5-Fluoruracil blocked giant cell tumor progression by suppressing osteoclastogenesis through NF-kappaB signals and blocking angiogenesis

Song, Dianwen; Meng, Tong; Xu, Wei; Hou, Tianhui; Zx, Lin; Yin, Huabin; Li, Bo; Zhou, Lei; Wang, Ting; Han, Shuai; Fan, Tianqi; Miao, Wujun; Liu, Mingyao; Luo, Jian; Wang, Zhou; Li, Zhenxi

doi:10.1016/j.bone.2015.04.047

Cited by 9 publications

(14 citation statements)

References 38 publications

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“…Chicken embryo chorioallantoic membrane assay is a well-established in vivo model to examine the angiogenesis along with tumor progression. The reliability of the chicken chorioallantoic membrane model has been validated for investigation of the progression and invasiveness of human GCT [32]. It also has been affirmed that rapid self-renewing human multipotent mesenchymal bone marrow stromal cells actively adhere to arterial endothelium in a chicken chorioallantoic membrane model [3,21].…”

Section: Methodsmentioning

confidence: 91%

“…It also has been affirmed that rapid self-renewing human multipotent mesenchymal bone marrow stromal cells actively adhere to arterial endothelium in a chicken chorioallantoic membrane model [3,21]. In particular, the chicken chorioallantoic membrane model has been used for evaluating the efficacy of pharmacologic treatment on GCTs by determining the level of angiogenesis [32]. In the current study, we used a previously published method [3,16,32] to develop tumor nodules in the chicken chorioallantoic membrane, and then treated them with liquid nitrogen or freezing nitrogen ethanol composite.…”

Section: Methodsmentioning

confidence: 99%

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Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone

Chen

Wang

et al. 2017

Clinical Orthopaedics &Amp; Related Research

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Section: Methodsmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone

Chen

Wang

et al. 2017

Clinical Orthopaedics &Amp; Related Research

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“…GCTSCs are currently accepted as the tumor component of GCTB and can recruit mononuclear cells to form giant cells. These giant cells can further absorb bone matrix and lead to bone breakdown [3,6,7]. RANKL/RANK are widely accepted to be key regulators of bone physiology that control osteoclast development.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

“…GCTSCs and BMSCs were isolated from GCTB samples and bone marrow from normal donors as previously described [3,6]. RAW 264.7 cells were obtained from the Type Culture Collection of the Chinese Academy of Sciences.…”

Section: Cell Culturementioning

confidence: 99%

“…GCTB predominantly occurs in the metaphysis, thoracic vertebra, and sacrum of individuals in their third and fourth decades of life and shows a female predilection [1,[3][4][5]. This kind of tumor is osteolytic and comprises three major cell populations: osteoclast-like multinuclear giant cells, mononuclear precursors of osteoclasts, and spindle-shaped stromal cells (GCTSCs) [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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Stromal Cell-Derived CCL20 Promotes Tumor Progression and Osteolysis in Giant Cell Tumor of Bone

Zhao

Wang

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Giant cell tumor of bone (GCTB), one of the most common primary bone tumors, leads to extensive bone destruction. However, the mechanisms underlying GCTB progression remain elusive and prognostic factors and treatment targets are required. In the current study, we explored the function of the chemokine family member CCL20 in GCTB progression. Methods: We explored the expression of CCL20 in stromal cells (GCTSCs) using microarray. Clinical analyses of the role of CCL20 in tumor progression were performed based on the patient cohort of our institution. The role of CCL20 in tumor proliferation was evaluated by MTS assay, migration ability was measured by a Transwell assay, and osteoclastogenesis was induced by CCL20 or GCTSC-conditioned medium. Quantitative PCR and western blot were used to measure the expression levels of mRNAs and proteins related to tumor progression. Results: CCL20 was upregulated in GCTSCs and correlated with tumor progression and prognosis. CCL20 induced GCTSC proliferation and migration in an autocrine manner. In addition, CCL20 recruited mononuclear cells and induced osteoclastogenesis by overactivating the AKT and NF-κB signaling pathways. Antibody blockade of CCL20 abolished the exacerbated osteoclastogenesis. Conclusion: Taken together, our data indicate that GCTSC secretion of CCL20 acts as a key modulator in the pathological progression of GCTB. It can promote GCTSC proliferation and migration in an autocrine manner and can recruit bone marrow monocytes to the tumor microenvironment and enhance osteoclastogenesis in a paracrine manner. These findings strongly indicate the potential prognostic and therapeutic value of CCL20 in GCTB.

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Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases

Schem

Tower

Kneissl

et al. 2016

Journal of Bone and Mineral Research

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Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolitebisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro-computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases.

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5-Fluoruracil blocked giant cell tumor progression by suppressing osteoclastogenesis through NF-kappaB signals and blocking angiogenesis

Cited by 9 publications

References 38 publications

Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone

Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone

Stromal Cell-Derived CCL20 Promotes Tumor Progression and Osteolysis in Giant Cell Tumor of Bone

Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases

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