RANKL/RANK System-Based Mechanism for Breast Cancer Bone Metastasis and Related Therapeutic Strategies

Wu, Xiaoqiu; Li, Fangfei; Dang, Lei; Liang, Chao; Lü, Aiping; Zhang, Ge

doi:10.3389/fcell.2020.00076

Cited by 69 publications

(54 citation statements)

References 107 publications

(117 reference statements)

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“…Breast cancer cells can also produce RANKL and normal cells in metastatic sites, such as osteoblasts in bone [ 30 , 40 , 41 , 42 , 43 ]. RANKL has also been reported to trigger the migration of human epithelial cancer and melanoma cells expressing RANK in a concentration-dependent manner, thus implying a chemotactic mechanism of action in bones [ 30 ].…”

Section: Role Of Rankl In the Survival Resistance Development Andmentioning

confidence: 99%

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The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL

Simatou

Sarantis

Koustas

et al. 2020

IJMS

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The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation and progression. Moreover, several studies supported the synergistic effect of RANK and epidermal growth factor receptor (EGFR) and described RANK’s involvement in epidermal growth factor receptor 2 (ERBB2)-positive carcinogenesis. Consequently, anti-RANKL treatment has been proposed as a new approach to preventing and treating breast cancer and metastases. Recently, RANKL/RANK signaling pathway inhibition has been shown to modulate the immune environment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. Clinical and experimental trials have emerged evaluating RANKL inhibition as an enhancer of the immune response, rendering resistant tumors responsive to immune therapies. Trials evaluating the combinatorial effect of immune checkpoint inhibitors and anti-RANKL treatment in double-positive (RANK+/ERBB2+) patients are encouraging.

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Section: Role Of Rankl In the Survival Resistance Development Andmentioning

confidence: 99%

“…Osteoclastic resorption results in an increased release of transforming growth factor (TGF-β) and other factors of the bone matrix, promoting the increased proliferation of cancer cells. A vicious cycle is thus established promoting bone destruction and metastasis [ 42 , 45 , 48 ].…”

Section: Role Of Rankl In the Survival Resistance Development Andmentioning

confidence: 99%

The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL

Simatou

Sarantis

Koustas

et al. 2020

IJMS

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“…Recently, the RANK/RANKL/OPG system has been observed to play a key role in tumor cell migration and invasion [7][8][9]. Studies have shown that TNFRSF11(RANK) is expressed in a variety of tumor tissues, such as osteosarcoma [10,11], chondrosarcoma [12], breast cancer [13], prostate cancer [14,15], renal cancer [16], oral squamous cell carcinoma [17], lung cancer [18], thyroid cancer [19], and melanoma [20]. However, the expression of TNFRSF11 in gastric cancer cells is rarely reported, and there is no report on the relationship between TNFRSF11 gene polymorphism and gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

Association of Genetic Polymorphisms in TNFRSF11 with the Progression of Genetic Susceptibility to Gastric Cancer

Fan

Pan

et al. 2020

Journal of Oncology

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Objective. To investigate the relationship between polymorphism of TNFRSF11 gene rs9533156 and rs2277438 and susceptibility to gastric cancer. Methods. A case-control study was conducted to select 577 cases of primary gastric cancer and 678 cases of normal control. We extracted whole blood genomic DNA and amplified the target gene fragment by PCR. The genotyping and allele were tested through the snapshot method. Results. In this case-control study, we observed that there was a difference in the genotype distribution of TNFRSF11 gene rs9533156 between the case group and the control group. The frequency distribution of TC heterozygous mutation in the case group was higher than that in the control group. The smoking rate in the case group (34.49%) was higher than that in the control group (27.29%), and the difference in frequency distribution between the two groups was statistically significant (P=0.006). Our findings suggest that TNFRSF11 rs9533156 is associated with susceptibility to GC, which is more evident among elderly patients (>62 years), nonsmokers, and patients who do not consume alcohol. The analysis of the relationship between the TNFSF11 gene rs9533156 site variant and clinical factors of gastric cancer showed that, compared with the tumor size <2 cm group, patients with tumor size ≥2 cm and whom carrying rs9533156 site mutations had a higher frequency distribution, and the difference was statistically significant (P=0.022). Compared with the nonhyperglycemic group, the frequency distribution of patients with rs9533156 site mutations in the diabetes group was higher, and the difference was statistically significant (P<0.001). Conclusion. This study shows that there is a correlation between smoking and the occurrence of gastric cancer. Based on our research, the functional SNP TNFRSF11 TC genotype may be an indicator of individual susceptibility to GC. The mutation at rs9533156 may be related to the size of gastric cancer. The mutation rate of rs9533156 of TNFSF11 gene is higher in diabetic gastric cancer patients.

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“…22,23 There is a significant interplay with the immune system and cytokine release, leading to bone remodeling and metabolism centered around RANK/RANKL, mTOR (mammalian target of rapamycin) and others (IL-33/IL31). 18,[24][25][26][27] Scagliotti et al…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of extended dosing intervals of denosumab in patients with solid cancers and bone metastases: a retrospective study

et al. 2020

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Aim: More than half of patients with breast, lung, or prostate cancer who have bone metastases have evidence of skeletal-related events (SREs). Denosumab is a fully human monoclonal antibody that binds to and neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts and their precursors. The United States Food and Drug Administration (FDA)-approved dose of denosumab is 120 mg every 4 weeks; however, other schedules have been used in practice for patient convenience. Evidence for the safety and efficacy of alternative dosing intervals is lacking. Patient & Methods: Adult patients with solid cancers and bone metastases who received at least two doses of denosumab 120 mg were reviewed. Patients were grouped based on an average denosumab dosing interval of <5 weeks (short-interval) versus 5–11 weeks (medium-interval) versus ⩾12 weeks (long-interval). The primary outcome was the time to first SRE while on denosumab between the short- and medium-interval groups. The secondary outcomes were overall survival (OS), efficacy comparisons between the other groups, and safety events. Results: There was no significant difference in median time to first SRE between the short- and medium-interval denosumab groups [33.2 versus 28.4 months, hazard ratio (HR): 1.13, 95% confidence interval (CI): 0.66–1.92, p = 0.91] or the medium- and long-interval dosing groups (28.4 versus 32.2 months, HR: 1.15, 95% CI: 0.66–2.01, p = 0.62). Median OS was not found to differ significantly between any of the groups. There were significantly more hospitalizations in the short-interval dosing group than the other groups (55.2% versus 33.8% versus 30.4%, p < 0.001). Conclusion: Extending denosumab dosing intervals does not appear to negatively impact time to first SRE and is associated with fewer hospitalizations in real-world patients with solid cancers and bone metastases.

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RANKL/RANK System-Based Mechanism for Breast Cancer Bone Metastasis and Related Therapeutic Strategies

Cited by 69 publications

References 107 publications

The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL

The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL

Association of Genetic Polymorphisms in TNFRSF11 with the Progression of Genetic Susceptibility to Gastric Cancer

Safety and efficacy of extended dosing intervals of denosumab in patients with solid cancers and bone metastases: a retrospective study

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