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.