Inhibition of HIF Prolyl Hydroxylase-2 Blocks Tumor Growth in Mice through the Antiproliferative Activity of TGFβ

Ameln, Anne Klotzsche–von; Muschter, Antje; Mamlouk, Soulafa; Kalucka, Joanna; Prade, Ina; Franke, Kristin; Rezaei, Maryam; Poitz, David M.; Breier, Georg; Wielockx, Ben

doi:10.1158/0008-5472.can-10-3838

Cited by 68 publications

(56 citation statements)

References 42 publications

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“…The effect of Phd2 knockdown in cancer cells depends on the tumor histotype (Ameln et al, 2011;Andersen et al, 2011;Bordoli et al, 2011;Chan et al, 2009;Kamphues et al, 2012;Lee et al, 2008;Peurala et al, 2012;Su et al, 2012), while our data show a better disease outcome when the tumor stroma is insufficient for Phd2. To assess the effect of combined Phd2 inactivation in cancer cells and stromal cells, we subcutaneously injected scramble and Phd2-silenced LLC cells in R26;Phd2 +/+ and R26;Phd2 L/+ mice.…”

Section: Acute Loss Of One or Two Phd2 Alleles Enhances Chemotherapysupporting

confidence: 44%

Gene-Targeting of Phd2 Improves Tumor Response to Chemotherapy and Prevents Side-Toxicity

et al. 2012

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The success of chemotherapy in cancer treatment is limited by scarce drug delivery to the tumor and severe side-toxicity. Prolyl hydroxylase domain protein 2 (PHD2) is an oxygen/redox-sensitive enzyme that induces cellular adaptations to stress conditions. Reduced activity of PHD2 in endothelial cells normalizes tumor vessels and enhances perfusion. Here, we show that tumor vessel normalization by genetic inactivation of Phd2 increases the delivery of chemotherapeutics to the tumor and, hence, their antitumor and antimetastatic effect, regardless of combined inhibition of Phd2 in cancer cells. In response to chemotherapy-induced oxidative stress, pharmacological inhibition or genetic inactivation of Phd2 enhances a hypoxia-inducible transcription factor (HIF)-mediated detoxification program in healthy organs, which prevents oxidative damage, organ failure, and tissue demise. Altogether, our study discloses alternative strategies for chemotherapy optimization.

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Section: Acute Loss Of One or Two Phd2 Alleles Enhances Chemotherapysupporting

confidence: 44%

Gene-Targeting of Phd2 Improves Tumor Response to Chemotherapy and Prevents Side-Toxicity

et al. 2012

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“…This has also been underscored by recent work from our group showing that silencing of PHD2 in several tumor lines typically leads to reduced tumor growth. 39 In mice, we (K.F. and B.W., unpublished data, October 2011) and others 14 have shown that PHD2 heterozygosity only results in a very mild form of erythrocytosis whereas global inactivation just before or after birth leads to severe and lethal polycythemia.…”

Section: Discussionmentioning

confidence: 89%

HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis

Franke¹,

Kalucka

Mamlouk

et al. 2013

Blood

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Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2␣. In contrast, HIF-1␣ served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1␣ resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2␣-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2␣-dependent erythrocytosis, whereas HIF-1␣ protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia. (Blood.

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“…How PHD2 can be downregulated in some tumours whilst acting as an oncogene in others [40] remains unclear [41]. Mutations in PHD2 associated with increased risk of tumours have been reported [42] and epigenetic silencing has been proposed for PHD3 [43].…”

Section: Phd2 Integration Of Lactate-driven Angiogenesismentioning

confidence: 99%

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

2013

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Abstract. Polet F, Feron O (Universit e catholique de Louvain (UCL), Brussels, Belgium) Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force (Review). J Intern Med 2013; 273: 156-165.Angiogenic endothelial cells and tumour cells can survive under hypoxic conditions and even proliferate and migrate in a low-oxygen environment. In both cell types, high rates of glycolysis (i.e. conversion of glucose to lactate) and glutaminolysis provide most of the required biosynthetic intermediates and energy to support sprouting and cell division without coupling to oxidative phosphorylation. This metabolic preference is observed under hypoxic conditions, but also in situations in which oxygen is present. In the case of tumour cells, this is known as the Warburg effect and is largely governed by oncogenes. In endothelial cells lining tumour blood vessels, the option of respirationindependent metabolism allows the neovasculature to resist the hostile environment of fluctuating oxygen tension (ranging from severe hypoxia to quasi-normal levels of oxygen). In addition, accumulation in tumours of lactate, the end-product of glycolysis, largely contributes to the angiogenic phenotype through inhibition of prolyl hydroxylase 2 and the activation of HIF1a and NFjB. Activation of the latter in a hypoxia-independent manner leads to the increased production of interleukin-8/CXCL8 which drives the autocrine stimulation of endothelial cell proliferation and maturation of neovessels. In conclusion, the addiction of proliferating endothelial cells for glucose and glutamine as fuels and the driving force of lactate to promote angiogenesis provide novel potential treatment options without the disadvantages of conventional anti-angiogenic drugs.

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Inhibition of HIF Prolyl Hydroxylase-2 Blocks Tumor Growth in Mice through the Antiproliferative Activity of TGFβ

Cited by 68 publications

References 42 publications

Gene-Targeting of Phd2 Improves Tumor Response to Chemotherapy and Prevents Side-Toxicity

Gene-Targeting of Phd2 Improves Tumor Response to Chemotherapy and Prevents Side-Toxicity

HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

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