Upregulation of osteoprotegerin expression correlates with bone invasion and predicts poor clinical outcome in oral cancer

Russmueller, Guenter; Moser, Doris; Würger, Tanja; Wrba, Friedrich; Christopoulos, Panagiotis; Kostakis, George; Seemann, Rudolf; Stadler, V.; Wimmer, Gejza; Kornek, Gabriela; Psyrri, Amanda; Filipits, Martin; Perisanidis, Christos

doi:10.1016/j.oraloncology.2014.11.010

Cited by 18 publications

(13 citation statements)

References 38 publications

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“…Although some studies have shown RANKL expression in tumour cells in close proximity to bone ( Ishikuro et al , 2008 ; Chaung et al , 2009 ; Kayamori et al , 2010 ), reports of OPG expression are variable and the absence of expression has also been reported in one study ( Ishikuro et al , 2008 ). However, a recent study has reported OPG upregulation in bone invasive OSCC ( Russmueller et al , 2015 ) suggesting that enhanced OPG expression depletes TNF-related apoptosis-inducing ligand (TRAIL) -induced cell apoptosis, hence promoting survival of tumour cells, which may explain the readily detectable levels of OPG in the stroma observed here.…”

Section: Discussionmentioning

confidence: 62%

Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

et al. 2017

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Background:The molecular mechanisms involved in the invasion of bone by oral squamous cell carcinomas (OSCC) are poorly understood, and little is known about the role of cancer-associated fibroblasts (CAF), the presence of which confers a poor prognosis.Methods:Clinicopathological data from 277 OSCC cases involving bone resections were reviewed, and 32 cases thoroughly analysed histologically. Immunohistochemistry was used to examine αSMA, RANKL and OPG. Western blotting and qPCR were used to assess myofibroblast (CAF-like) differentiation, RANKL and OPG expression in vitro, and RANKL secretion was analysed by ELISA. Osteoclastogenesis was examined using TRAP staining, multinucleation and pit forming assays.Results:Fibrous stroma intervened between tumour and bone in the majority of cases, with no direct contact between cancer cells and bone. RANKL and OPG, two proteins key to regulating bone resorption, were expressed in tumour cells as well as fibrous stroma adjacent to bone and αSMA-positive myofibroblastic CAF were consistently seen infiltrating into bone ahead of tumour cells. Human primary osteoblasts cultured with conditioned media from human OSCC-derived cells and human primary CAF showed a significant increase in RANKL and a decline in OPG mRNA expression. RANKL secretion was significantly increased in primary oral fibroblasts induced to differentiate into a CAF-like phenotype by transforming growth factor-β1 (TGF-β1) treatment and in primary CAF. Indirect co-culture of murine macrophages with conditioned media from CAF (experimentally derived and isolated from OSCCs) resulted in a marked increase in osteoclastogenesis (in excess of that provoked by cancer cells) determined by tartrate-resistant acid phosphatase activity, multinucleation and resorption pit formation.Conclusions:This study is the first to describe a functional role for CAFs in bone invasion and turnover, identifying a novel potential therapeutic target and diagnostic indicator in this difficult to treat bone invasive malignancy.

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Section: Discussionmentioning

confidence: 62%

Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

et al. 2017

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“…OPG is a secreted member of the tumor necrosis factor (TNF) receptor super-family, prominently known for its role as a decoy receptor in bone resorption in vivo, and for its inhibition of TNF-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in vitro [ 16 , 17 ]. There is increasing evidence for a role of OPG in cancer, as OPG expression has been found elevated in more aggressive solid tumors [ 18 – 21 ]. A number of studies support a tumor-promoting effect of OPG in breast cancer [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells

