title: Myeloid-specific expression of Api6/AIM/Sp alpha induces systemic inflammation and adenocarcinoma in the lung.
abstract: 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.
authors.affiliation: Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Qu
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D005110:Extracellular Space / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D051116:Receptors, Scavenger
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011971:Receptors, Immunologic; C117272:Cd5l protein, mouse; D051017:Apoptosis Regulatory Proteins; D051116:Receptors, Scavenger