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.
AuthorsC Robert, I Bolon, S Gazzeri, S Veyrenc, C Brambilla, E Brambilla
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 5 Issue 8 Pg. 2094-102 (Aug 1999) ISSN: 1078-0432 [Print] UNITED STATES
PMID10473092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Plasminogen Activator Inhibitor 1
  • Plasminogen Activator Inhibitor 2
  • Serine Proteinase Inhibitors
  • Urokinase-Type Plasminogen Activator
  • Carcinoma, Neuroendocrine (metabolism)
  • Carcinoma, Non-Small-Cell Lung (metabolism)
  • Disease Progression
  • Fibroblasts (metabolism)
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Lung Neoplasms (metabolism)
  • Neoplasm Staging
  • Plasminogen Activator Inhibitor 1 (biosynthesis)
  • Plasminogen Activator Inhibitor 2 (biosynthesis)
  • Serine Proteinase Inhibitors (biosynthesis)
  • Urokinase-Type Plasminogen Activator (biosynthesis)

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