+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

RANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastases

RANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastases

Journal of Thoracic Oncology 9(3): 345-354

Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non-small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression. We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses. OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts. These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden.

(PDF emailed within 0-6 h: $19.90)

Accession: 055333174

Download citation: RISBibTeXText

PMID: 24496001

DOI: 10.1097/JTO.0000000000000070

Related references

RANKL inhibition blocks lung cancer-induced osteolytic lesions and reduces skeletal tumor burden in both RANK-expressing and RANK-negative lung cancers. 2007

Combined therapy with the RANKL inhibitor RANK-Fc and rhApo2L/TRAIL/dulanermin reduces bone lesions and skeletal tumor burden in a model of breast cancer skeletal metastasis. Cancer Biology & Therapy 9(7): 539-550, 2011

OPG inhibits the progression of bone destruction and skeletal tumor burden in mice with established osteolytic MDA-231 breast cancer metastases. Journal of Bone & Mineral Research 17(Suppl 1): S147, September, 2002

Inhibition of p38alpha mitogen-activated protein kinase prevents the development of osteolytic bone disease, reduces tumor burden, and increases survival in murine models of multiple myeloma. Cancer Research 67(10): 4572-4577, 2007

Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clinical & Experimental Metastasis 25(2): 119-129, 2007

Ibandronate reduces osteolytic lesions but not tumor burden in a murine model of myeloma bone disease. Blood 93(5): 1697-1706, 1999

miR-335 inhibits small cell lung cancer bone metastases via IGF-IR and RANKL pathways. Molecular Cancer Research 12(1): 101-110, 2014

Silencing of skeletal metastasis-associated genes impairs migration of breast cancer cells and reduces osteolytic bone lesions. Clinical & Experimental Metastasis 29(5): 441-456, 2012

Inhibition of alphavbeta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental human prostate cancer bone metastases. Clinical & Experimental Metastasis 19(Supplement): 47, 2002

Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. Clinical & Experimental Metastasis 20(5): 413-420, 2003

CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models. Prostate 75(12): 1227-1246, 2015

Predictors of skeletal-related events in non-small cell lung cancer patients with bone metastases. Lung Cancer 71(1): 89-93, 2011

Comparison of FDG-PET and Bone Scans for Detecting Skeletal Metastases in Patients with Non-small Cell Lung Cancer. Clinical Positron Imaging 3(3): 97-105, 2000

The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain. European Journal of Cancer Care 19(6): 755-760, 2011

Use of zoledronic acid for lung cancer with bone metastases - a study on reossification of osteolytic bone metastases. Gan to Kagaku Ryoho. Cancer & ChemoTherapy 40(7): 871-875, 2013