et al. 2017

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BackgroundIt is widely recognized that inflammation promotes breast cancer invasion and metastasis. Given the complex nature of the breast tumor inflammatory microenvironment, much remains to be understood of the molecular mechanisms that govern these effects. We have previously shown that osteoprotegerin knockdown in breast cancer cells resulted in reduced invasion and metastasis. Here we present novel insight into the role of osteoprotegerin in inflammation-driven tumor progression in breast cancer by investigating the link between osteoprotegerin, macrophages and the potent pro-inflammatory cytokine Interleukin-1beta.MethodsWe used human breast cancer cell lines to investigate the effects of Interleukin-1beta treatment on osteoprotegerin secretion as measured by ELISA. We analyzed public datasets containing human breast cancer genome-wide mRNA expression data to reveal a significant and positive correlation between osteoprotegerin mRNA expression and the mRNA expression of Interleukin-1beta and of monocyte chemoattractant protein CC-chemokine ligand 2. Osteoprotegerin, Interleukin-1beta and CC-chemokine ligand 2 mRNA levels were also examined by qPCR on cDNA from normal and cancerous human breast tissue. We determined the effect of Interleukin-1beta–producing macrophages on osteoprotegerin expression by co-culturing breast cancer cells and differentiated THP-1 macrophages. Immunohistochemistry was performed on human breast tumor tissue microarrays to assess macrophage infiltration and osteoprotegerin expression. To demonstrate that osteoprotegerin mediated functional effects of Interleukin-1beta we performed cell invasion studies with control and OPG siRNA knockdown on Interleukin-1beta-treated breast cancer cells.ResultsWe report that Interleukin-1beta induces osteoprotegerin secretion, independent of breast cancer subtype and basal osteoprotegerin levels. Co-culture of breast cancer cells with Interleukin-1beta-secreting macrophages resulted in a similar increase in osteoprotegerin secretion in breast cancer cells as Interleukin-1beta treatment. Macrophage infiltration correlates with osteoprotegerin secretion in human breast tumor tissue samples. We show that osteoprotegerin secretion is regulated by Interleukin-1beta in a p38- and p42/44-dependent manner. We also demonstrate that osteoprotegerin knockdown represses Interleukin-1beta expression, Interleukin-1beta-mediated breast cancer cell invasion and MMP3 expression.ConclusionsThese data indicate a novel role for osteoprotegerin as a mediator of inflammation- promoted breast cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0606-y) contains supplementary material, which is available to authorized users.

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“…Efficient markers to quickly identify the presence of bone invasion and effective targets to successfully treat patients are required. Russmueller et al ( 21 ) demonstrated that the upregulation of osteoprotegrin expression was associated with bone invasion, poor tumor regression and decreased long-term survival in 93 patients with OSCC. Tada et al ( 22 ) evaluated the effects of an NF-κB inhibitor (IMD-0560) using a mouse model of jaw bone invasion.…”

Section: Discussionmentioning

confidence: 99%

Mutant monocyte chemoattractant protein-1 protein (7ND) inhibits osteoclast differentiation and reduces oral squamous carcinoma cell bone invasion

et al. 2018

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The seven-amino acid truncated (7ND) protein is an N-terminal deletion mutant of monocyte chemoattractant protein-1 (MCP-1) and it functions as a dominant-negative inhibitor. 7ND and wild-type MCP-1 form a heterodimer, which binds to MCP-1 receptors and inhibits monocyte chemotaxis. In the present study, the 7ND protein was cloned, expressed and purified. An MTT assay revealed that the proliferation of oral squamous cell carcinoma (OSCC) SCC25 cells was not affected following 3 days of treatment with synthetic 7ND protein. Serial dilutions of the 7ND protein were tested for monocyte migration and osteoclast differentiation, and tartrate-resistant acid phosphatase staining demonstrated that significantly fewer osteoclasts were differentiated from cluster of differentiation 14+ (CD14+) monocytes using magnetic activated cell sorting. Immunofluorescence confirmed these results and significantly less F-actin staining was observed in 7ND-treated osteoclasts. Furthermore, bone invasion was examined by subcutaneously injecting SCC25 cells into the area overlaying the calvariae of nude mice. The results demonstrated that the average tumor volume of SCC25 cells with 7ND protein was similar to the average volume of tumors formed by untreated SCC25 cells. Flow cytometric analysis suggested that the CD14+ subpopulation in the bone marrow of 7ND-treated mice was reduced compared with that of untreated mice. Micro-computed tomography imaging revealed significantly less bone resorption in the calvariae injected with SCC25 cells plus the 7ND protein. Taken together, the results of the present study demonstrated the potential therapeutic value of the 7ND protein. The 7ND MCP-1 variant not only functions in vitro to inhibit osteoclast differentiation, but also reduces the progression of bone invasion by OSCC cells in vivo.

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Upregulation of osteoprotegerin expression correlates with bone invasion and predicts poor clinical outcome in oral cancer

Cited by 18 publications

References 38 publications

Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells

Mutant monocyte chemoattractant protein-1 protein (7ND) inhibits osteoclast differentiation and reduces oral squamous carcinoma cell bone invasion

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