title: Critical role of PPARγ in myeloid-derived suppressor cell-stimulated cancer cell proliferation and metastasis.
abstract: Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal-/-) mice directly stimulate cancer cell proliferation. PPARγ ligand treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro. In addition, PPARγ ligand treatment impaired lal-/- MDSCs transendothelial migration, and differentiation from lineage-negative cells. The corrective effects of PPARγ ligand on lal-/- MDSCs functions were mediated by regulating the mammalian target of rapamycin (mTOR) pathway, and subsequently blocking MDSCs ROS overproduction. Furthermore, in the myeloid-specific dominant-negative PPARγ (dnPPARγ) overexpression bitransgenic mouse model, tumor growth and metastasis were enhanced, and MDSCs from these mice stimulated tumor cell proliferation and migration. MDSCs with dnPPARγ overexpression showed increased transendothelial migration, overactivation of the mTOR pathway, and ROS overproduction. These results indicate that PPARγ plays a critical role in neutral lipid metabolic signaling controlled by LAL, which provides a mechanistic basis for clinically targeting MDSCs to reduce the risk of cancer proliferation, growth and metastasis.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D020022:Genetic Predisposition to Disease; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002787:Sterol Esterase / Q000172:deficiency / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration; D014162:Transfection; D047368:Tumor Burden
chemical_list: D000950:Antigens, Ly; D044243:Linoleic Acids, Conjugated; C480309:Ly6G antigen, mouse; D047495:PPAR gamma; D017382:Reactive Oxygen Species; C024347:9-hydroxy-10,12-octadecadienoic acid; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse
keywords: lipid metabolic signaling; lysosomal acid lipase; myeloid-derived suppressor cells; peroxisome proliferator-activated receptor-γ; tumor growth and metastasis