While the progression from early stage to middle stage LADC can be potentially induced by the hypoxic tumor microenvironment exposed to nicotine, the dysfunctions of IGF-1R, ITGB1 (CD29), and TNS1 signaling, the regulation of miR-106b, the epigenetic modifications of HIF1α, IGF-1, and ETS1, the DNA methylations of ITGB1, TNS1, and miR-21, and the dysregulation of cellular functions, such as lymphangiogenesis, cell migration, and ECM degradation. Here, HIF1A is linked to neoplasm.