Cancer and stromal cells often have restricted access to nutrients and oxygen during tumor development and progression. Most solid tumors have regions permanently or transitorily subjected to hypoxia because of deviant vascularization and a poor blood supply. To meet oxygen demands, hypoxic cancer cells activate transcriptional, post-transcriptional and translational mechanism that leads to the generation of new blood vessels from pre-existing ones (angiogenesis) which is a prerequisite not only for Oxygen delivery, but also for tumor growth and metastasis.
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SIGNALING MECHANISM DRIVING ANGIOGENESIS IN HYPOXIC TUMOR MICRO-ENVIRONMENT
1. SIGNALING MECHANISM DRIVING ANGIOGENESIS IN HYPOXIC TUMOR MICRO-ENVIRONMENT
Minali Singh*
*Department of Biological Sciences, Birla Institute of Science and Technology-Pilani, Hyderabad Campus.
Hypoxic tumoral angiogenesis is a complex
cellular process controlled at the molecular level
by transcriptional activation through hypoxia-
inducible factor HIF which contains an oxygen-
sensitive HIF-α subunit along-with constitutively
expressed HIF-β subunit. This duo activates the
transcription of several target genes to adapt to
the hypoxic environment in human cancer cells.
HYPOXIA
Figure2: Activation of angiogenesis via various intermediates in VEGF signaling pathway.
Dark arrows represent stimulation and dotted arrows as multistep activation.
VEGF Receptor
Background: Studies have reported vascular endothelial growth factor (VEGF) as a leading
candidate causing tumor angiogenesis. It not only induces the proliferation, differentiation
and migration of vascular endothelial cells but also enhances their survival by preventing
apoptosis. The major attribute of angiogenesis is capillary sprouting and tube formation by
migrating endothelial cells. The expression of VEGF receptors: VEGFR-1 and VEGFR-2 are
up regulated by hypoxia. VEGFR-1 is directly up regulated by hypoxia, via a HIF binding
enhancer element located in the VEGFR-1 promoter, while the up regulation of VEGFR-2 by
hypoxia is mediated by post-transcriptional regulation. This data suggests that endothelial
cells have the capability to tightly regulate their hypoxic responses in coordination with
changes in the oxygenation of surrounding tissues.
Methodology:
1.To analyze the effect of HIF-1α null endothelial cells and VEGF null endothelial cells in
angiogenesis.
2. To determine the involvement of HIF-1α and its dependency on VEGF expression
induced by hypoxia; endothelial cells from wild type, HIF-1 α null and VEGF null were
isolated from conditionally deleted animals and cultured in vitro.
Results:
VEGF: The Leading
candidate!
HIF-1 α
Wild type VEGF null
20%
Oxygen
0.5%
Oxygen
Vascular endothelial growth factor (VEGF) is characterized as a major
contributor to tumor angiogenesis, was originally purified from tumor cell ascites
as vascular permeability factor (VPF), and also reported to have biological
effects on endothelial cell mitogenesis. Pro-angiogenic factors, for example,
VEGF, activate angiogenesis through the VEGF receptors (VEGFRs) and
ligands (Figure2)
The induction and progression of angiogenesis proceed in distinct steps during
tumor development can be observed through the mechanism of action of VEGF.
Once it is expressed it binds to its receptor (VEGFR) located on the surface of
endothelial cells. After binding it consequently activates the trans-membrane
tyrosine kinase receptors on the surface of the cell, which leads to dimerization,
auto-phosphorylation, and activation of the downstream signaling pathway. This
process is followed by the survival, proliferation, migration of the endothelial
cells, followed by inhibition of apoptosis, tube formation and sprouting which
eventually transforms into a developed network of new blood vessels.
Figure1: Images taken after phase-contrast microscopy. (Ref: Tang et al, 2004)
Mechanism of VEGF signaling
Studies have revealed that tumor cells produce
both pro and anti-angiogenic proteins that is
responsible for the activation and stimulation of
angiogenesis respectively. The switching on and
off depends on the level of transcription of genes
in tumors. The machinery is activated when there
is an increased level of pro-angiogenic factors
and reduced levels of anti-angiogeneic genes. For
the formation of new blood vessels, activation of
hypoxia and the HIF pathway is critical, since it
is responsible for the regulation and expression
of pro-angiogenic genes. These include VEGF
platelet-derived
angiopoietin-1,
i.e. a pro-angiogenic factor,
growth factor (PDGF)
angiopoietin-2 etc.
Cancer and stromal cells often have restricted access to nutrients and oxygen during tumor development and progression. Most solid tumors
have regions permanently or transitorily subjected to hypoxia because of deviant vascularization and a poor blood supply. Tomeet oxygen
demands, hypoxic cancer cells activate transcriptional, post-transcriptional and translational mechanism that leads to the generation of new
blood vessels from pre-existing ones (angiogenesis) which is a prerequisite not only for Oxygen delivery, but also for tumor growth and
metastasis.
Hypoxic tumoral angiogenesis Angiogeneic Targets of HIF! Angiogenic switch?
1. Schito L, Rey S. Hypoxia: Turning vessels into vassals of cancer immunotolerance.
Cancer Letters. 2020 May 26.
2. Chen L, Endler A, Shibasaki F. Hypoxia and angiogenesis: regulation of hypoxia-
inducible factors via novel binding factors. Experimental & molecular medicine. 2009
Dec;41(12):849-57.
3. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS.
Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop
necessary for tumorigenesis. Cancer cell. 2004 Nov 1;6(5):485-95.
References
Discussion
Tumors that starve blood/ oxygen supply stop proliferating and henceforth
undergo necrosis. The opposite happens in case of systemic circulation
which eventually leads to metastasis and thus spreading of cancer. The use
of anti-VEGF/ anti-angiogenesis therapies can be a potential foundation for
identifying drugs, drug targets, and also provide better understanding in
mechanisms involved in the impairment of tumor angiogenesis, growth,
and migration.
I would like to thank Dr. K Naga Mohan for his supervision and
guidance.
Acknowledgements
Editor's Notes
Cancer and stromal cells often have restricted access to nutrients and oxygen during tumor development and progression. Most solid tumors have regions permanently or transitorily subjected to hypoxia because of deviant vascularization and a poor blood supply. To meet oxygen demands, hypoxic cancer cells activate transcriptional, post-transcriptional and translational mechanism that leads to the generation of new blood vessels from pre-existing ones (angiogenesis) which is a prerequisite not only for Oxygen delivery, but also for tumor growth and metastasis.