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Endothelial hypoxic metabolism in carcinogenesis and dissemination: HIF-A isoforms are a NO metastatic phenomenon.

Branco-Price C, Evans CE, Johnson RS - Oncotarget (2013)

Bottom Line: Tumor biology is a broad and encompassing field of research, particularly given recent demonstrations of the multicellular nature of solid tumors, which have led to studies of molecular and metabolic intercellular interactions that regulate cancer progression.Here, we describe the interactions between endothelial HIF and NO during tumor growth and spread, and outline the effects of endothelial HIF/NO signalling on cancer progression.In doing so, we attempt to identify areas of metastasis research that require attention, in order to ultimately facilitate the development of novel treatments that reduce or prevent tumour dissemination.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.

ABSTRACT
Tumor biology is a broad and encompassing field of research, particularly given recent demonstrations of the multicellular nature of solid tumors, which have led to studies of molecular and metabolic intercellular interactions that regulate cancer progression. Hypoxia is a broad stimulus that results in activation of hypoxia inducible factors (HIFs). Downstream HIF targets include angiogenic factors (e.g. vascular endothelial growth factor, VEGF) and highly reactive molecules (e.g. nitric oxide, NO) that act as cell-specific switches with unique spatial and temporal effects on cancer progression. The effect of cell-specific responses to hypoxia on tumour progression and spread, as well as potential therapeutic strategies to target metastatic disease, are currently under active investigation. Vascular endothelial remodelling events at tumour and metastatic sites are responsive to hypoxia, HIF activation, and NO signalling. Here, we describe the interactions between endothelial HIF and NO during tumor growth and spread, and outline the effects of endothelial HIF/NO signalling on cancer progression. In doing so, we attempt to identify areas of metastasis research that require attention, in order to ultimately facilitate the development of novel treatments that reduce or prevent tumour dissemination.

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Related in: MedlinePlus

Filling the gaps in endothelial HIF-alpha, NO signalling and subsequent changes that can contribute to metastatic eventsAt the site of extravasation, endothelial HIF-1a or HIF-2a activation results in differential activation of iNOS, with direct influences on NO production. Hypoxia- and HIF-independent signals can also stimulate NO production, and the origin, concentration, and duration of NO may affect metastatic success. Downstream effects of endothelial HIF/NO signaling, such as endothelial permeability and endothelial cell-tumor cell adhesion, could be targeted to reduce or prevent extravasation.
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Figure 2: Filling the gaps in endothelial HIF-alpha, NO signalling and subsequent changes that can contribute to metastatic eventsAt the site of extravasation, endothelial HIF-1a or HIF-2a activation results in differential activation of iNOS, with direct influences on NO production. Hypoxia- and HIF-independent signals can also stimulate NO production, and the origin, concentration, and duration of NO may affect metastatic success. Downstream effects of endothelial HIF/NO signaling, such as endothelial permeability and endothelial cell-tumor cell adhesion, could be targeted to reduce or prevent extravasation.

Mentions: Key questions remain when characterizing the role of the vasculature in metastatic disease, e.g. what roles do EC-specific HIF and NO play during intravasation, and what cell-specific molecular signalling pathways regulate the extravasation and viability of colonizing cancer cells? Although mechanisms that regulate endothelial HIF/NO-mediated cancer progression are not fully understood, therapeutic or gene-mediated disruption of this signalling cascade could potentially reduce metastatic success (Figure 2).


Endothelial hypoxic metabolism in carcinogenesis and dissemination: HIF-A isoforms are a NO metastatic phenomenon.

Branco-Price C, Evans CE, Johnson RS - Oncotarget (2013)

Filling the gaps in endothelial HIF-alpha, NO signalling and subsequent changes that can contribute to metastatic eventsAt the site of extravasation, endothelial HIF-1a or HIF-2a activation results in differential activation of iNOS, with direct influences on NO production. Hypoxia- and HIF-independent signals can also stimulate NO production, and the origin, concentration, and duration of NO may affect metastatic success. Downstream effects of endothelial HIF/NO signaling, such as endothelial permeability and endothelial cell-tumor cell adhesion, could be targeted to reduce or prevent extravasation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926849&req=5

Figure 2: Filling the gaps in endothelial HIF-alpha, NO signalling and subsequent changes that can contribute to metastatic eventsAt the site of extravasation, endothelial HIF-1a or HIF-2a activation results in differential activation of iNOS, with direct influences on NO production. Hypoxia- and HIF-independent signals can also stimulate NO production, and the origin, concentration, and duration of NO may affect metastatic success. Downstream effects of endothelial HIF/NO signaling, such as endothelial permeability and endothelial cell-tumor cell adhesion, could be targeted to reduce or prevent extravasation.
Mentions: Key questions remain when characterizing the role of the vasculature in metastatic disease, e.g. what roles do EC-specific HIF and NO play during intravasation, and what cell-specific molecular signalling pathways regulate the extravasation and viability of colonizing cancer cells? Although mechanisms that regulate endothelial HIF/NO-mediated cancer progression are not fully understood, therapeutic or gene-mediated disruption of this signalling cascade could potentially reduce metastatic success (Figure 2).

Bottom Line: Tumor biology is a broad and encompassing field of research, particularly given recent demonstrations of the multicellular nature of solid tumors, which have led to studies of molecular and metabolic intercellular interactions that regulate cancer progression.Here, we describe the interactions between endothelial HIF and NO during tumor growth and spread, and outline the effects of endothelial HIF/NO signalling on cancer progression.In doing so, we attempt to identify areas of metastasis research that require attention, in order to ultimately facilitate the development of novel treatments that reduce or prevent tumour dissemination.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.

ABSTRACT
Tumor biology is a broad and encompassing field of research, particularly given recent demonstrations of the multicellular nature of solid tumors, which have led to studies of molecular and metabolic intercellular interactions that regulate cancer progression. Hypoxia is a broad stimulus that results in activation of hypoxia inducible factors (HIFs). Downstream HIF targets include angiogenic factors (e.g. vascular endothelial growth factor, VEGF) and highly reactive molecules (e.g. nitric oxide, NO) that act as cell-specific switches with unique spatial and temporal effects on cancer progression. The effect of cell-specific responses to hypoxia on tumour progression and spread, as well as potential therapeutic strategies to target metastatic disease, are currently under active investigation. Vascular endothelial remodelling events at tumour and metastatic sites are responsive to hypoxia, HIF activation, and NO signalling. Here, we describe the interactions between endothelial HIF and NO during tumor growth and spread, and outline the effects of endothelial HIF/NO signalling on cancer progression. In doing so, we attempt to identify areas of metastasis research that require attention, in order to ultimately facilitate the development of novel treatments that reduce or prevent tumour dissemination.

Show MeSH
Related in: MedlinePlus