title: Activation of mTOR pathway in myeloid-derived suppressor cells stimulates cancer cell proliferation and metastasis in lal(-/-) mice.
abstract: Inflammation critically contributes to cancer metastasis, in which myeloid-derived suppressor cells (MDSCs) are an important participant. Although MDSCs are known to suppress immune surveillance, their roles in directly stimulating cancer cell proliferation and metastasis currently remain unclear. Lysosomal acid lipase (LAL) deficiency causes systemic expansion and infiltration of MDSCs in multiple organs and subsequent inflammation. In the LAL-deficient (lal(-/-)) mouse model, melanoma metastasized massively in allogeneic lal(-/-) mice, which was suppressed in allogeneic lal(+/+) mice owing to immune rejection. Here we report for the first time that MDSCs from lal(-/-) mice directly stimulated B16 melanoma cell in vitro proliferation and in vivo growth and metastasis. Cytokines, that is, interleukin-1β and tumor necrosis factor-α from MDSCs are required for B16 melanoma cell proliferation in vitro. Myeloid-specific expression of human LAL (hLAL) in lal(-/-) mice rescues these malignant phenotypes in vitro and in vivo. The tumor-promoting function of lal(-/-) MDSCs is mediated, at least in part, through overactivation of the mammalian target of rapamycin (mTOR) pathway. Knockdown of mTOR, Raptor or Rictor in lal(-/-) MDSCs suppressed their stimulation on proliferation of cancer cells, including B16 melanoma, Lewis lung carcinoma and transgenic mouse prostate cancer-C2 cancer cells. Our results indicate that LAL has a critical role in regulating MDSCs' ability to directly stimulate cancer cell proliferation and overcome immune rejection of cancer metastasis in allogeneic mice through modulation of the mTOR pathway, which provides a mechanistic basis for targeting MDSCs to reduce the risk of cancer metastasis. Therefore MDSCs possess dual functions to facilitate cancer metastasis: suppress immune surveillance and stimulate cancer cell proliferation and growth.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: T
authors.initials: T
authors.lastname: Zhao
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA [2] IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Walls
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA [2] IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA [3] Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D018920:Coculture Techniques; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D002787:Sterol Esterase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C503451:LIPA protein, human; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse