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Role proteases <strong>of</strong> Kupffer cells in murine tumor development and<br />
metastasing<br />
T. V. Alexeenko1, T. A. Korolenko1, S. Ya. Zhanaeva1, V. I. Kaledin2<br />
1Laboratory <strong>of</strong> Cell Biochemistry, Institute <strong>of</strong> Physiology, Academy <strong>of</strong> Medical Sciences, Siberian Branch,<br />
Novosibirsk, Russia; 2Institute <strong>of</strong> Cytology and Genetics <strong>of</strong> Russian Academy <strong>of</strong> Sciences, Novosibirsk,<br />
Russia<br />
Activated macrophages (Mphs) play the important role in the degradation <strong>of</strong> ECM due<br />
to production <strong>of</strong> MMPs (Overall, Butler, 2007). Gadolinium chloride (GC) is a rare<br />
lanthanide which induced selective depression <strong>of</strong> liver Mphs in vivo has been used to<br />
abrogate Mph function to understand their role in pathology. Kupffer cells was shown<br />
to be enriched by cathepsin D, cathepsin B, as well as MMPs (MMP-2, MMP-13). The<br />
aim: to evaluate the role <strong>of</strong> proteases <strong>of</strong> Kupffer cells in tumor growth and metastazing<br />
process.<br />
The concentrations <strong>of</strong> MMP-2 (R&D ELISA kits, USA) and TIMP-1 (BioRay ELISA<br />
kits, USA) was assayed in tumor tissue, serum and liver homogenate <strong>of</strong> CBA/C57Bl mice<br />
with Lewis lung adenocarcinoma – a solid tumor metastasing into lung. Cathepsins B,<br />
L and S activity was measured by fluorometric methods (Kirschke, Barrett, 1981) with<br />
inhibitors. Gadolinium concentration in tumor and liver tissue was assayed by adsorption<br />
spectrometer ( Jober Ivon, France) after single intravenous administration <strong>of</strong> GC<br />
(10 mg/kg) to mice.<br />
Gagolinium was shown to concentrate mainly in liver <strong>of</strong> non-parenchymal cells, and<br />
tumor Mphs were able to uptake <strong>of</strong> gadolinium (up to 5 % from the dose administered).<br />
GC pretreatment or treatment (before metastases forming, at the 4-5th days after tumor<br />
transplantation) significantly decreased the rate <strong>of</strong> tumor metastazing into lung. Electron<br />
microscopic morphometric study revealed that GC reduced the number <strong>of</strong> liver Mphs,<br />
decreased cathepsin B and cathepsin D specific activity in liver tissue. Cathepsin B activity<br />
in lung tissue increased during onset <strong>of</strong> metastazing. Increased production <strong>of</strong> TNF-α<br />
by new “phenotype” <strong>of</strong> liver Mphs, recruited after GC administration, was followed by<br />
increased TIMP-1 concentration in liver (not in serum) and decreased level <strong>of</strong> MMP-2<br />
(ECM remodeling and increased mobility <strong>of</strong> liver Mphs).<br />
Remodeling <strong>of</strong> ECM after abrogation <strong>of</strong> Kupffer cells in vivo plays the role in murine<br />
tumor development and prevention <strong>of</strong> metastazing.<br />
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