PMID- 24882582
OWN - NLM
STAT- MEDLINE
DCOM- 20150622
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 15
DP  - 2015 Apr 9
TI  - Activation of mTOR pathway in myeloid-derived suppressor cells stimulates cancer 
      cell proliferation and metastasis in lal(-/-) mice.
PG  - 1938-48
LID - 10.1038/onc.2014.143 [doi]
AB  - 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-1beta and tumor necrosis factor-alpha 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.
FAU - Zhao, T
AU  - Zhao T
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN, USA.
FAU - Du, H
AU  - Du H
AD  - 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.
FAU - Ding, X
AU  - Ding X
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN, USA.
FAU - Walls, K
AU  - Walls K
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN, USA.
FAU - Yan, C
AU  - Yan C
AD  - 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.
LA  - eng
GR  - R01 CA138759/CA/NCI NIH HHS/United States
GR  - R01 HL087001/HL/NHLBI NIH HHS/United States
GR  - CA152099/CA/NCI NIH HHS/United States
GR  - CA138759/CA/NCI NIH HHS/United States
GR  - HL087001/HL/NHLBI NIH HHS/United States
GR  - R01 CA152099/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140602
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.1.13 (LIPA protein, human)
RN  - EC 3.1.1.13 (Sterol Esterase)
RN  - EC 3.1.1.13 (lysosomal acid lipase, mouse)
SB  - IM
MH  - Animals
MH  - Carcinoma, Lewis Lung/genetics/metabolism/pathology
MH  - Cell Proliferation
MH  - Coculture Techniques
MH  - Humans
MH  - Male
MH  - Melanoma, Experimental/enzymology/genetics/*metabolism/*pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Myeloid Cells/metabolism/pathology
MH  - Neoplasm Metastasis
MH  - Prostatic Neoplasms/genetics/metabolism/pathology
MH  - Signal Transduction
MH  - Sterol Esterase/biosynthesis/*deficiency/genetics
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Transfection
PMC - PMC4254377
MID - NIHMS583205
COIS- Conflict of interest The authors declare no conflict of interest.
EDAT- 2014/06/03 06:00
MHDA- 2015/06/24 06:00
PMCR- 2015/10/09
CRDT- 2014/06/03 06:00
PHST- 2013/10/15 00:00 [received]
PHST- 2014/03/06 00:00 [revised]
PHST- 2014/04/03 00:00 [accepted]
PHST- 2014/06/03 06:00 [entrez]
PHST- 2014/06/03 06:00 [pubmed]
PHST- 2015/06/24 06:00 [medline]
PHST- 2015/10/09 00:00 [pmc-release]
AID - onc2014143 [pii]
AID - 10.1038/onc.2014.143 [doi]
PST - ppublish
SO  - Oncogene. 2015 Apr 9;34(15):1938-48. doi: 10.1038/onc.2014.143. Epub 2014 Jun 2.