Role of hypoxia in the hallmarks of human cancer

Ruan, Kai; Song, Gang; Ouyang, Gaoliang

doi:10.1002/jcb.22214

Cited by 426 publications

(375 citation statements)

References 122 publications

(138 reference statements)

Supporting

Mentioning

365

Contrasting

Order By: Relevance

“…Several previous studies have indicated an impact of the oxygen concentration on cell migration, especially in the context of tumor cell metastasis (42,43). The molecular link and the signaling pathways involved, however, are not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Prolyl Hydroxylase Domain (PHD) 2 Affects Cell Migration and F-actin Formation via RhoA/Rho-associated Kinase-dependent Cofilin Phosphorylation

Vogel

Wottawa

Farhat

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cells are responding to hypoxia via prolyl-4-hydroxylase domain (PHD) enzymes, which are responsible for oxygen-dependent hydroxylation of the hypoxia-inducible factor (HIF)-1␣ subunit. To gain further insight into PHD function, we generated knockdown cell models for the PHD2 isoform, which is the main isoform regulating HIF-1␣ hydroxylation and thus stability in normoxia. Induction of a PHD2 knockdown in tetracycline-inducible HeLa PHD2 knockdown cells resulted in increased F-actin formation as detected by phalloidin staining. A similar effect could be observed in the stably transfected PHD2 knockdown cell clones 1B6 and 3B7. F-actin is at least in part responsible for shaping cell morphology as well as regulating cell migration. Cell migration was impaired significantly as a consequence of PHD2 knockdown in a scratch assay. Mechanistically, PHD2 knockdown resulted in activation of the RhoA (Ras homolog gene family member A)/Rho-associated kinase pathway with subsequent phosphorylation of cofilin. Because cofilin phosphorylation impairs its actin-severing function, this may explain the F-actin phenotype, thereby providing a functional link between PHD2-dependent signaling and cell motility.

show abstract

Section: Discussionmentioning

confidence: 99%

Prolyl Hydroxylase Domain (PHD) 2 Affects Cell Migration and F-actin Formation via RhoA/Rho-associated Kinase-dependent Cofilin Phosphorylation

Vogel

Wottawa

Farhat

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Tumour hypoxia is an important marker of cancer prognosis, being associated with aggressive growth, metastasis, and resistance to anticancer therapy [1]. Noninvasive PET imaging with hypoxia-specific 2-nitroimidazoles has the ability to quantify tumour hypoxia and could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers [2].…”

Section: Introductionmentioning

confidence: 99%

PET imaging of hypoxia using [18F]HX4: a phase I trial

Loon

Janssen

Öllers

et al. 2010

Eur J Nucl Med Mol Imaging

View full text Add to dashboard Cite

Background and purpose Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [ 18 F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging. Methods Patients with a histologically proven solid cancer without curative treatment options were eligible for this study. A study design with two dose steps was used in which a single dose of a maximum of 222 MBq (step 1) or 444 MBq (step 2) [ 18 F]HX4 was injected. Toxicity was scored on day 0 and on days 3 and 7 after injection, according to the CTCAE 3.0 scoring system. PET/CT images of the largest tumour site were acquired 30, 60 and 120 min after injection. Results Six patients with stage IV carcinoma were included, four with non-small-cell lung carcinoma, one with thymus carcinoma, and one with colon carcinoma. No toxicity was observed in any of the patients at either dose level. The median tumour to muscle ratio 120 min after injection was 1.40 (range 0.63-1.98). Conclusion The findings of this study showed that [ 18 F] HX4 PET imaging for the detection of hypoxia is not associated with any toxicity. Imaging was successful; however, future trials are needed to determine the optimal image parameters.

show abstract

“…2). Hypoxic conditions in tumors stimulate the expression of proangiogenic molecules by activating hypoxia-inducible factors (HIFs) in macrophages [19,[50][51][52][53][54][55][56][57][58]. Activated macrophages also release nitric oxide (NO), a molecule that provokes increased vascular flow [46,[59][60][61][62][63][64].…”

Section: Angiogenesis Hypoxia and Oxygen Regulationmentioning

confidence: 99%

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

Schwendener¹,

Mete²

2013

Frontiers in Clinical Drug Research - Anti-Cancer Agents

View full text Add to dashboard Cite

Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed. lt;/pgt;lt;pgt; This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed. This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.

show abstract

Role of hypoxia in the hallmarks of human cancer

Cited by 426 publications

References 122 publications

Prolyl Hydroxylase Domain (PHD) 2 Affects Cell Migration and F-actin Formation via RhoA/Rho-associated Kinase-dependent Cofilin Phosphorylation

Prolyl Hydroxylase Domain (PHD) 2 Affects Cell Migration and F-actin Formation via RhoA/Rho-associated Kinase-dependent Cofilin Phosphorylation

PET imaging of hypoxia using [18F]HX4: a phase I trial

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

Contact Info

Product

Resources

About