Myeloid-Specific Expression of Api6/AIM/Sp Induces Systemic Inflammation and Adenocarcinoma in the Lung

Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2009; 182(3):1648-59. DOI: 10.4049/jimmunol.182.3.1648
Source: PubMed


To study the functional role of apoptosis inhibition of myeloid lineage cells in tumor formation, apoptosis inhibitor 6 (Api6/AIM/Sp alpha) was overexpressed in a myeloid-specific c-fms-rtTA/(TetO)(7)-CMV-Api6 bitransgenic mouse model under the control of the c-fms promoter/intron 2. In this bitransgenic system, the Api6-Flag fusion protein was expressed in myeloid lineage cells after doxycycline treatment. Induction of Api6 abnormally elevated levels of macrophages, neutrophils, and dendritic cells in the bone marrow, blood, and lung in vivo. BrdU incorporation and annexin V binding studies showed systemically increased cell proliferation and inhibition of apoptosis in myeloid lineage cells. Api6 overexpression activated oncogenic signaling pathways, including Stat3, Erk1/2, and p38 in myeloid lineage cells in multiple organs of the bitransgenic mice. In the lung, severe inflammation and massive tissue remodeling were observed in association with increased expression of procancer cytokines/chemokines, decreased expression of proapoptosis molecule genes, and increased expression of matrix metalloproteinase genes as a result of Api6 overexpression. Oncogenic CD11b(+)/Gr-1(+) myeloid-derived suppressor cells were systemically increased. After Api6 overexpression, lung adenocarcinoma was observed in bitransgenic mice with a 35% incidence rate. These studies suggest that dysregulation of myeloid cell populations by extracellular Api6 signaling leads to abnormal myelopoiesis and lung cancer.

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    • "Interestingly, serum AIM increased with the progression of obesity in mice fed a high-fat diet (HFD) [31]. Other studies have suggested that AIM is multifunctional and effective in cell types other than macrophages, including B and natural killer T lymphocytes [33–35]. In addition, Lozano's group reported that AIM attaches to certain bacteria and induces their coagulation [36]. "
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    • "AIM has also been involved in atherosclerosis by facilitating MФ survival within atherosclerotic lesions [31]. Evidence of a potential pro-oncogenic role of mAIM arises from two studies in transgenic mice in which its overexpression induced lung adenocarcinoma [30,32]. More recently, it has been described that AIM is incorporated into adipocytes, thereby reducing the activity of cytosolic fatty acid synthase, which stimulates lipolysis, thus resulting in the induction of adipocyte inflammation in association with metabolic disorders subsequent to obesity [33–35]. "
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    • "There is an urgent need for identifying biomarkers that can be used to predict lung cancer occurrence. Recently, we demonstrated that both lung epithelial cell-initiated regional inflammation and myeloid cell-initiated systemic inflammation can induce spontaneous lung tumorigenesis in multiple lung tumor animal models [1], [2], [3], [4], [5], indicating that inflammatory molecules are potentially useful for lung cancer prediction. These inflammation-induced lung tumor animal models are ideal and valuable systems for identification and verification of lung cancer biomarkers. "
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