TFPI-2 silencing increases tumour progression and promotes metalloproteinase 1 and 3 induction through tumour-stromal cell interactions.

Abstract

Tissue factor pathway inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin which activates matrix metalloproteinases (MMPs) involved in degradation of the extracellular matrix. Its secretion in the tumour microenvironment makes TFPI-2 a potential inhibitor of tumour invasion and metastasis. As demonstrated in aggressive cancers, TFPI-2 is frequently down-regulated in cancer cells, but the mechanisms involved in the inhibition of tumour progression remained unclear. We showed in this study that stable TFPI-2 down-regulation in the National Cancer Institute (NCI)-H460 non-small cell lung cancer cell line using specific micro interfering micro-interfering RNA promoted tumour progression in a nude mice orthotopic model that resulted in an increase in cell invasion. Moreover, TFPI-2 down-regulation enhanced cell adhesion to collagen IV and laminin via an increase in α(1) integrin on cell surface, and increased MMP expression (mainly MMP-1 and -3) contributing to cancer cell invasion through basement membrane components. This study also reveals for the first time that pulmonary fibroblasts incubated with conditioned media from TFPI-2 silencing cancer cells exhibited increased expression of MMPs, particularly MMP-1, -3 and -7, that are likely involved in lung cancer cell invasion through the surrounding stromal tissue, thus enhancing formation of metastases.

• Authors: Guillaume Gaud, Sophie Iochmann, Audrey Guillon-Munos, Benjamin Brillet, Stéphanie Petiot, Florian Seigneuret, Antoine Touzé, Nathalie Heuzé-Vourc'h, Yves Courty, Stéphanie Lerondel, Yves Gruel, Pascale Reverdiau
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 15 Issue 2 Pg. 196-208 (Feb 2011) ISSN: 1582-4934 [Electronic] England
• PMID: 20015200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Collagen Type IV
• Glycoproteins
• Integrin alpha1
• Laminin
• tissue-factor-pathway inhibitor 2
• Matrix Metalloproteinases

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (genetics, pathology, physiopathology)
• Cell Adhesion
• Cell Line, Tumor
• Cell Proliferation
• Collagen Type IV (metabolism)
• Down-Regulation
• Extracellular Matrix (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Glycoproteins (genetics, metabolism)
• Humans
• Integrin alpha1 (biosynthesis)
• Laminin (metabolism)
• Lung Neoplasms (genetics, pathology, physiopathology)
• Male
• Matrix Metalloproteinases (biosynthesis, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Transplantation
• RNA Interference
• Signal Transduction
• Stromal Cells
• Transplantation, Heterologous
• Tumor Microenvironment