Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-kappaB ligand.
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.
Wilson
Thomas J
TJ
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5845, USA.
Nannuru
Kalyan C
KC
Futakuchi
Mitsuru
M
Sadanandam
Anguraj
A
Singh
Rakesh K
RK
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000378:metabolism; D010014:Osteolysis; D053245:RANK Ligand / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000502:physiology*
D016328:NF-kappa B; D053245:RANK Ligand; D002403:Cathepsins; D012697:Serine Endopeptidases; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9