PMID- 33142239
OWN - NLM
STAT- MEDLINE
DCOM- 20210816
LR  - 20210816
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 22
IP  - 12
DP  - 2020 Dec
TI  - Tumor cell endogenous HIF-1alpha activity induces aberrant angiogenesis and interacts 
      with TRAF6 pathway required for colorectal cancer development.
PG  - 745-758
LID - S1476-5586(20)30161-5 [pii]
LID - 10.1016/j.neo.2020.10.006 [doi]
AB  - Hypoxia and inflammation are key factors for colorectal cancer tumorigenesis. The 
      colonic epithelium belongs to the tissues with the lowest partial pressure of 
      oxygen in the body, and chronic inflammation is associated with an increased 
      chance to develop colon cancer. How the colonic epithelium responds to hypoxia 
      and inflammation during tumorigenesis remains to be elucidated. Here we show, 
      that murine colon adenocarcinoma cells with attenuated response to hypoxia, due 
      to a knock-down (KD) of HIF-1alpha, produce smaller and less hypoxic tumors in an 
      orthotopic mouse model when compared to tumors induced with control cells. 
      HIF-1alpha-KD tumors showed more functional perfused vasculature associated with 
      increased levels of vessel-stabilizing factors and reduced levels of 
      proangiogenic factors, including extracellular matrix protein Cyr61/CCN1. 
      Intratumoral injection of Cyr61 in HIF-1alpha-KD tumors revealed an in increased 
      vessel permeability and tumor hypoxia. Further bioinformatics analysis identified 
      a possible interaction between HIF-1alpha and TRAF6, an upstream effector of the 
      NF-kappaB pathway that was confirmed by coimmunoprecipitation in MC-38 and CT26 colon 
      adenocarcinoma cells and in situ by proximity ligation assay. Down-regulation of 
      TRAF6 resulted in virtual abrogation of orthotopic tumor growth. Subcutaneous 
      TRAF6-KD tumors were smaller and contained reduced vessel size and differently 
      polarized macrophages. These data demonstrate that the tumor cell response to 
      increased hypoxia in the colon leads to promotion of nonfunctional angiogenesis, 
      regulated by both hypoxia and TRAF6 pathways.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Glaus Garzon, Jesus F
AU  - Glaus Garzon JF
AD  - Institute of Physiology, University of Zurich, Zurich, Switzerland.
FAU - Pastrello, Chiara
AU  - Pastrello C
AD  - Krembil Research Institute, UHN, Toronto, ON, Canada.
FAU - Jurisica, Igor
AU  - Jurisica I
AD  - Krembil Research Institute, UHN, Toronto, ON, Canada; Departments of Medical 
      Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada.
FAU - Hottiger, Michael O
AU  - Hottiger MO
AD  - Department of Molecular Mechanism of Disease, University of Zurich, Zurich, 
      Switzerland.
FAU - Wenger, Roland H
AU  - Wenger RH
AD  - Institute of Physiology, University of Zurich, Zurich, Switzerland.
FAU - Borsig, Lubor
AU  - Borsig L
AD  - Institute of Physiology, University of Zurich, Zurich, Switzerland; Comprehensive 
      Cancer Center Zurich, Zurich, Switzerland. Electronic address: 
      lborsig@access.uzh.ch.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201024
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Inflammation Mediators)
RN  - 0 (NF-kappa B)
RN  - 0 (TNF Receptor-Associated Factor 6)
SB  - IM
MH  - Animals
MH  - Capillary Permeability
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Colorectal Neoplasms/*etiology/*metabolism/pathology
MH  - *Disease Susceptibility
MH  - Gene Knockdown Techniques
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Immunohistochemistry
MH  - Inflammation Mediators/metabolism
MH  - Mice
MH  - NF-kappa B/metabolism
MH  - Neovascularization, Pathologic/genetics/*metabolism
MH  - Protein Binding
MH  - TNF Receptor-Associated Factor 6/genetics/*metabolism
MH  - Tumor Microenvironment
PMC - PMC7588814
OTO - NOTNLM
OT  - Colorectal cancer
OT  - HIF-1alpha
OT  - Inflammation
OT  - TRAF6
OT  - Tumor hypoxia
OT  - Tumorigenesis
EDAT- 2020/11/04 06:00
MHDA- 2021/08/17 06:00
PMCR- 2020/10/24
CRDT- 2020/11/03 20:14
PHST- 2020/07/20 00:00 [received]
PHST- 2020/10/04 00:00 [revised]
PHST- 2020/10/04 00:00 [accepted]
PHST- 2020/11/04 06:00 [pubmed]
PHST- 2021/08/17 06:00 [medline]
PHST- 2020/11/03 20:14 [entrez]
PHST- 2020/10/24 00:00 [pmc-release]
AID - S1476-5586(20)30161-5 [pii]
AID - 10.1016/j.neo.2020.10.006 [doi]
PST - ppublish
SO  - Neoplasia. 2020 Dec;22(12):745-758. doi: 10.1016/j.neo.2020.10.006. Epub 2020 Oct 
      24.