Expression of plasminogen activator inhibitors 1 and 2 in lung cancer and their role in tumor progression.
The plasminogen activator cascade initiated by urokinase type plasminogen activator (u-PA) is involved in extracellular matrix degradation during the tumor invasion process. The plasminogen activator inhibitors 1 (PAI-1) and 2 (PAI-2) are two specific inhibitors of u-PA. We hypothesized that the balance between u-PA and its two inhibitors could be disrupted to favor plasminogen activation during lung cancer progression. Using immunohistochemistry, we analyzed the pattern of expression of u-PA, PAI-1, and PAI-2 in non-small cell lung carcinomas (NSCLC) and neuroendocrine (NE) lung tumors. u-PA and PAI-1 were both detected in stromal fibroblasts and in tumor cells. In 84 NSCLCs, their epithelial expression was strongly correlated and linked to the presence of node metastasis (P = 0.008), whereas their coexpression in fibroblasts was associated with larger tumor size (P = 0.04) and advanced stages (P = 0.009). In 72 NE tumors, u-PA and PAI-1 were more frequently expressed in fibroblasts in high-grade NE tumors (SCLC and large cell NE tumors) than in low- and intermediate-grade tumors (typical and atypical carcinoids). Comparison of in situ hybridization and immunohistochemistry in 14 cases showed that PAI-1 was consistently expressed by stromal fibroblasts, although the protein was also localized in tumor cells. In contrast, the expression of PAI-2 was restricted to fibroblasts and correlated with the absence of nodal involvement (P = 0.005). Considering NE tumors, the frequency of PAI-2 expression decreased along the NE spectrum from typical carcinoids to SCLCs. These data suggest that PAI-lacts in synergy with u-PA to favor tumor invasion process and connotes aggressivity, in contrast with PAI-2, which may block u-PA-mediated proteolysis and is inversely correlated with tumor progression.
Robert
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C
Lung Cancer Research Group, Institut National de la Santé et de la Recherche Médicale, CJF 97-01, Institut A. Bonniot, La Tronche, France.
Bolon
I
I
Gazzeri
S
S
Veyrenc
S
S
Brambilla
C
C
Brambilla
E
E
D018278:Carcinoma, Neuroendocrine / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000378:metabolism*; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis*; D015842:Serine Proteinase Inhibitors / Q000096:biosynthesis*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator