Receptor activator of nuclear factor-κB ligand (RANKL) directly modulates the gene expression profile of RANK-positive Saos-2 human osteosarcoma cells

Mori, Kanji; Berreur, Martine; Blanchard, Frédéric; Chevalier, Catherine; Guisle-Marsollier, Isabelle; Masson, Martial; Rédini, Françoise; Heymann, Dominique

doi:10.3892/or.18.6.1365

Cited by 44 publications

(51 citation statements)

References 27 publications

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“…Dysregulation of this system has been observed in multiple tumours of various origins, including malignant bone tumours, multiple myeloma, breast cancer and prostate cancer. The RANK/RANKL system induces osteolytic bone lesions, and blocking of this system prevents bone destruction (4)(5)(6)(7)(8)(9)(10). The results of the present study confirm previous data indicating that the chemotherapy responsiveness of patients with tumours that are RANK positive is equal to that of patients with RANK-negative tumours, whereas RANK-positive tumours are associated with a significantly higher mortality rate (11).…”

Section: Discussionsupporting

confidence: 82%

Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Trieb

Windhager

2015

Oncology Letters

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Abstract. Receptor activator of nuclear factor κB (RANK), a member of the tumour necrosis factor family, is activated by its ligand and regulates the differentiation of osteoclasts and dendritic cells. Local growth of osteosarcoma involves destruction of the host bone by osteoclasts and proteolytic mechanisms. Although the prognosis of patients with osteosarcoma has been improved by advances in chemotherapy over the last four decades, the issues of non-responders, and the lack of effective prognostic markers have remained. The present study aimed to investigate the prognostic and predictive value of RANK expression in human osteosarcoma. The expression of RANK was immunohistochemically evaluated in biopsies of 43 patients (mean age 25.4 years) with high-grade osteosarcoma, and was found to be correlated with histological response to chemotherapy, disease-free status and overall survival. RANK expression was detected in eight of the 43 osteosarcoma specimens (18%), whereas the remaining specimens were negative for RANK. A statistically significant correlation was detected between RANK expression and the overall survival of patients. A total of 7/8 patients with RANK-expressing tumours succumbed to the disease (88% mortality rate amongst patients with RANK-positive tumours vs. 37% with RANK-negative tumours; P<0.05). No significant difference was found when comparing RANK expression status with response to chemotherapy; 50% of RANK-positive patients exhibited a poor response to chemotherapy, compared with 66% in the RANK negative group. In addition, the appearance of metastases was not correlated with RANK expression status (38% metastases in RANK-positive tumours vs. 34% in RANK-negative tumours). In conclusion, the results of the present study suggested that RANK expression is likely to be of prognostic, but not of predictive, value.

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Section: Discussionsupporting

confidence: 82%

Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Trieb

Windhager

2015

Oncology Letters

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“…Given that RANKL expression has been shown previously in the POS-1 tumor by immunohistochemical analyses (9), the present data suggest that inhibition of RANKL activity diminishes the osteosarcoma progression. Moreover, other experiments done in our laboratory have shown that osteosarcoma cells express RANK and that RANKL is able to induce modulation of gene expression in these cells (24,38,39). Targeting RANKL is therefore a promising approach in bone tumor therapy.…”

Section: Discussionmentioning

confidence: 89%

Therapeutic efficacy of soluble receptor activator of nuclear factor-κB-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma

Lamoureux

Picarda

Rousseau

et al. 2008

Molecular Cancer Therapeutics

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Osteosarcoma is the most frequent primary bone tumor that develops mainly during youth, the median age of diagnosis being 18 years. Despite improvement in osteosarcoma treatment, survival rate is only 30% after 5 years for patients with pulmonary metastases at diagnosis. This warrants exploration of new therapeutic options. The anti-bone resorption molecule receptor activator of NF-KB (RANK) is very promising, as it may block the vicious cycle between bone resorption and tumor proliferation that takes place during tumor development in bone site. The cDNA encoding murine RANK-Fc (mRANK-Fc) was administered by gene transfer using an amphiphilic polymer in a mouse model of osteolytic osteosarcoma. Clinical and bone microarchitecture variables were assessed by radiography and micro-CT analyses. In vitro experiments were designed to determine the mechanism of action of RANK-Fc on tumor cell proliferation (XTT assays), apoptosis (caspase activation), cell cycle distribution (fluorescence-activated cell sorting analysis), or gene expression (reverse transcription-PCR). RANK-Fc was effective in preventing the formation of osteolytic lesions associated with osteosarcoma development and in reducing the tumor incidence, the local tumor growth, and the lung metastases dissemination leading to a 3.9-fold augmentation of mice survival 28 days after implantation. On the contrary, mRANK-Fc did not prevent the development of nonosseous tumor nodules, suggesting that bone environment is necessary for mRANK-Fc therapeutic efficacy. Furthermore, mRANK-Fc has no direct activity on osteosarcoma cells in vitro. mRANK-Fc exerts an indirect inhibitory effect on osteosarcoma progression through inhibition of bone resorption. [Mol Cancer Ther 2008;7(10):3389 -98]

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“…Interestingly, recent studies found that functional RANK was expressed in some primary and some secondary bone tumors, including osteosarcoma (5,6), chondrosarcoma (7), breast cancer (8), prostate cancer (9,10), renal cell cancer (11) and malignant melanoma (8). RANKL can promote cancer cell migration and invasion in in vitro experiments, and induce osteoclast chemotaxis (7,10,12).…”

Section: Introductionmentioning

confidence: 99%

RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation

Tang

Zhang²,

Tang³

et al. 2011

Oncol Rep

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Abstract. Accumulating studies have shown that the receptor activator of nuclear factor-κB ligand (RANKL)/RANK pathway plays an important role in tumor metastasis. However, the involvement of the RANKL/RANK signal transduction pathway in breast cancer metastasis remains unclear. The present study, therefore, investigated the role of downstream molecules of RANKL/RANK signaling in breast cancer cells using Transwell chemotaxis assays. RANKL was shown to direct the migration of MDA-MB-231 breast cancer cells. Osteoprotegerin (OPG; soluble decoy receptor of RANKL) inhibited RANKL-induced migration. RANKL activated Src kinase in MDA-MB-231 cells, as shown by Western blotting, and pretreatment with a Src inhibitor abrogated RANKL-induced cell migration, in a similar manner to OPG. Short-hairpin RNA against RANK, delivered via a lentiviral vector, significantly abolished the expression of phosphorylated Src. Stimulation by RANKL induced the phosphorylation of mitogen-activated protein kinases (MAPKs) (ERK, p38, JNK), and specific inhibitors of MAPKs blocked RANKL-induced cell migration. Furthermore, the expression of phosphorylated MAPKs could be blocked by a Src inhibitor and by small interfering RNA against Src. These findings suggest that Src and MAPK pathways may be involved in RANKL-induced MDA-MB-231 breast cancer cell migration.

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Receptor activator of nuclear factor-κB ligand (RANKL) directly modulates the gene expression profile of RANK-positive Saos-2 human osteosarcoma cells

Cited by 44 publications

References 27 publications

Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Therapeutic efficacy of soluble receptor activator of nuclear factor-κB-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma

RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation

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