Cyr61 Silencing Reduces Vascularization and Dissemination of Osteosarcoma Tumors

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2014 Jul 29

PMID 25065593

Citations 13

Authors

N Habel

M Vilalta

O Bawa

P Opolon

J Blanco

O Fromigue

Affiliations

Soon will be listed here.

Abstract

Osteosarcoma is the most prevalent primary pediatric cancer-related bone disease. These tumors frequently develop resistance to chemotherapy and are highly metastatic, leading to poor outcome. Thus, there is a need for new therapeutic strategies that can prevent cell dissemination. We previously showed that CYR61/CCN1 expression in osteosarcoma cells is correlated to aggressiveness both in vitro and in vivo in mouse models, as well as in patients. In this study, we found that CYR61 is a critical contributor to the vascularization of primary tumor. We demonstrate that silencing CYR61, using lentiviral transduction, leads to a significant reduction in expression level of pro-angiogenic markers such as VEGF, FGF2, PECAM and angiopoietins concomitantly to an increased expression of major anti-angiogenic markers such as thrombospondin-1 and SPARC. Matrix metalloproteinase-2 family member expression, a key pathway in osteosarcoma metastatic capacity was also downregulated when CYR61 was downregulated in osteosarcoma cells. Using a metastatic murine model, we show that CYR61 silencing in osteosarcoma cells results in reduced tumor vasculature and slows tumor growth compared with control. We also find that microvessel density correlates with lung metastasis occurrence and that CYR61 silencing in osteosarcoma cells limits the number of metastases. Taken together, our data indicate that CYR61 silencing can blunt the malignant behavior of osteosarcoma tumor cells by limiting primary tumor growth and dissemination process.

Citing Articles

C-terminal binding protein-2 triggers CYR61-induced metastatic dissemination of osteosarcoma in a non-hypoxic microenvironment.

Di Patria L, Habel N, Olaso R, Fernandes R, Brenner C, Stefanovska B J Exp Clin Cancer Res. 2025; 44(1):83.

PMID: 40038783 PMC: 11881356. DOI: 10.1186/s13046-025-03350-6.

Drug Resistance in Glioma Cells Induced by a Mesenchymal-Amoeboid Migratory Switch.

Ketchen S, Gamboa-Esteves F, Lawler S, Nowicki M, Rohwedder A, Knipp S Biomedicines. 2022; 10(1).

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Osteosarcoma and Metastasis.

Sheng G, Gao Y, Yang Y, Wu H Front Oncol. 2021; 11:780264.

PMID: 34956899 PMC: 8702962. DOI: 10.3389/fonc.2021.780264.

CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology.

Giusti V, Scotlandi K J Cell Commun Signal. 2021; 15(4):545-566.

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Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases.

Stucker S, Chen J, Watt F, Kusumbe A Front Cell Dev Biol. 2020; 8:602269.

PMID: 33324652 PMC: 7726257. DOI: 10.3389/fcell.2020.602269.

References

Grignani G, Palmerini E, Dileo P, Asaftei S, DAmbrosio L, Pignochino Y . A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2011; 23(2):508-16. DOI: 10.1093/annonc/mdr151. View

Chen D, Zhang Y, Zhu K, Wang W . A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma. Tumour Biol. 2013; 34(3):1895-9. DOI: 10.1007/s13277-013-0733-z. View

Yang J, Yang D, Sun Y, Sun B, Wang G, Trent J . Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma. Cancer. 2011; 117(21):4925-38. PMC: 3465081. DOI: 10.1002/cncr.26116. View

Pignochino Y, Grignani G, Cavalloni G, Motta M, Tapparo M, Bruno S . Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer. 2009; 8:118. PMC: 2804605. DOI: 10.1186/1476-4598-8-118. View

Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M . Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res. 2000; 6(2):572-7. View

Kreuter M, Bieker R, Bielack S, Auras T, Buerger H, Gosheger G . Prognostic relevance of increased angiogenesis in osteosarcoma. Clin Cancer Res. 2004; 10(24):8531-7. DOI: 10.1158/1078-0432.CCR-04-0969. View

Kireeva M, Lam S, Lau L . Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through integrin alphavbeta3. J Biol Chem. 1998; 273(5):3090-6. DOI: 10.1074/jbc.273.5.3090. View

Sabile A, Arlt M, Muff R, Bode B, Langsam B, Bertz J . Cyr61 expression in osteosarcoma indicates poor prognosis and promotes intratibial growth and lung metastasis in mice. J Bone Miner Res. 2011; 27(1):58-67. DOI: 10.1002/jbmr.535. View

Oda Y, Yamamoto H, Tamiya S, Matsuda S, Tanaka K, Yokoyama R . CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: analysis within a group of patients, all of whom developed lung metastasis. Mod Pathol. 2006; 19(5):738-45. DOI: 10.1038/modpathol.3800587. View

10.

Rastogi S, Kumar R, Sankineani S, Marimuthu K, Rijal L, Prakash S . Role of vascular endothelial growth factor as a tumour marker in osteosarcoma: a prospective study. Int Orthop. 2012; 36(11):2315-21. PMC: 3479274. DOI: 10.1007/s00264-012-1663-x. View

11.

Wang L, Zhang Q, Chen W, Shan B, Ding Y, Zhang G . B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One. 2013; 8(8):e70689. PMC: 3734259. DOI: 10.1371/journal.pone.0070689. View

12.

Wen X, Liu H, Yu K, Liu Y . Matrix metalloproteinase 2 expression and survival of patients with osteosarcoma: a meta-analysis. Tumour Biol. 2013; 35(1):845-8. DOI: 10.1007/s13277-013-1116-1. View

13.

Estrada R, Li N, Sarojini H, An J, Lee M, Wang E . Secretome from mesenchymal stem cells induces angiogenesis via Cyr61. J Cell Physiol. 2009; 219(3):563-71. PMC: 2860629. DOI: 10.1002/jcp.21701. View

14.

Zhou Q, Zhu Y, Deng Z, Long H, Zhang S, Chen X . VEGF and EMMPRIN expression correlates with survival of patients with osteosarcoma. Surg Oncol. 2009; 20(1):13-9. DOI: 10.1016/j.suronc.2009.09.002. View

15.

Babic A, Kireeva M, Kolesnikova T, Lau L . CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1998; 95(11):6355-60. PMC: 27701. DOI: 10.1073/pnas.95.11.6355. View

16.

Fromigue O, Hamidouche Z, Marie P . Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. J Biol Chem. 2008; 283(45):30549-56. PMC: 2662148. DOI: 10.1074/jbc.M801436200. View

17.

Maris J, Courtright J, Houghton P, Morton C, Gorlick R, Kolb E . Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2007; 50(3):581-7. DOI: 10.1002/pbc.21232. View

18.

Odagiri H, Kadomatsu T, Endo M, Masuda T, Morioka M, Fukuhara S . The secreted protein ANGPTL2 promotes metastasis of osteosarcoma cells through integrin α5β1, p38 MAPK, and matrix metalloproteinases. Sci Signal. 2014; 7(309):ra7. DOI: 10.1126/scisignal.2004612. View

19.

Mintz M, Sowers R, Brown K, Hilmer S, Mazza B, Huvos A . An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Res. 2005; 65(5):1748-54. DOI: 10.1158/0008-5472.CAN-04-2463. View

20.

Chen N, Leu S, Todorovic V, Lam S, Lau L . Identification of a novel integrin alphavbeta3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells. J Biol Chem. 2004; 279(42):44166-76. DOI: 10.1074/jbc.M406813200. View