Faculty Bibliography

The leading cause of lung cancer is exposure to cigarette smoke and other environmental pollutants, which include formaldehyde, acrolein, benzene, dioxin, and polycyclic aromatic hydrocarbons (PAHs). PAHs and dioxins are exogenous ligands that directly bind to the aryl hydrocarbon receptor (AhR), a transcription factor that activates xenobiotic metabolism, histone modification (an important step in DNA methylation) and, ultimately, tumorigenesis. In this review article we summarize the current understanding of AhR and its role in the development of lung cancer, including its influence on cell proliferation, angiogenesis, inflammation, and apoptosis.

Decreasing the risk of lung cancer, or preventing its development in high-risk individuals, would have a huge impact on public health. The most effective means to decrease lung cancer incidence is to eliminate exposure to carcinogens. However, with recent advances in the understanding of pulmonary carcinogenesis and the identification of intermediate biomarkers, the prospects for the field of chemoprevention research have improved dramatically. Here we review the most recent research in lung cancer chemoprevention-focusing on those agents that have been investigated in human clinical trials. These agents fall into three major categories. First, oxidative stress plays an important role in pulmonary carcinogenesis; and therefore, antioxidants (including vitamins, selenium, green tea extracts, and isothiocyanates) may be particularly effective in preventing the development of lung cancer. Second, inflammation is increasingly accepted as a crucial factor in carcinogenesis, and many investigators have focused on anti-inflammatory agents, such as glucocorticoids, NSAIDs, statins, and PPARgamma agonists. Finally, the PI3K/AKT/mTOR pathway is recognized to play a central role in tobacco-induced carcinogenesis, and inhibitors of this pathway, including myoinositol and metformin, are promising agents for lung cancer prevention. Successful chemoprevention will likely require targeting of multiple pathways to carcinogenesis-both to minimize toxicity and maximize efficacy.

Rationale: Cigarette smoke causes a field of injury and molecular changes in the airways even in histologically normal areas termed "field cancerization" which describes the site(s) of neoplasia and adjacent normal tissue with molecular abnormalities in common. MicroRNAs ( miRNAs) are small, non-coding RNAs that act as post-transcriptional regulators of gene expression by recognizing target sites in the 3' untranslated regions (3'UTRs) via incomplete base-pairing and induce mRNA degradation or translational repression. Deregulation of miRNAs has been linked to cancer initiation and progression, and miRNAs may act as tumor suppressor genes or oncogenes. We hypothesized that miRNA expression in the peripheral airways of smokers with lung cancer is distinct from that of smokers without lung cancer and therefore, miRNAs can be used as biomarkers for the early detection of lung cancer. Methods: We collected human peripheral airway epithelial cells by bronchoscopic brushing from the unaffected lung of thirteen smokers with lung adenocarcinoma and twelve control smokers. Total RNA was extracted from the peripheral airway epithelial cells by miRNAeasy and miRNA profiling was performed using the TaqMan Quantitative qRT-PCR miRNA Assay. Results: Comparison of miRNA levels in peripheral airway epithelial cells from smokers with or without lung cancer demonstrated 53 miRNAs that were significantly different (p<0.05) between the two groups. The majority of miRNAs were up-regulated (41 miRNAs) in lung cancer patients, including miR-21, miR-26a, miR-31, miR-34c, and miR-205. Down-regulated miRNAs included let-7b, let-7e, and miR-126. Several of the miRNAs with increased expression are of interest: miR-21 inhibits tumor suppressor protein PTEN, miR-26a suppresses PTEN and increases AKT phosphorylation and nuclear factor kappaB (NFkappaB) activation, miR-31 represses tumor suppressor genes LATS2 and PPP2R2A, miR-205 is associated with cancer relapses, and miR-34c, a p53 target induced by DNA damage, suggests the involvement of p53 pathway in field carcinogenesis. Down-regulated let-7b leads to higher expression of CYP2J2 and decreased miR-126 enhances adhesion, migration and invasion through increased Crk protein. Further gene expression and pathway analyses will corroborate the relationship between miRNAs and predicted pathways in real time. Conclusion: We discovered a profile of miRNAs in the contralateral lung of patients with lung cancer as biomarkers of field cancerization in smokers with lung adenocarcinoma. Further knowledge of field cancerization may lead to better understanding of tumorigenesis and development of biomarkers for early lung cancer detection

Introduction: Endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA) is utilized for the diagnosis and staging of mediastinal lesions. However, currently no consensus identifies the quantity of tissue or the number of immunhisotchemical (IHC) staining required for the processing of common molecular mutation profiles. In collaboration with out cytopathology department we developed and implemented a two-step protocol to optimize tissue sampling. First, we mandated two additional passes after a tissue specimen has been deemed diagnostic by rapid on-site cytopathologic examinations (ROSE). Second, the cytology department implemented a tissue-sparing algorithm proposed by Mukhopadhyay and Katzenstein to further characterize non-small cell lung cancer (NSCLC). The purpose of this study is to evaluate the effectiveness of the algorithm to yield adequate tissue for molecular mutation profiling. Methods: This retrospective study reviewed all patients who had undergone EBUS-TBNA at NYU Langone Medical Center from January 2009 to July 2012. The study identified patients with a diagnosis of lung adenocarcinoma or unclassifiable NSCLC. Excluded from this study were adenocarcinoma of non-lung origin and negative lymph nodes. For Each EBUS-TBNA sampling we documented patient's baseline characteristics, size and location of lymph nodes, number of needle passes, and the number of IHC stains. Analyses were also made to compare data before and after July 2011, when a new implemented two-step protocol took place. Results: 293 patients underwent EBUS-TBNA, and thirty-four patients were diagnosed with lung adenocarcinoma or NSCLC-NOS. Thirteen patients had molecular mutation testing completed. Prior to July 2011, 1/19 patients had molecular mutation profiles compared to 12/14 patients after July 2011. Several factors increased the success of the protocol, such as lymph node size and number of IHC stains. Average lymph node size for adequate tissue sampling was 25.1mm compared to 18.0mm (p value <0.05). Minimization of IHC staining was also significant. Specimens that yielded molecular profiles involved IHC staining limited to mean of 3.0 slides vs 5.4 slides (p value <0.05). Conclusion: The results of this study shows that utility of EBUS-TBNA to obtain molecular mutation profile is associated with lymph node size and IHC staining. The implementation of our algorithm significantly increased the number of patients with adequate tissue to complete molecular mutation profiles