The role of host matrix metalloproteinases in lung tumor formation.

摘要

Matrix metalloproteinases (MMPs) are involved in multiple stages of tumor progression including invasion and metastasis and early tumor growth. Using mouse models of lung metastasis and primary lung tumor growth, we have determined the role of specific MMPs in lung tumor formation. Interestingly, we found that host-derived MMPs can play both pro- and anti-tumorigenic roles in the lung microenvironment. Genetic ablation of MMP9 leads to reduced metastasis to the lung and reduced development of primary tumors in the lung, whereas genetic ablation of MMP7 leads to increased metastasis to the lung. Further examination of MMP9 in lung metastasis revealed that MMP9 derived from bone marrow precursor cells was responsible for this phenotype. This effect of MMP9 on lung metastasis occurred very early after introduction of tumor cells into the lung and subsequent growth of tumors was independent of MMP9. The absence of MMP9 resulted in significantly more tumor cells undergoing apoptosis six hours after tumor cell inoculation compared to control mice.; Further exploration of host- and tumor-derived MMPs and other proteases in lung tumor formation was performed using a Hu/Mu ProtIn microarray chip. This chip can distinguish mouse and human proteases using oligonucleotides specific for each species. Examination of species-specific host-derived MMPs in lung tumor formation revealed that MMP12, MMP13 and cathepsin K were upregulated in the tumor compared to normal lung. Functional analysis revealed that host-derived MMP12 was playing a role in metastasis to the lung by limiting lung tumor growth.; Collectively, we provide data to indicate that host-derived MMPs are playing both pro-tumorigenic and protective roles in lung cancer. Despite extensive preclinical data indicating efficacy, inhibition of MMPs using broad-spectrum MMP inhibitors (MMPIs) in clinical trials was unsuccessful. We demonstrated that targeting MMP9 is likely to be effective only at the time of initial seeding of metastatic lesions, whereas the clinical trials were performed on patients with late-stage disease. In addition, we provide evidence that supports the conclusion that broad-spectrum inhibition of MMPs would eliminate protective as well as tumorigenic influences of individual MMP family members and is an additional likely contributor to the negative clinical trial results.