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 α1 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.

Promoter hypermethylation and silencing of tissue factor pathway inhibitor-2 in oral squamous cell carcinoma

“…Although TFPI-2 has been found to reduce the cell proliferation rate in various human tumors [40,43–46] by triggering apoptosis [24,44], it has been suggested by some that TFPI-2 has no antiproliferation effect [47–49]. Therefore, the effect of TFPI-2 on cell proliferation and apoptosis may be complex and cell-type specific.…”

Effect of 5-aza-2'-deoxycytidine on Cell Proliferation of Non-small Cell Lung Cancer Cell Line A549 Cells and Expression of the TFPI-2 Gene

“…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 tumor microenvironment makes TFPI-2 as potential inhibitor of tumor invasion and metastasis (Gaud et al, 2011). The gene that codes for TFPI-2 has been mapped to chromosome 7q22 by fluorescence in situ hybridization (Kempaiah et al, 2007).…”

Monitoring of tumour progression using bioluminescence imaging and computed tomography scanning in a nude mouse orthotopic model of human small cell lung cancer

“…Orthotopic animal models have been developed only with nonsmall cell lung cancer cells [5,25,26] and our aim was therefore to propose a clinically relevant animal model that mimics various stages of human small cell lung cancer and that would be suitable to study the molecular aspects of tumour growth. As previously described, we administered EDTA with cells that could disrupt cadherin-mediated cell-cell adhesion, facilitating tumour cell migration through the epithelial barrier and parenchymal matrix [27].…”