PMID- 30620384
OWN - NLM
STAT- In-Data-Review
LR  - 20190401
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Linking)
VI  - 125
IP  - 8
DP  - 2019 Apr 15
TI  - The role of vascular endothelial growth factor, interleukin 8, and insulinlike
      growth factor in sustaining autophagic DIRAS3-induced dormant ovarian cancer
      xenografts.
PG  - 1267-1280
LID - 10.1002/cncr.31935 [doi]
AB  - BACKGROUND: Re-expression of the imprinted tumor suppressor gene DIRAS family
      GTPase 3 (DIRAS3) (aplysia ras homology member I [ARHI]) induces autophagy and
      tumor dormancy in ovarian cancer xenografts, but drives autophagic cancer cell
      death in cell culture. The current study explored the tumor and host factors
      required to prevent autophagic cancer cell death in xenografts and the use of
      antibodies against those factors or their receptors to eliminate dormant
      autophagic ovarian cancer cells. METHODS: Survival factors (insulinlike growth
      factor 1 [IGF-1], vascular endothelial growth factor [VEGF], and interleukin 8
      [IL-8]) were detected with growth factor arrays and measured using enzyme-linked 
      immunoadsorbent assay analysis. Phosphorylation of protein kinase B (AKT),
      phosphorylation of extracellular signal-regulated kinase (ERK), nuclear
      localization of translocation factor EB (TFEB) or forkhead box O3a (FOXo3a), and 
      expression of microtubule-associated proteins 1A/1B light chain 3B (MAPLC3B;
      LC3B) were examined using Western blot analysis. The effect of treatment with
      antibodies against survival factors or their receptors was studied using
      DIRAS3-induced dormant xenograft models. RESULTS: Ovarian cancer cells grown
      subcutaneously in nude mice exhibited higher levels of phosphorylated ERK/AKT
      activity and lower levels of nuclear TFEB/FOXo3a, MAPLC3B, and autophagy compared
      with cells grown in culture. Induction of autophagy and dormancy with DIRAS3 was 
      associated with decreased ERK/AKT signaling. The addition of VEGF, IGF-1, and
      IL-8 weakened the inhibitory effect of DIRAS3 on ERK/AKT activity and reduced
      DIRAS3-mediated TFEB or FOXo3a nuclear localization and MAPLC3B expression in
      ovarian cancer cells. Treatment with antibodies against VEGF, IL-8, and IGF
      receptor inhibited the growth of dormant xenografts, thereby prolonging survival 
      from 99 to >220 days (P < .05) and curing a percentage of mice. CONCLUSIONS:
      Treatment with a combination of anti-VEGF, anti-IL-8, and anti-IGF receptor
      antibodies prevented the outgrowth of dormant cells and prolonged survival in a
      preclinical model.
CI  - (c) 2019 American Cancer Society.
FAU - Mao, Weiqun
AU  - Mao W
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Peters, Haley L
AU  - Peters HL
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Sutton, Margie N
AU  - Sutton MN
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Orozco, Aaron F
AU  - Orozco AF
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Pang, Lan
AU  - Pang L
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Yang, Hailing
AU  - Yang H
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Lu, Zhen
AU  - Lu Z
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Bast, Robert C Jr
AU  - Bast RC Jr
AUID- ORCID: https://orcid.org/0000-0003-4621-8462
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
LA  - eng
GR  - R01 CA135354/National Cancer Institute
GR  - RP110595-P1/Cancer Prevention and Research Institute of Texas
GR  - NCI P50 CA83639/The University of Texas MD Anderson Cancer Center SPORE
GR  - NCI P50 CA217685/The University of Texas MD Anderson Cancer Center SPORE
GR  - NCI P30 CA16672/Shared Resources of The University of Texas MD Anderson Cancer
      Center Cancer Center Support
GR  - National Foundation for Cancer Research
GR  - Stuart and Gaye-Lynn Zarrow
GR  - Mossy Foundation
GR  - RP170067/Cancer Prevention Research Institute of Texas Research Training Program
GR  - R01 CA135354/National Cancer Institute (NCI)
GR  - NCI P50 CA83639/The University of Texas MD Anderson Cancer Center SPORE Grants in
      Ovarian Cancer
GR  - P50 CA217685/BC/NCI NIH HHS/United States
GR  - NCI P30 CA16672/The University of Texas MD Anderson Cancer Center
GR  - The National Foundation for Cancer Research
PT  - Journal Article
DEP - 20190108
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
OTO - NOTNLM
OT  - autophagy
OT  - insulinlike growth factor receptor (IGF-R)
OT  - interleukin 8 (IL-8)
OT  - ovarian cancer
OT  - tumor dormancy
OT  - vascular endothelial growth factor (VEGF)
EDAT- 2019/01/09 06:00
MHDA- 2019/01/09 06:00
CRDT- 2019/01/09 06:00
PHST- 2018/07/09 00:00 [received]
PHST- 2018/11/13 00:00 [revised]
PHST- 2018/11/14 00:00 [accepted]
PHST- 2019/01/09 06:00 [pubmed]
PHST- 2019/01/09 06:00 [medline]
PHST- 2019/01/09 06:00 [entrez]
AID - 10.1002/cncr.31935 [doi]
PST - ppublish
SO  - Cancer. 2019 Apr 15;125(8):1267-1280. doi: 10.1002/cncr.31935. Epub 2019 Jan 8.