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

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 tumor-stromal 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-kappaB 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.
AuthorsThomas J Wilson, Kalyan C Nannuru, Mitsuru Futakuchi, Anguraj Sadanandam, Rakesh K Singh
JournalCancer research (Cancer Res) Vol. 68 Issue 14 Pg. 5803-11 (Jul 15 2008) ISSN: 1538-7445 [Electronic] United States
PMID18632634 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-kappa B
  • RANK Ligand
  • Cathepsins
  • Serine Endopeptidases
  • Cathepsin G
  • Ctsg protein, mouse
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 9
Topics
  • Animals
  • Bone Neoplasms (pathology, secondary)
  • Cathepsin G
  • Cathepsins (physiology)
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Mammary Neoplasms, Animal (metabolism)
  • Matrix Metalloproteinase 13 (metabolism)
  • Matrix Metalloproteinase 9 (metabolism)
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B (metabolism)
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Osteoclasts (metabolism)
  • Osteolysis
  • RANK Ligand (metabolism)
  • Serine Endopeptidases (physiology)

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