The Aging Lung and Cancer: Evidence of Field Cancerization from Transcriptional Profiles of Normal Human and Mouse Lung Tissues

The effect of increased age on gene expression has not previously been evaluated in lung tissues. Cancer incidence increases with age, and lung cancer in particular has been found to have an incidence that peaks in the later decades of life. Based on previously published studies of aging effects in human muscle, kidney and retinal tissues, significant transcriptional changes are anticipated in both mouse and human aged lung tissues that may predispose to the development of cancer. We examined lung aging between young and old mice (6 vs. 30 months), using a hybrid mouse model (CB6F1) and an experimental colorectal metastasis model (CT26 cells). We also recruited young (<30 years) and aged (>60 years) human patients. Microarray analysis of mouse lung tissues using MOE430v2 and human lung tissues suing HG U133 2.0+ Affymetrix arrays was performed using total lung RNA, after which expression values were computed from .CEL files by applying RMA normalization within sets of replicate samples. Statistical testing was performed using the significance analysis of microarrays algorithm. Statistically significant transcripts were validated by histochemical staining and quantitative polymerase chain reactions (PCR). In mouse tissues, induced metastatic disease was found to be associated with reduced overall survival in older mice. The pattern of pulmonary metastases was more diffuse as compared to younger mice. Age-related transcriptional changes in the lung of extremely old hybrid mice were related to altered effectors of the immune system, regulators of angiogenesis and elements of DNA repair mechanisms, likely explaining the molecular basis behind the altered patterns of pulmonary metastasis observed in the extremely old mice. In human tissues, eighty-two genes were differentially expressed in a statistically significantly manner. Most genes were downregulated in aged lung tissue and included collagen isoforms and proteins responsible for extracellular matrix synthesis and turnover. A single upregulated transcript was a MYC binding protein. Selected transcripts were validated by PCR and histochemical staining. This is the first examination of lung metastases and the molecular biology of lung tissues at the extremes of age. Alterations to gene expression profiles was observed in both mouse and human lung tissues, and supports the concept of a field defect in normal lung tissues that develops with increased age