Enhanced expression and shedding of receptor activator of NF-κB ligand during tumor-bone interaction potentiates mammary tumor-induced osteolysis

Kalyan C. Nannuru, Mitsuru Futakuchi, Anguraj Sadanandam, Thomas J. Wilson, Michelle L. Varney, Kathleen J. Myers, Xiaodong Li, Eric G. Marcusson, Rakesh K. Singh

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The bone microenvironment plays a critical role in tumor-induced osteolysis and osteolytic metastasis through tumor-bone (TB)-interaction. Receptor activator of nuclear factor-κB (RANK) ligand (RANKL) is one of the critical signaling molecules involved in osteolysis and bone metastasis. However, the regulation and functional significance of RANKL at the TB-interface in tumor-induced osteolysis remains unclear. In this report, we examined the role of tumor-stromal interaction in the regulation of RANKL expression and its functional significance in tumor-induced osteolysis. Using a novel mammary tumor model, we identified that RANKL expression was upregulated at the TB-interface as compared to the tumor alone area. We demonstrate increased generation of sRANKL at the TB-interface, which is associated with tumor-induced osteolysis. The ratio of RANKL to osteoprotegrin (OPG), a decoy receptor for RANKL, at the TB-interface was also increased. Targeting RANKL expression with antisense oligonucleotides (RANKL-ASO), significantly abrogated tumor-induced osteolysis, decreased RANKL expression and the RANKL:OPG ratio at the TB-interface. Together, these results demonstrate that upregulation of RANKL expression and sRANKL generation at the TB-interface potentiates tumor-induced osteolysis.

Original languageEnglish (US)
Pages (from-to)797-808
Number of pages12
JournalClinical and Experimental Metastasis
Volume26
Issue number7
DOIs
StatePublished - Oct 2009

Keywords

  • Anti-sense therapeutics
  • Bone metastasis
  • RANKL
  • Soluble RANKL
  • Tumor-bone interaction
  • Tumor-induced osteolysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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