Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-κB ligand

Thomas J. Wilson, Kalyan C. Nannuru, Mitsuru Futakuchi, Anguraj Sadanandam, Rakesh K Singh

Research output: Contribution to journalArticle

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Abstract

Breast cancer commonly causes osteolytic metastases in bone, a process that is dependent on tumor-stromal interaction. Proteases play an important role in modulating tumorstromal interactions in a manner that favors tumor establishment and progression. Whereas several studies have examined the role of proteases in modulating the bone microenvironment, little is currently known about their role in tumor-bone interaction during osteolytic metastasis. In cancer-induced osteolytic lesions, cleavage of receptor activator of nuclear factor-κB ligand (RANKL) to a soluble version (sRANKL) is critical for widespread osteoclast activation. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G, cathepsin K, matrix metalloproteinase (MMP)-9, and MMP13 to be proteases that are up-regulated at the tumor-bone interface using comparative cDNA microarray analysis and quantitative reverse transcription-PCR. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of RANKL, generating active sRANKL that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G at the tumor-bone interface seems to be osteoclasts that up-regulate production of cathepsin G via interaction with tumor cells. Furthermore, we showed that in vitro osteoclastogenesis is reduced by inhibition of cathepsin G in a coculture model and that in vivo inhibition of cathepsin G reduces mammary tumor-induced osteolysis. Together, our data indicate that cathepsin G activity at the tumor-bone interface plays an important role in mammary tumor-induced osteolysis and suggest that cathepsin G is a potentially novel therapeutic target in the treatment of breast cancer bone metastasis.

Original languageEnglish (US)
Pages (from-to)5803-5811
Number of pages9
JournalCancer Research
Volume68
Issue number14
DOIs
StatePublished - Jul 15 2008

Fingerprint

Cathepsin G
Osteolysis
Complement Factor B
Cytoplasmic and Nuclear Receptors
Breast Neoplasms
Ligands
Bone and Bones
Neoplasms
Osteoclasts
Neoplasm Metastasis
Bone Neoplasms
Peptide Hydrolases
Cathepsin K
Matrix Metalloproteinase 9
Microarray Analysis
Coculture Techniques
Oligonucleotide Array Sequence Analysis
Osteogenesis
Reverse Transcription
Up-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-κB ligand. / Wilson, Thomas J.; Nannuru, Kalyan C.; Futakuchi, Mitsuru; Sadanandam, Anguraj; Singh, Rakesh K.

In: Cancer Research, Vol. 68, No. 14, 15.07.2008, p. 5803-5811.

Research output: Contribution to journalArticle

Wilson, Thomas J. ; Nannuru, Kalyan C. ; Futakuchi, Mitsuru ; Sadanandam, Anguraj ; Singh, Rakesh K. / Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-κB ligand. In: Cancer Research. 2008 ; Vol. 68, No. 14. pp. 5803-5811.
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