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

Abstract

SummaryAging 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 Kras G12D was activated specifically in lungs of young (3–5 months) and old (19–24 months) mice. Activation of Kras G12D in old mice resulted in shorter survival and development of higher‐grade lung tumors. Six weeks after Kras G12D 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‐1β, 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 Kras G12D 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.

The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells

“…Our observations are consistent with other age-related cancer models including breast, colon, liver (7,(33)(34)(35); however, there are also discrepancies, most likely related to the tumor cell of origin (36,37). For instance, tumor progression of Lewis lung cancer cells is substantially inhibited in 24-month-old C57BL/6 syngeneic mice compared with three younger age groups (36).…”

A human tissue‐specific transcriptomic analysis reveals a complex relationship between aging, cancer, and cellular senescence

“…One possible interpretation is that molecular changes during aging processes may oppose cancer development. Another potential interpretation for our results, from an evolutionary perspective, is that aging‐related changes in tissue microenvironment, leading to the decrease in tissue robustness, might provide a selective advantage for cells harboring oncogenic mutations (Henry, Marusyk, Zaberezhnyy, Adane, & DeGregori, ; Parikh, Shuck, Gagea, Shen, & Donehower, ). We note that the incidences of thyroid and uterine cancer are different from others, they plateau at an younger age than other cancers (de Magalhaes, ).…”

Decoy fitness peaks, tumor suppression, and aging

“…For this model, we incorporate a previously substantiated concept—that the fitness impact of mutations can be highly context‐dependent. In particular, previous studies have demonstrated that oncogenic mutations are differentially selected for in tissues of young and old mice, with adaptation promoted in the aged context (Henry et al, ; Henry, Marusyk, Zaberezhnyy, Adane, & DeGregori, ; Parikh, Shuck, Gagea, Shen, & Donehower, ; Rozhok, Salstrom, & DeGregori, ; Vas, Wandhoff, Dörr, Niebel, & Geiger, ). Young tissues are inherently tumor suppressive, as mutations (including oncogenic ones) that change phenotype should typically result in loss of the mutated clone from the progenitor cell pool (DeGregori, ).…”