This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shiraga, M. Articles by Sone, S. Search for Related Content PubMed PubMed Citation Articles by Shiraga, M. Articles by Sone, S.

Organ Heterogeneity of Host-derived Matrix Metalloproteinase Expression and Its Involvement in Multiple-Organ Metastasis by Lung Cancer Cell Lines¹

Department of Internal Medicine and Molecular Therapeutics, University of Tokushima School of Medicine, Tokushima 770-8503, Japan

Cancer metastasis is tightly regulated by the interaction of tumor cells and host organ microenvironments. Matrix metalloproteinases (MMPs), produced by both tumor cells and host stromal cells, play a central role in tumor invasion and angiogenesis. We determined whether metastatic potential of lung cancer to multiple organs is dependent solely on the expression of MMPs by tumor cells, using two metastasis models of human lung cancer cell lines expressing various levels of MMPs and a MMP inhibitor (ONO-4817). In the lung metastasis model, tumor cells (PC14, PC14PE6, H226, A549) inoculated i.v. into nude or SCID mice metastasized only in the lung. In the multiple-organ metastasis model, tumor cells (RERF-LC-AI, SBC-3/DOX, H69/VP, which express low levels of MMPs) inoculated i.v. into natural killer cell-depleted SCID mice metastasized into the liver, kidneys, and systemic lymph nodes. Film in situ zymography analysis revealed that the nontumor parenchyma of the lung had no gelatinolytic activity, whereas gelatinolytic activity of the liver and kidney was high and low, respectively. In the lung metastasis model, gelatinolytic activity of lung nodules directly correlated with the in vitro expression of MMP-2 and MMP-9 by tumor cells. Inhibition of MMP activity by ONO-4817 suppressed lung metastasis by the cell lines that expressed MMPs, but not those that did not express MMP, via the inhibition of MMP activity of lung tumors. In the multiple-organ metastasis model, liver parenchyma, but not liver nodules, showed gelatinolytic activity. The MMP inhibition reduced metastasis to the liver, but not to the kidney or lymph nodes, via inhibition of MMP activity of liver parenchyma. These findings suggest that MMP expression varies among the host organ microenvironments and that stromal MMPs may promote metastasis of lung cancer. Therefore, antimetastatic effects based on MMP inhibition may be dependent on MMPs derived not only from tumor cells but also from organ-specific microenvironments.

This article has been cited by other articles:

				B. Sung, M. K. Pandey, Y. Nakajima, H. Nishida, T. Konishi, M. M. Chaturvedi, and B. B. Aggarwal Identification of a novel blocker of I{kappa}B{alpha} kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-{kappa}B Mol. Cancer Ther., January 1, 2008; 7(1): 191 - 201. [Abstract] [Full Text] [PDF]

				K. S. Ahn, G. Sethi, T.-H. Chao, S. T. C. Neuteboom, M. M. Chaturvedi, M. A. Palladino, A. Younes, and B. B. Aggarwal Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-{kappa}B regulated gene products Blood, October 1, 2007; 110(7): 2286 - 2295. [Abstract] [Full Text] [PDF]

				A. S. Nair, S. Shishodia, K. S. Ahn, A. B. Kunnumakkara, G. Sethi, and B. B. Aggarwal Deguelin, an Akt Inhibitor, Suppresses I{kappa}B{alpha} Kinase Activation Leading to Suppression of NF-{kappa}B-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion J. Immunol., October 15, 2006; 177(8): 5612 - 5622. [Abstract] [Full Text] [PDF]

				G. Sethi, K. S. Ahn, S. K. Sandur, X. Lin, M. M. Chaturvedi, and B. B. Aggarwal Indirubin Enhances Tumor Necrosis Factor-induced Apoptosis through Modulation of Nuclear Factor-{kappa}B Signaling Pathway J. Biol. Chem., August 18, 2006; 281(33): 23425 - 23435. [Abstract] [Full Text] [PDF]

				S. Aggarwal, H. Ichikawa, Y. Takada, S. K. Sandur, S. Shishodia, and B. B. Aggarwal Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of I{kappa}B{alpha} Kinase and Akt Activation Mol. Pharmacol., January 1, 2006; 69(1): 195 - 206. [Abstract] [Full Text] [PDF]

				S. Yano, H. Muguruma, Y. Matsumori, H. Goto, E. Nakataki, N. Edakuni, H. Tomimoto, S. Kakiuchi, A. Yamamoto, H. Uehara, et al. Antitumor Vascular Strategy for Controlling Experimental Metastatic Spread of Human Small-Cell Lung Cancer Cells with ZD6474 in Natural Killer Cell-Depleted Severe Combined Immunodeficient Mice Clin. Cancer Res., December 15, 2005; 11(24): 8789 - 8798. [Abstract] [Full Text] [PDF]

				Y. Takada, Y. Kobayashi, and B. B. Aggarwal Evodiamine Abolishes Constitutive and Inducible NF-{kappa}B Activation by Inhibiting I{kappa}B{alpha} Kinase Activation, Thereby Suppressing NF-{kappa}B-regulated Antiapoptotic and Metastatic Gene Expression, Up-regulating Apoptosis, and Inhibiting Invasion J. Biol. Chem., April 29, 2005; 280(17): 17203 - 17212. [Abstract] [Full Text] [PDF]

				H. Goto, S. Yano, Y. Matsumori, H. Ogawa, D. C. Blakey, and S. Sone Sensitization of Tumor-Associated Endothelial Cell Apoptosis by the Novel Vascular-Targeting Agent ZD6126 in Combination with Cisplatin Clin. Cancer Res., November 15, 2004; 10(22): 7671 - 7676. [Abstract] [Full Text] [PDF]

				S. Shishodia and B. B. Aggarwal Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates Activation of Cigarette Smoke-Induced Nuclear Factor (NF)-{kappa}B by Suppressing Activation of I-{kappa}B {alpha} Kinase in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of Cyclin D1, COX-2, and Matrix Metalloproteinase-9 Cancer Res., July 15, 2004; 64(14): 5004 - 5012. [Abstract] [Full Text] [PDF]

				S. Shishodia, P. Potdar, C. G. Gairola, and B. B. Aggarwal Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-{kappa}B activation through inhibition of I{kappa}B{alpha} kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1 Carcinogenesis, July 1, 2003; 24(7): 1269 - 1279. [Abstract] [Full Text] [PDF]