Activation of the Signal Transducers and Activators of the Transcription 3 Pathway in Alveolar Epithelial Cells Induces Inflammation and Adenocarcinomas in Mouse Lung

Abstract

The lung is an organ for host defense to clear up pathogens through innate and adaptive immunity. This process involves up-regulation of proinflammatory cytokines and chemokines that lead to activation of the signal transducers and activators of the transcription 3 (Stat3) signaling pathway. Overexpression of Stat3C in alveolar type II epithelial cells of CCSP-rtTA/ (tetO) 7 -Stat3C bitransgenic mice leads to severe pulmonary inflammation, including immune cell infiltration and upregulation of proinflammatory cytokines and chemokines in the lung. As a consequence, spontaneous lung bronchoalveolar adenocarcinoma was observed in bitransgenic mice. Aberrantly expressed genes in the bitransgenic model were identified and served as biomarkers for human bronchoalveolar adenocarcinoma. During tumorigenesis, genes that are critical to epithelial cell proliferation in lung development were reactivated. Therefore, Stat3 is a potent proinflammatory molecule that directly causes spontaneous lung cancer in vivo. [Cancer Res 2007;67(18):8494-503]

Signal Transducer and Activator of Transcription 3 (Stat3C) Promotes Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Lung Tumorigenesis

“…This concept has been directly proven in a CCSP-rtTA/(tetO) 7 -CMV-Stat3C bitransgenic mouse model in which persistent activation of the Stat3 pathway by overexpressing Stat3C in AT II epithelial cells leads to lung adenocarcinoma. 1 The formation of lung adenocarcinoma is a complex process that involves cancerous transformation of epithelial cells by reactivation of developmental programs, 23 introduction of mutations causing genetic instability, 24 and epigenetic changes. 25 Under normal physiological conditions, spontaneous cancerous transformation is constantly monitored by the immune surveillance system, which destroys any transformed cells that impose danger to the body.…”

“…*P Ͻ 0.05; **P Ͻ 0.01. of doxycycline treatment in bitransgenic mice, as we have reported previously. 1 Compared with doxycycline-untreated bitransgenic mice, the percentages of the CD11b ϩ Ly6G ϩ cell population were steadily increased in blood and lung of doxycycline-treated bitransgenic mice (Figure 2, A and B), but not in bone marrow and spleen. The absolute number of CD11b ϩ Ly6G ϩ cells was also significantly increased in lung of doxycycline-treated bitransgenic mice.…”

“…4 cytokines are up-regulated in AT II epithelial cells of bitransgenic mice at a very early stage (1 month of doxycycline treatment). 1 It is likely, therefore, that Stat3C-induced CD11b ϩ Gr-1 ϩ cell expansion is initiated by synthesis and secretion of these cytokines from AT II epithelial cells into BALF and blood.…”

“…1 The process is initiated by synthesis and induction of proinflammatory cytokines and chemokines in AT II epithelial cells, triggering heightened levels of inflammatory cell infiltration. Subsequent studies showed that persistent activation of Stat3 in AT II epithelial cells is a common phenomenon in inflammation-induced lung tumor animal models, as demonstrated by matrix metalloproteinase 12 (MMP12) and apoptosis inhibitor 6 (Api6) overexpression bitransgenic mouse models.…”

“…6 Persistent activation of the Stat3 pathway induces bronchioalveolar adenocarcinoma through both nonimmune and immune mechanisms in the CCSP-rtTA/(tetO) 7 -Stat3C bitransgenic mouse model. 1 The nonimmune mechanism involves reactivation of lung developmental genes to promote epithelial outgrowth. The immune mechanism is less clear.…”