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Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development


Mamlouk, Soulafa; Kalucka, Joanna; Singh, Rashim Pal; Franke, Kristin; Muschter, Antje; Langer, Anika; Jakob, Christiane; Gassmann, Max; Baretton, Gustavo B; Wielockx, Ben (2014). Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development. International Journal of Cancer, 134(4):849-858.

Abstract

The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase 2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In the current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall down regulation of pro- as well as anti-tumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future. © 2013 Wiley Periodicals, Inc.

Abstract

The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase 2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In the current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall down regulation of pro- as well as anti-tumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future. © 2013 Wiley Periodicals, Inc.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2014
Deposited On:08 Aug 2013 13:20
Last Modified:05 Apr 2016 16:53
Publisher:Wiley-Blackwell
ISSN:0020-7136
Publisher DOI:https://doi.org/10.1002/ijc.28409
PubMed ID:23913502

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