1):2. PMC: 6939340. DOI: 10.1186/s12929-019-0600-3. View

15.

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

16.

Goldring S, Roelke M, Petrison K, Bhan A . Human giant cell tumors of bone identification and characterization of cell types. J Clin Invest. 1987; 79(2):483-91. PMC: 424109. DOI: 10.1172/JCI112838. View

17.

Grujic M, Braga T, Lukinius A, Eloranta M, Knight S, Pejler G . Serglycin-deficient cytotoxic T lymphocytes display defective secretory granule maturation and granzyme B storage. J Biol Chem. 2005; 280(39):33411-8. DOI: 10.1074/jbc.M501708200. View

18.

Jin H, Li D, Wang S, Luo S, Li Q, Huang P . miR-125a Promotes the Progression of Giant Cell Tumors of Bone by Stimulating IL-17A and β-Catenin Expression. Mol Ther Nucleic Acids. 2018; 13:493-502. PMC: 6205328. DOI: 10.1016/j.omtn.2018.09.021. View

19.

Zhao C, Wang D, Tang L, Zhang Z, Li S, Qian M . Stromal Cell-Derived CCL20 Promotes Tumor Progression and Osteolysis in Giant Cell Tumor of Bone. Cell Physiol Biochem. 2018; 51(5):2472-2483. DOI: 10.1159/000495903. View

20.

Zhou Z, Li Y, Wang X, Hu J, Kuang M, Wang Z . ALCAM stromal cells: role in giant cell tumor of bone progression. Cell Death Dis. 2018; 9(3):299. PMC: 5833735. DOI: 10.1038/s41419-018-0361-z. View