Loss of Osteoclasts Contributes to Development of Osteosarcoma Pulmonary Metastases

Endo‐Munoz, Liliana; Cumming, A.; Rickwood, Danny; Wilson, Danielle; Cueva, Claudia; Ng, Charlotte K.Y.; Strutton, Geoffrey; Cassady, A. I.; Evdokiou, Andreas; Sommerville, Scott; Dickinson, Ian C.; Guminski, Alexander; Saunders, Nicholas A.

doi:10.1158/0008-5472.can-09-4291

Cited by 76 publications

(78 citation statements)

References 56 publications

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“…For microarray analysis, complementary RNA was generated with the Illumina TotalPrep RNA Amplification Kit and hybridized with Illumina HumanHT-12 v4 Expression BeadChips (Illumina) as per the manufacturer's protocol. Expression data from the microarrays were analyzed as previously described (25). The microarray data reported in this article have been deposited in the NCBI's Gene Expression Omnibus (GEO) database under the accession number GSE58074.…”

Section: Gene-expression Studiesmentioning

confidence: 99%

A Novel E2F/Sphingosine Kinase 1 Axis Regulates Anthracycline Response in Squamous Cell Carcinoma

Hazar-Rethinam

Long

Gannon

et al. 2015

Clinical Cancer Research

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Purpose: Head and neck squamous cell carcinomas (HNSCC) are frequently drug resistant and have a mortality rate of 45%. We have previously shown that E2F7 may contribute to drug resistance in SCC cells. However, the mechanism and pathways involved remain unknown.Experimental Design: We used transcriptomic profiling to identify candidate pathways that may contribute to E2F7-dependent resistance to anthracyclines. We then manipulated the activity/expression of the candidate pathway using overexpression, knockdown, and pharmacological inhibitors in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and a downstream effector in a tissue microarray (TMA) generated from HNSCC patient samples.Results: E2F7-deficient keratinocytes were selectively sensitive to doxorubicin and this was reversed by overexpressing E2F7.Transcriptomic profiling identified Sphingosine kinase 1 (Sphk1) as a potential mediator of E2F7-dependent drug resistance. Knockdown and overexpression studies revealed that Sphk1 was a downstream target of E2F7. TMA studies showed that E2F7 overexpression correlated with Sphk1 overexpression in human HNSCC. Moreover, inhibition of Sphk1 by shRNA or the Sphk1-specific inhibitor, SK1-I (BML-EI411), enhanced the sensitivity of SCC cells to doxorubicin in vitro and in vivo. Furthermore, E2F7-induced doxorubicin resistance was mediated via Sphk1-dependent activation of AKT in vitro and in vivo.Conclusion: We identify a novel drugable pathway in which E2F7 directly increases the transcription and activity of the Sphk1/ S1P axis resulting in activation of AKT and subsequent drug resistance. Collectively, this novel combinatorial therapy can potentially be trialed in humans using existing agents. Clin Cancer Res; 21(2); 417-27. Ó2014 AACR.

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Section: Gene-expression Studiesmentioning

confidence: 99%

A Novel E2F/Sphingosine Kinase 1 Axis Regulates Anthracycline Response in Squamous Cell Carcinoma

Hazar-Rethinam

Long

Gannon

et al. 2015

Clinical Cancer Research

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“…OPG is a potent apoptosis inhibitor of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on tumor cells. The loss of osteoclasts in the primary tumors enhances the OS metastases (Endo-Munoz et al, 2010a). The decrease of osteoclasts is consistent with a decreased antigen-presenting activity, an enhanced chemoresistance and an impaired osteoclastogenesis (Endo-Munoz et al, 2010b).…”

Section: Deregulation Of Bone Destruction Mechanisms and Cells (Osteomentioning

confidence: 59%

Bone Formation Deregulations Are the Oncogenesis Keys in Osteosarcomas

Entz‐Werlé¹

2012

Osteosarcoma

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“…Metastatic potential of a tumor is primarily dependent on the migratory ability of the cells (25,26).…”

Section: Discussionmentioning

confidence: 99%

Vasodilator-stimulated phosphoprotein regulates osteosarcoma cell migration

Wei

et al. 2011

Oncol Rep

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Abstract. Vasodilator-stimulated phosphoprotein (VASP) has been reported to play an important role in the process of cell migration and tumor metastasis. However, to date, no study has examined VASP expression and its function in osteocarcoma cells. In this study, we analyzed the effect of VASP on osteosarcoma cell migration and the signal transduction pathways involved. We used two osteosarcoma cell strains (Mg-63 and Saos-2 cells) with different metastatic potential. Silencing of VASP gene expression was carried out using RNA interference in these cells. Knockdown of expression at the transcriptional or translational level was determined by RT-PCR or Western blot analysis, respectively. The metastatic potential of the tumor cells was determined by a wound healing migration assay. VASP mRNA expression was also determined in 30 human osteosarcoma samples. Furthermore, Rac1 was determined as a regulator of VASP function. RT-PCR and Western blotting showed that Mg-63 cells had a significantly higher VASP expression at both the transcriptional and translational levels compared to Saos-2 cells. The wound healing assay revealed that Mg-63 cells had more migratory potential compared to Saos-2 cells. The effect was found to be reversible when VASP was knocked down by siRNA in Mg-63 cells. Specimens from human patients with metastases had higher VASP expression compared to specimens of patients without metastases. Knockdown of Rac1 resulted in inhibition of VASP expression in sarcoma cells. These results suggest that VASP protein regulates osteosarcoma cell migration and metastasis. Rac1 and VASP interaction may be a potential target for osteosarcoma treatment. IntroductionOsteosarcoma is the most prevalent primary malignant bone tumor in children and young adults. Although the life expectancy of osteosarcoma patients has been prolonged due to improvement of neoadjuvant chemotherapy and surgical resection during the past three decades, the long-term survival and quality of life is still unsatisfactory. Poor outcome of osteosarcoma is mainly caused by metastatic disease, and previous studies have demonstrated that more than 30% of patients already display distant metastasis without clinical detectable signs at the time of diagnosis (1,2).Vasodilator-stimulated phosphoprotein (VASP), a member of the Ena/VASP family, has been implicated in regulating key cellular functions, such as shape change, adhesion and migration, which is mainly due to its ability to modify dynamic action cytoskeleton (3). In addition to its role in normal cell growth (4,5), embryonic development (6) and homeostasis (7), VASP plays an essential role in many diseases, such as cancer metastasis (8,9), thrombosis (10), arteriosclerosis (11) and nephritis (12).Expression of VASP has been reported to be dysregulated in several types of malignancies and is relevant to tumor metastasis. For example, its level was found to be significantly increased in lung adenocarcinomas and gastric carcinomas compared to normal tissue, and this increase was correlated wit...

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Loss of Osteoclasts Contributes to Development of Osteosarcoma Pulmonary Metastases

Cited by 76 publications

References 56 publications

A Novel E2F/Sphingosine Kinase 1 Axis Regulates Anthracycline Response in Squamous Cell Carcinoma

A Novel E2F/Sphingosine Kinase 1 Axis Regulates Anthracycline Response in Squamous Cell Carcinoma

Bone Formation Deregulations Are the Oncogenesis Keys in Osteosarcomas

Vasodilator-stimulated phosphoprotein regulates osteosarcoma cell migration

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