RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro

Casimiro, Sandra; Mohammad, Khalid S.; Pires, Ricardo A.; Tato-Costa, Joana; Alho, Irina; Teixeira, Rui; Carvalho, António; Ribeiro, Sofia; Lipton, Allan; Guise, Theresa A.; Costa, Luís

doi:10.1371/journal.pone.0063153

Cited by 65 publications

(64 citation statements)

References 40 publications

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“…RANK-RANKL pathway is a key regulator of bone physiology [1, 2], but also a central player in the onset of BM, as RANKL acts as a chemoattractant for RANK-positive tumor cells [20, 21]. Other studies also revealed its role in tumor cell tropism for sites outside bone, such as lung [22].…”

Section: Discussionmentioning

confidence: 99%

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases

et al. 2016

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Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group (P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04–5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55–12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78–3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42–3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17–1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.

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Section: Discussionmentioning

confidence: 99%

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases

et al. 2016

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“…Multiple recent studies have demonstrated functional RANK protein expression on the surface of various cancer cell lines, and in vitro experiments suggest that RANKL stimulation will directly induce molecular pathways associated with tumor cell metastasis. Exposure of RANK-expressing human breast, lung, melanoma and prostate cancer cell lines to RANKL in vitro resulted in increased migration and invasion through collagen or fibronectin matrices 41444647484950. The RANKL-dependent effect is correlated with upregulation of several factors involved in migration, angiogenesis and invasion.…”

Section: Direct (Osteoclast-independent) Pro-metastatic Effects Of Ranklmentioning

confidence: 99%

Targeting RANKL in metastasis

Dougall¹,

Holen²,

Gonzalez-Suarez³

2014

BoneKEy Reports

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Acting through its cognate receptor, receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival. Preclinical data have now firmly established that blockade of tumor-induced osteoclastogenesis by RANKL inhibition will not only protect against bone destruction but will also inhibit the progression of established bone metastases and delay the formation of de novo bone metastases in cancer models. In patients with bone metastases, skeletal complications are driven by increased osteoclastic activity and may result in pathological fractures, spinal cord compression and the need for radiotherapy to the bone or orthopedic surgery (collectively known as skeletal-related events (SREs)). Denosumab, a fully human monoclonal antibody against RANKL, has been demonstrated to prevent or delay SREs in patients with solid tumors that have metastasized to bone. In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts. For example, RANKL also stimulates metastasis via activity on RANK-expressing cancer cells, resulting in increased invasion and migration. Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells. This review describes these distinct but potentially overlapping mechanisms by which RANKL may promote metastases.

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“…This can lead to new prognostic and predictive markers, and to new potential therapeutic molecules specifically targeting the tumor compartment of bone metastases. Dr. Casimiro showed how pre-clinical research with cancer cell lines and animal models is being translated into clinical models, by sharing gene expression signatures of metastases [15], and showed evidence that targeting RANKL-RANK pathway may also affect the tumor compartment of bone metastases [21].…”

Section: Need To Integrate Microenvironment and Metabolomics With Canmentioning

confidence: 99%

The global cancer genomics consortium's third annual symposium: from oncogenomics to cancer care

et al. 2014

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The Global Cancer Genomics Consortium (GCGC) is a cohesive network of oncologists, cancer biologists and structural and genomic experts residing in six institutions from Portugal, United Kingdom, Japan, India, and United States. The team is using its combined resources and infrastructures to address carefully selected, shared, burning questions in cancer medicine. The Third Annual Symposium was organized by the Institute of Molecular Medicine, Lisbon Medical School, Lisbon, Portugal, from September 18 to 20, 2013. To highlight the benefits and limitations of recent advances in cancer genomics, the meeting focused on how to better translate our gains in oncogenomics to cancer patients while engaging our younger colleagues in cancer medicine at-large. Over two hundreds participants actively discussed some of the most recent advances in the areas cancer genomics, transcriptomics and cancer system biology and how to best apply such knowledge to cancer therapeutics, biomarkers discovery and drug development, and an essential role played by biobanking throughout the process. In brief, the GCGC symposium provided a platform for students and translational cancer researchers to share their excitement and worries as we are beginning to translate the gains in oncogenomics to a better cancer patient treatment.

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RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro

Cited by 65 publications

References 40 publications

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases

Targeting RANKL in metastasis

The global cancer genomics consortium's third annual symposium: from oncogenomics to cancer care

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