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Tumor cell endogenous HIF-1α activity induces aberrant angiogenesis and interacts with TRAF6 pathway required for colorectal cancer development


Glaus Garzon, Jesus F; Pastrello, Chiara; Jurisica, Igor; Hottiger, Michael O; Wenger, Roland H; Borsig, Lubor (2020). Tumor cell endogenous HIF-1α activity induces aberrant angiogenesis and interacts with TRAF6 pathway required for colorectal cancer development. Neoplasia, 22(12):745-758.

Abstract

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-1 α, produce smaller and less hypoxic tumors in an orthotopic mouse model when compared to tumors induced with control cells. HIF-1 α- 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-1 α- KD tumors revealed an in increased vessel permeability and tumor hypoxia. Further bioinformatics analysis identified a possible interaction between HIF-1 αand TRAF6, an upstream effector of the NF- κB 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.

Abstract

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-1 α, produce smaller and less hypoxic tumors in an orthotopic mouse model when compared to tumors induced with control cells. HIF-1 α- 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-1 α- KD tumors revealed an in increased vessel permeability and tumor hypoxia. Further bioinformatics analysis identified a possible interaction between HIF-1 αand TRAF6, an upstream effector of the NF- κB 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Cancer Research
Language:English
Date:1 December 2020
Deposited On:27 Oct 2020 16:54
Last Modified:03 May 2021 15:25
Publisher:Neoplasia Press
ISSN:1476-5586
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.neo.2020.10.006
Project Information:
  • : FunderSNSF
  • : Grant IDPDFMP3_127315
  • : Project TitleInterplay between hypoxic and inflammatory pathways in colon cancer metastasis

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