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Title: Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene-induced lung tumors in aged mice

Author
item PARIKH, NEHA - Baylor College Of Medicine
item SHUCK, RYAN - Baylor College Of Medicine
item GAGEA, MIHAI - Md Anderson Cancer Center
item SHEN, LANLAN - Children'S Nutrition Research Center (CNRC)
item DONEHOWER, LAWRENCE - Baylor College Of Medicine

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/11/2017
Publication Date: 10/18/2017
Citation: Parikh, N., Shuck, R.L., Gagea, M., Shen, L., Donehower, L.A. 2017. Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene-induced lung tumors in aged mice. Aging Cell. http://dx.doi.org/10.1111/acel.12691.

Interpretive Summary: Lung cancer is the leading cause of cancer death worldwide. Every year, lung cancer causes more than 1.6 million deaths; more than breast, colon and prostate cancers combined. Clearly, there is a significant need for continued research into the mechanisms of lung cancer development, such that new therapies and treatments may be discovered. In this respect, our studies focus on the mechanisms by which aging increases lung tumor susceptibility. Using genetic engineering approaches and mouse models, we demonstrated that enhanced inflammation and epigenetic dysregulation of tumor suppressor contribute to the increased incidence of lung cancer in aged mice. It is well recognized that nutrition, inflammation and environmental factors play critical roles in the regulation of age-related epigenetic changes. Therefore, our results provides important mechanistic insights for future dietary studies to identify new and improved therapeutic interventions.

Technical Abstract: Aging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic KrasG12D was activated specifically in lungs of young (3-5 months) and old (19-24 months) mice. Activation of KrasG12D in old mice resulted in shorter survival and development of higher-grade lung tumors. Six weeks after KrasG12D activation, old lung tissues contained higher numbers of adenomas than their young tissue counterparts. Lung tumors in old mice displayed higher proliferation rates, as well as attenuated DNA damage and p53 tumor suppressor responses. Gene expression comparison of lung tumors from young and old mice revealed upregulation of extracellular matrix-related genes in young tumors, indicative of a robust cancer-associated fibroblast response. In old tumors, numerous inflammation-related genes such as Ccl7, IL-1B, Cxcr6, and IL-15ra were consistently upregulated. Increased numbers of immune cells were localized around the periphery of lung adenomas from old mice. Our experiments indicate that more aggressive lung tumor formation in older KrasG12D mice may be in part the result of subdued tumor suppressor and DNA damage responses, an enhanced inflammatory milieu, and a more accommodating tissue microenvironment.