TFPI-2 silencing increases tumour progression and promotes metalloproteinase 1 and 3 induction through tumour-stromal cell interactions.
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.
Gaud
Guillaume
G
Inserm, U618, Université François Rabelais, Tours, France.
Iochmann
Sophie
S
Guillon-Munos
Audrey
A
Brillet
Benjamin
B
Petiot
Stéphanie
S
Seigneuret
Florian
F
Touzé
Antoine
A
Heuzé-Vourc'h
Nathalie
N
Courty
Yves
Y
Lerondel
Stéphanie
S
Gruel
Yves
Y
Reverdiau
Pascale
P
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D024141:Collagen Type IV / Q000378:metabolism; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D039423:Integrin alpha1 / Q000096:biosynthesis; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D034622:RNA Interference; D015398:Signal Transduction; D017154:Stromal Cells; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
D024141:Collagen Type IV; D006023:Glycoproteins; D039423:Integrin alpha1; D007797:Laminin; C021240:tissue-factor-pathway inhibitor 2; D020782:Matrix Metalloproteinases