Faculty Bibliography

Objective: Glycomics is an emerging area for understanding carcinogenesis; studies in glycobiology have documented that aberrant glycosylation accompanies malignant transformation. We have used glycomic profiling of serum using nano-liquid chromatography-mass spectrometry and using biostatistics we report glycomics patterns distinguishing between non-small cell lung cancer cases (NSCLC) versus healthy controls. Methods: First, we obtained pre-operative sera of non-small lung cancer cases (Stages I-II) and healthy controls from the NYU biorepository. The serum sample set consisted of 50 lung cancer (adenocarcinoma) patients, 50 healthy controls and 28 COPD patients, matched on gender, smoking status, pack/year for smokers, and as best as possible for age. The samples are analyzed by extracting the N-glycans in sera and measuring the relative concentrations using nano-liquid chromatography-mass spectrometry (nano-LC-MS). Bioinformatic analysis was performed to identify glycans that are differentially present in patients with cancer compared to COPD and healthy controls using feature selection and classification algorithms. We further investigated whether a combination of multiple glycans (i.e. multiplex classifier) could improve predictive performance over individual glycans. Results: Of 330 glycans detected in the NYU serum set, twenty glycans were significantly differentiating (either over- or under-expressed) between cancer, COPD and controls at a false discovery rate < 0.05. Of these glycan features, 11 were different between cancer samples and control samples, while 14 glycans differed significantly between cancer samples and COPD samples. COPD samples differed significantly from Control samples for only one glycan in concentration, indicating large similarity in the glycosylation pattern between COPD and controls. Based on the glycomic profiles, cancer cases were well separated from both control and COPD samples, while COPD and control samples were not discriminated well from each other. Th!

We have previously identified a putative tumor suppressor gene, NISCH, whose promoter is methylated in lung tumor tissue as well as in plasma obtained from lung cancer patients. NISCH was observed to be more frequently methylated in smoker lung cancer patients than in non-smoker lung cancer patients. Here, we investigated the effect of tobacco smoke exposure on methylation of the NISCH gene. We tested methylation of NISCH after oral keratinocytes were exposed to mainstream and side stream cigarette smoke extract in culture. Methylation of the promoter region of the NISCH gene was also evaluated in plasma obtained from lifetime non-smokers and light smokers (< 20 pack/year), with and without lung tumors, and heavy smokers (20+ pack/year) without disease. Promoter methylation of NISCH was tested by quantitative fluorogenic real-time PCR in all samples. Promoter methylation of NISCH occurred after exposure to mainstream tobacco smoke as well as to side stream tobacco smoke in normal oral keratinocyte cell lines. NISCH methylation was also detected in 68% of high-risk, heavy smokers without detectable tumors. Interestingly, in light smokers, NISCH methylation was present in 69% of patients with lung cancer and absent in those without disease. Our pilot study indicates that tobacco smoke induces methylation changes in the NISCH gene promoter before any detectable cancer. Methylation of the NISCH gene was also found in lung cancer patients' plasma samples. After confirming these findings in longitudinally collected plasma samples from high-risk populations (such as heavy smokers), examining patients for hypermethylation of the NISCH gene may aid in identifying those who should undergo additional screening for lung cancer.

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.