Hypoxia‐inducible factors as key regulators of tumor inflammation

Mamlouk, Soulafa; Wielockx, Ben

doi:10.1002/ijc.27901

Cited by 58 publications

(50 citation statements)

References 140 publications

(245 reference statements)

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“…Further elucidation of these and other signatures should improve personalized therapeutic efficacy (26). Nutrient deprivation (SW) and hypoxia are also common features of tumors and are important when considering the regulation of inflammatory proteins associated with poor survival (31,32). Hypoxia increases NOS2 and COX2 mRNA in MDA-MB-231 (16) and NOS2 mRNA in MCF-7 cells (15).…”

Section: Discussionmentioning

confidence: 99%

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Heinecke¹,

Ridnour²,

Cheng³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

151

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Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance our mechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER − and ER + breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-γ, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase-1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB-231 tumor xenographs and cell metastases from the fat pad to the brain were significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.I nflammation is a major component of the tumor microenvironment and a driving force in cancer initiation, promotion, and progression (1-3). Epithelial cancers express markers of inflammation that promote disease progression and drug resistance through evasion of cell death pathways and increased tumor metastasis. Rapid cancer growth leads to tumor hypoxia and nutrient deprivation, which promotes chronic inflammatory feed-forward signaling and selection of resistant tumors that are clinically challenging and sometimes untreatable.Several proinflammatory proteins such as COX2, NF-κB, IL-6, IL-8, S100 calcium binding protein A8 (S100A8), and VEGF are markers of chronic inflammation in the tumor microenvironment. In addition, these proinflammatory mediators directly correlate with inducible nitric oxide synthase (NOS2), which is an emerging biomarker of aggressive tumors that predicts poor survival in patients with elevated tumor NOS2 expression (4-8). These and other clinical studies warrant an improved mechanistic understanding of intratumoral NOS2 regulation and endogenous NO production, which may be therapeutically beneficial.Toward this end, our laboratory and others have used NO donors to study NO signaling in cancer. However, intratumoral NOS2 induction by components of the tumor microenv...

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Section: Discussionmentioning

confidence: 99%

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Heinecke¹,

Ridnour²,

Cheng³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

151

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“…HIF1α activation in T-cells is associated with a detrimental effect during cancer, as this outcome has been negatively correlated with T-cell receptor signal transduction 107. Regulatory T-cells are able to suppress the functions of the antitumor cytotoxic T-cells, allowing further development of the tumor 107,111.…”

Section: The Role Of Phd2 In Pathologymentioning

confidence: 99%

PHD2: from hypoxia regulation to disease progression

Meneses¹,

Wielockx²

2016

Self Cite

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Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential.

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“…Moreover, activation of TNFα, IFN and hypoxia pathways could cause resistance of cancer cells to chemotherapy and radiotherapy. 31,32,48 Therefore, activation of the EGFR pathway, with the cooperation of several other pathways, as indicated in the 7-pathway pattern, is more likely to cause resistance of BRAF-mutated melanoma cells to the BRAF/MEK inhibitors than EGFR pathway activation alone. Further studies to experimentally test this hypothesis may shed new light on the treatment of melanomas that are resistant to BRAF/MEK inhibitors.…”

Section: Association Between the 7-pathway Pattern And The Response Omentioning

confidence: 99%

Activities of multiple cancer-related pathways are associated withBRAFmutation and predict the resistance to BRAF/MEK inhibitors in melanoma cells

Liu

Xing

2013

Cell Cycle

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Hypoxia‐inducible factors as key regulators of tumor inflammation

Cited by 58 publications

References 140 publications

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

PHD2: from hypoxia regulation to disease progression

Activities of multiple cancer-related pathways are associated withBRAFmutation and predict the resistance to BRAF/MEK inhibitors in melanoma cells

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