Tissue factor pathway inhibitor-2 (TFPI-2) is a potent inhibitor of
plasmin, a
protease which is involved in tumour progression by activating (
MMPs). This therefore makes
TFPI-2 a potential inhibitor of invasiveness and the development of
metastases. In this study, low levels of
TFPI-2 expression were found in 65% of patients with
small cell lung cancer (SCLC), the most aggressive type of
lung cancer. To study the impact of
TFPI-2 in tumour progression,
TFPI-2 was overexpressed in NCI-H209 SCLC cells which were orthotopically implanted in nude mice. Investigations showed that
TFPI-2 inhibited lung tumour growth. Such inhibition could be explained in vitro by a decrease in tumour cell viability, blockade of G1/S phase cell cycle transition and an increase in apoptosis shown in NCI-H209 cells expressing
TFPI-2. We also demonstrated that
TFPI-2 upregulation in NCI-H209 cells decreased
MMP expression, particularly by downregulating MMP-1 and MMP-3. Moreover,
TFPI-2 inhibited phosphorylation of the MAPK signalling pathway
proteins involved in the induction of
MMP transcripts, among which MMP-1 was predominant in SCLC tissues and was inversely expressed with
TFPI-2 in 35% of cases. These results suggest that downregulation of
TFPI-2 expression could favour the development of SCLC.