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1.  Differential Matrix Metalloproteinase Levels in Adenocarcinoma and Squamous Cell Carcinoma of the Lung 
Objective
The matrix metalloproteinases (MMPs) have been implicated in the aggressive course of non-small cell lung cancer (NSCLC). However, there are a large number of MMP subtypes with diverse proteolytic substrates and different induction pathways. This study tested the hypothesis that a differential MMP profile would exist between NSCLC and normal lung and that MMP patterns would differ between NSCLC histologic type.
Methods
NSCLC samples and remote normal samples were obtained from patients with stage I or II NSCLC with either squamous cell (n=22) or adenocarcinoma (n=19) histology. Absolute concentrations for each of the MMP subclasses; collagenases (MMP-1, 8, -13), gelatinases (MMP-2,-9), lysins (MMP-2, -7) and elastase (MMP-12) were determined by a calibrated and validated multiplex suspension array.
Results
Overall, MMP levels were significantly increased in NSCLC compared to normal. For example, MMP-1 and MMP-7 increased by approximately 10 fold in NSCLC (p<0.05). Moreover, a different MMP portfolio was observed between NSCLC histologic types. For example MMP-1,-8,-9 and -12 increased by over 4-fold in squamous cell versus adenocarcinoma (p<0.05). In those patients who recurred within 3 years of resection, 3-fold higher levels of MMP-8 and -9 were observed (p<0.05).
Conclusion
Increased levels of a number of MMP types occur with NSCLC, but the MMP profile was distinctly different between histologic types and in those patients with recurrence. These different MMP profiles may be important in the mechanistic basis for the natural history of different NSCLC types, as well as identifying potential prognostic and therapeutic targets.
doi:10.1016/j.jtcvs.2009.12.016
PMCID: PMC2844342  PMID: 20304142
matrix metalloproteinases; lung cancer; multiplex; recurrence
2.  A Simple Two-Gene Prognostic Model for Adenocarcinoma of the Lung 
Objective
We hypothesized that clinical outcome of resected early stage adenocarcinoma of the lung can be predicted by the expression of a few critically important genes as measured by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) in formalin fixed paraffin-embedded (FFPE) primary tumors.
Methods
Twenty-two prognostic genes for the metastatic phenotype were identified through cDNA microarray analysis of four cancer cell lines and bioinformatics analysis. Expression levels of a subset of these genes (n=13) were measured by real-time RT-PCR in FFPE primary adenocarcinoma from patients who recurred within 2 years (n=9) and who did not recur (n=11). ROC curve analysis was performed to establish prognostic values of single genes. The most informative gene was combined with the remaining genes to determine if there was a particular pair(s) that yielded high diagnostic accuracy. A small validation study was performed.
Results
ROC curve analysis of the single genes revealed that high expression of CK19 was associated with non-recurrence (AUC=0.859, CI=0.651–0.970). The CK19/EpCAM2 gene ratio had the most reproducible prognostic accuracy, followed by the CK19/P-cadherin ratio. A Kaplan Meier survival analysis generated from the CK19/EpCAM2 ratio resulted in highly significant curves as a function of marker positivity (p=0.0007; HR=10.7). Significance declined but was maintained in the validation study.
Conclusions
This preliminary study provides evidence that the CK19/EpCAM2 and/or CK19/P-cadherin ratio(s) may be a simple and accurate prognostic indicator of clinical outcome in early stage adenocarcinoma of the lung. If further validation studies from large patient cohorts confirm the results, adjuvant therapy could be targeted to this high risk group.
doi:10.1016/j.jtcvs.2007.10.058
PMCID: PMC2774741  PMID: 18329483
lung cancer; molecular markers

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