Cyr61 expression in osteosarcoma indicates poor prognosis and promotes intratibial growth and lung metastasis in mice

Abstract

Osteosarcoma is the most frequent primary malignant bone tumor in children and adolescents with a high propensity for lung metastasis, the major cause of disease-related death. Reliable outcome-predictive markers and targets for osteosarcoma metastasissuppressing drugs are urgently needed for more effective treatment of metastasizing osteosarcoma, which has a current mean 5-year survival rate of approximately 20%. This study investigated the prognostic value and the biological relevance of the extracellular matrixassociated growth factor Cyr61 of the CCN family of secreted proteins in osteosarcoma and metastasis. The prognostic value of Cyr61 was assessed with Kaplan-Meier analyses based on Cyr61 immunostaining of a tissue microarray of osteosarcoma biopsies collected from 60 patients with local or metastatic disease. Effects of Cyr61 overexpression on intratibial tumor growth and lung metastasis of the low metastatic human SaOS-2 osteosarcoma cell line were examined in severe combined immunodeficiency (SCID) mice. Cyr61-provoked signaling was studied in vitro in nonmanipulated SaOS-2 cells. Cyr61 immunostaining of osteosarcoma tissue cores correlated significantly (p ¼ 0.02) with poor patient survival. Mice intratibially injected with Cyr61-overexpressing SaOS-2 cells showed faster tumor growth and an increase in number and outgrowth of lung metastases and consequently significantly (p ¼ 0.0018) shorter survival than mice injected with control SaOS-2 cells. Cyr61-evoked PI-3K/Akt/GSK3b signaling in SaOS-2 cells resulted in a subcellular redistribution of the cell cycle inhibitor p21 Cip1/WAF1 . Cyr61 has considerable potential as a novel marker for poor prognosis in osteosarcoma and is an attractive target for primary tumor-and metastases-suppressing drugs. ß

E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα

“…Osteosarcoma is the most frequent primary bone sarcoma, [1][2][3][4] which is generally regarded as a differentiation disease that is caused by genetic and epigenetic disruptions of terminal differentiation of osteoblasts. [5][6][7] Despite modern treatment protocols that combine chemotherapy, surgery, and sometimes radiotherapy, the 5-year survival rate for patients diagnosed with osteosarcoma remains at 60%~70% since the 1970s.…”

CYR61 (cysteine-rich, angiogenic inducer, 61)

“…Over-expressing CYR61 in osteosarcoma cell lines enhanced tumorigenecity and lung metastasis in nude mice (Sabile et al, 2012), while silencing CYR61 abrogated cell Matrigel invasion in vitro, and lung metastasis in vivo (Fromigue et al, 2011). These results suggest that CYR61 may promote osteosarcoma tumorigenesis and metastasis.…”

“…Note Immunohistochemical analysis of osteosarcoma tissue microarrays using anti-CYR61 antibodies shows that higher CYR61 levels are associated with higher tumor grades and shorter patient survival (Sabile et al, 2012;Fromigue et al, 2011). Over-expressing CYR61 in osteosarcoma cell lines enhanced tumorigenecity and lung metastasis in nude mice (Sabile et al, 2012), while silencing CYR61 abrogated cell Matrigel invasion in vitro, and lung metastasis in vivo (Fromigue et al, 2011).…”

Overexpression of NDRG2 Can Inhibit Neuroblastoma Cell Proliferation through Negative Regulation by CYR61

“…CYR61, a member of the CCN family of tissue growth factors (CYR61/CTGF/NOV), is highly expressed in various cancer tissues (Li et al, 2012;Sabile et al, 2012). CYR61 regulates multiple cellular activities such as cell proliferation, adhesion, migration, survival and apoptosis (Chien et al, 2004;Yu et al, 2008;Jandova et al, 2012;Lee et al, 2012).…”