RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs

Beuselinck, Benoît; Jean-Baptiste, J.; Couchy, Gabrielle; Job, Sylvie; Reyniès, Aurélien de; Wolter, Pascal; Théodore, Christine; Gravis, Gwénaëlle; Rousseau, Benoı̂t; Albigès, Laurence; Joniau, Steven; Verkarre, Virginie; Lerut, Evelyne; Patard, Jean‐Jacques; Schöffski, Patrick; Méjean, Arnaud; Elaidi, R.T.; Oudard, Stéphane; Zucman‐Rossi, Jessica

doi:10.1038/bjc.2015.352

Cited by 20 publications

(14 citation statements)

References 31 publications

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“…These factors are the receptor activator of NF-kappa B (RANK), its ligand RANKL and the decoy receptor for RANKL, osteoprotegerin (OPG) [ 40 ]. Binding of RANKL to RANK triggers intricate and distinct signaling cascades to induce osteoclast development from haematopoietic progenitor cells as well as to activate mature osteoclasts [ 41 ]. Meanwhile, OPG negatively regulates RANKL binding to RANK and therefore inhibits bone turnover by osteoclasts [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, OPG negatively regulates RANKL binding to RANK and therefore inhibits bone turnover by osteoclasts [ 42 ]. Several researches demonstrated that stimulation of RANK results in strong NF-kappa B activation and the NF-kappa B signaling pathway is relevant for RANKL-RANK-regulated osteoclast development and function [ 41 , 42 ]. These results indicate that ANGPLT4 might promote GCT progression by activating GCTSC proliferation and angiogenesis through the regulation of a series of downstream cytokines.…”

Section: Discussionmentioning

confidence: 99%

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TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

Qian

Cao

et al. 2017

Oncotarget

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Although emerging studies have implicated that Aiopoietin-like 4 Protein (ANGPTL4) is related to the aggressiveness and metastasis of many tumors, the role of ANGPLT4 in giant cell tumor (GCT) of bone was rarely investigated. The mechanism of ANGPLT4 in tumor-induced osteoclastogenesis still remains unclear. In this study, we first demonstrated that ANGPTL4 was highly expressed in GCT compared to normal tissues, while we showed that TGF-β2 released by osteoclasts induced bone resorption could increase the expression of ANGPTL4 in GCTSCs. By using the luciferase reporter assay, we found that two downstreams of TGF-β2, Smad3 and Smad4, could directly activate the promoter of ANGPTL4, which might explain the mechanism of TGF-β2-induced ANGPLT4 expression. Moreover, knockout of ANGPTL4 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. By using the chick chorio-allantoic membrane (CAM) models, we further showed that inhibition of ANGPTL4 suppressed tumor growth and giant cell formation in vivo. In addition, some new pathways involved in ANGPTL4 application were identified through microarray assay, which may partly explain the mechanism of ANGPTL4 in GCT. Taken together, our study for the first time identified the role of ANGPLT4 in GCT of bone, which may provide a new target for the diagnosis and treatment of GCT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

Qian

Cao

et al. 2017

Oncotarget

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“…The relative levels of RANK/RANKL/OPG expression may influence prognosis in numerous cancer types including breast, lung, endometrial, renal cell and gastric cancers, osteosarcoma and multiple myeloma (Fig. 4a, b) [34][35][36][37][38][39][40][41]. In breast cancer, microarray analysis demonstrated that low RANK and high OPG expression were associated with longer OS (p = 0.0078 and p = 0.034, respectively) and disease-free survival (p = 0.059 and p = 0.040, respectively) [34].…”

Section: The Rank-rankl Axis In Cancer Biologymentioning

confidence: 99%

“…In another study, low RANKL expression has been associated with increased risk for bone metastases (p = 0.018) and shorter disease-free survival (p = 0.018) in breast cancer [40]. In metastatic clear cell renal cell carcinoma, an elevated RANK/OPG ratio has been associated with a shorter median time to metastasis (p = 0.014), progression-free survival (PFS) (p = 0.001) and OS (p = 0.0001) [35]. Moreover, RANK expression in clear cell renal cell carcinoma has been identified as an independent negative prognostic factor for both cancer-specific survival and recurrence-free survival (p < 0.001) [42].…”

Section: The Rank-rankl Axis In Cancer Biologymentioning

confidence: 99%

The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

et al. 2019

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Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

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“…A study by Beuselinck [ 25 ] involving 129 RCC patients treated with anti-VEGFR-TKIs revealed that an elevated RANK/OPG ratio was associated with shorter time to bone metastasis, shorter median overall survival from initial diagnosis and shorter median progression-free survival. The results suggested that the RANK/OPG ratio in RCC might be associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs [ 25 ]. Nonetheless, further validation is warranted.…”

Section: Interactions Among the Immune System Bone And Tumormentioning

confidence: 99%

Bone Metastasis from Renal Cell Carcinoma

Chen

Kuo

2016

IJMS

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About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The “vicious cycle” hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden.

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RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs

Cited by 20 publications

References 31 publications

TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

Bone Metastasis from Renal Cell Carcinoma

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