Angiogenesis and matrix metalloproteinases in non-small cell lung cancer

The aim of this study was to evaluate potential invasive and metastatic pathways in order to develop a biological prognostic model for operable NSCLC.;Initially an immunohistochemical study of angiogenesis, growth factor receptors (EGFR, c-erbB-2), regulators of apoptosis (p53, Bcl-2) and matrix metalloproteinases and their inhibitors (MMP-2, MMP-9 and TIMP-2) was performed in a retrospective series of resected NSCLC tumours. Chalkley counting of CD34-immunostained microvessels was used as an indirect measure of angiogenesis. A high Chalkley count was an independent marker of poor outcome. Bcl-2 expression correlated with good prognosis suggesting that loss of Bcl-2 expression may indicate more severe molecular dedifferentiation resulting in a more aggressive phenotype. MMP-2, MMP-9 and TIMP-2 were frequently demonstrated in both tumour cells and the surrounding stroma. Tumour cell MMP-9 expression was independently associated with poor prognosis and significantly correlated with EGFR immunoreactivity. A stage-independent prognostic model using the immunohistochemical markers CD34, EGFR, MMP-9 and Bcl-2 performed on routinely processed tissue was developed. This model identified patients at particular risk of recurrence after resection who could receive adjuvant treatment with either traditional cytotoxic chemotherapy or potentially individualised therapy with more targeted therapeutic agents.;In vitro studies demonstrated that EGF up-regulated MMP-9 mRNA expression in 4/5NSCLC cell-lines with no effect on MMP-2, MTI-MMP, TIMP-1 or TIMP-2 mRNA expression. These results suggest EGFR is involved in the specific up-regulation of MMP-9 and supports the use of novel therapies including MMP inhibitors and EGFR tyrosine kinase antagonists in the treatment of NSCLC.