Regulation of cancer cell migration and bone metastasis by RANKL

Jones, D. Holstead; Nakashima, Tomoki; Sánchez, Otto; Kozieradzki, I.; Komarova, Svetlana V.; Sarosi, Ildiko; Morony, Sean; Rubin, Evelyn; Sarao, Renu; Hojilla, Carlo V.; Komnenovic, Vukoslav; Kong, Young‐Yun; Schreiber, Martin; Dixon, S. Jeffrey; Sims, Stephen M.; Khokha, Rama; Wada, Teiji; Penninger, Josef

doi:10.1038/nature04524

Cited by 719 publications

(623 citation statements)

References 20 publications

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“…The ability of RANKL to act directly on RANK-expressing tumor cells that we observe in this study is consistent with a recently described role for RANKL in migration of prostate tumor cells [20] or other tumor cells [19]. Given the stimulation of tumor cell migration by RANKL, the authors of this study suggest that the rich source of RANKL within the bone may serve as a soil factor which attracts RANKexpressing tumor cells.…”

Section: Discussionsupporting

confidence: 92%

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RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

et al. 2007

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BACKGROUND. Metastases to bone are a frequent complication of human prostate cancer and result in the development of osteoblastic lesions that include an underlying osteoclastic component. Previous studies in rodent models of breast and prostate cancer have established that receptor activator of NF-kB ligand (RANKL) inhibition decreases bone lesion development and tumor growth in bone. RANK is essential for osteoclast differentiation, activation, and survival via its expression on osteoclasts and their precursors. RANK expression has also been observed in some tumor cell types such as breast and colon, suggesting that RANKL may play a direct role on tumor cells. METHODS. Male CB17 severe combined immunodeficient (SCID) mice were injected with PC3 cells intratibially and treated with either PBS or human osteprotegerin (OPG)-Fc, a RANKL antagonist. The formation of osteolytic lesions was analyzed by X-ray, and local and systemic levels of RANKL and OPG were analyzed. RANK mRNA and protein expression were assessed on multiple prostate cancer cell lines, and events downstream of RANK activation were studied in PC3 cells in vitro. RESULTS. OPG-Fc treatment of PC3 tumor-bearing mice decreased lesion formation and tumor burden. Systemic and local levels of RANKL expression were increased in PC3 tumor bearing mice. PC3 cells responded to RANKL by activating multiple signaling pathways which resulted in significant changes in expression of genes involved in osteolysis and migration. RANK activation via RANKL resulted in increased invasion of PC3 cells through a collagen matrix.CONCLUSION. These data demonstrate that host stromal RANKL is induced systemically and locally as a result of PC3 prostate tumor growth within the skeleton. RANK is expressed on prostate cancer cells and promotes invasion in a RANKL-dependent manner.

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Section: Discussionsupporting

confidence: 92%

“…The functional role of RANK on mammary epithelial cells [25] and tumors of epithelial origin [19,26,20] …”

Section: Rank Is Expressed On Prostate Cancer Cell Linesmentioning

confidence: 99%

RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

et al. 2007

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“…Blocking RANKL markedly reduced tumor burden in bones (47). We extended previous reports in breast cancer and lung cancer literature by showing that downregulation of RANKL in SBC-5 miR-335 þ markedly reduced osteoclast induction, and that miR-335 þ abrogated or reduced skeletal osteolysis induced by miR-335 þ xenografts.…”

Section: Discussionsupporting

confidence: 83%

MiR-335 Inhibits Small Cell Lung Cancer Bone Metastases via IGF-IR and RANKL Pathways

Gong

Guillemette

et al. 2014

Molecular Cancer Research

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Small cell lung cancer (SCLC) is a rapidly progressing, incurable cancer that frequently spreads to bone. New insights are needed to identify therapeutic targets to prevent or retard SCLC metastatic progression. Human SCLC SBC-5 cells in mouse xenograft models home to skeletal and nonskeletal sites, whereas human SCLC SBC-3 cells only pervade nonskeletal sites. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of SCLC. miRNA expression profiling revealed selective and reduced expression of miRNA (miR)-335 and miR-29a in SBC-5 cells, compared with SBC-3 cells. In SBC-5 cells, miR-335 expression correlated with bone osteolytic lesions, whereas miR-29a expression did not. Overexpression of miR-335 in SBC-5 cells significantly reduced cell migration, invasion, proliferation, colony formation, and osteoclast induction in vitro. Importantly, in miR-335 overexpressing SBC-5 cell xenografts (n ¼ 10), there were minimal osteolytic lesions in the majority of mice and none in three mice. Expression of RANK ligand (RANKL) and insulin-like growth factor-I receptor (IGF-IR), key mediators of bone metastases, were elevated in SBC-5 as compared with SBC-3 cells. Mechanistically, overexpression of miR-335 in SBC-5 cells reduced RANKL and IGF-IR expression. In conclusion, loss of miR-335 promoted SCLC metastatic skeletal lesions via deregulation of IGF-IR and RANKL pathways and was associated with metastatic osteolytic skeletal lesions.

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“…Neutralization of RANKL by OPG in a mouse model of melanoma resulted in a marked reduction of tumor burden in bones but not in other organs. This further supports the role if RANKL in bone specific metastasis [134].…”

Section: Cross Talk Between the Cancer Cell And The Bone Microenvironsupporting

confidence: 76%

Homing of Cancer Cells to the Bone

Mishra

Shiozawa

Pienta

et al. 2011

Cancer Microenvironment

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A variety of tumor cells preferentially home to the bone. The homing of cancer cells to the bone represents a multi-step process that involves malignant progression of the tumor, invasion of the tumor through the extracellular matrix and the blood vessels and settling of the tumor cells in the bone. Gaining a greater understanding as to the mechanisms used by cancer cells in these processes will facilitate the design of drugs which could specifically target the homing process. In this review we will discuss the properties of tumor cells and the bone microenvironment which promote homing of a cancer cell to the bone. We will highlight the different steps and the molecular pathways involved when a cancer cell metastasize to the bone. Since bone is the major home for hematopoietic stem cells (HSCs), we will also highlight the similarities between the homing of cancer and HSC to the bone. Finally we will conclude with therapeutic and early detection strategies which can prevent homing of a cancer cell to the bone.

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Regulation of cancer cell migration and bone metastasis by RANKL

Cited by 719 publications

References 20 publications

RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

MiR-335 Inhibits Small Cell Lung Cancer Bone Metastases via IGF-IR and RANKL Pathways

Homing of Cancer Cells to the Bone

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