Hipoxia 2

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Hypoxia-inducible factors (HIFs)

Transcriptionfactors that facilitate oxygendelivery
and adaptation to oxygen deprivation by regulating
the expression of genes that are
involved in many cellular processes:
- glucose uptake and metabolism,
- angiogenesis,
- erythropoiesis,
- cell proliferation
- apoptosis.

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Hypoxia-inducible factors (HIFs)

HIF-1 has been designated the global

regulator of hypoxia-inducible gene
expression because it is ubiquitously
expressed and induces the expression
of most hypoxia inducible genes

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Hypoxia-inducible factors (HIFs)

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Hypoxia-inducible factors (HIFs)

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Important Roles of Hypoxia-Inducible

Factor in Tumors
The ability of tumor cells to adapt and survive
their growth inhibitory microenvironment is
accomplished in part by HIF activation.

HIFs have been found to promote key steps in

tumor progression,
angiogenesis,
metabolism,
metastasis.
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Tumor Angiogenesis
Unlike normal tissues where there is a balance
between proangiogenic and antiangiogenic factors,
tumors tip the balance toward proangiogenic factors.

Of all the proangiogenic factors induced by HIF, vascular

endothelial growth factor-A (VEGF-A) appears to be the
most critical:
- it has potent proangiogenic properties
- It is expressed in a large number of human tumors.

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Tumor Metabolism
Cancer cells shift glucose metabolism from an oxidative
to glycolytic pathway - Warburg effect. It is characterized
by decreased mitochondrial respiration and increased
lactate production even with oxygen.

Numerous studies have established that HIF-1

regulates the expression of genes involved in glycolytic
metabolism including glucose transporters,
glycolytic enzymes, lactate production.

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Tumor Metastasis
• Metastasis occurs in a series of distinct steps:
• include tumor cell invasion, intravasation,
extravasation and proliferation.

• HIF activation correlates with metastasis in multiple

tumors and promotes metastasis through the
regulation of key factors in:

• cell adhesion,
• extracellular matrix formation
• cell migration

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Hypoxia-Inducible Factor and

Radiotherapy
• HIF-1 plays an important role in determining tumor
response to radiotherapy and tumor regrowth.

• Radiation results in a reoxygenation-dependent

increase in HIF-1 activity by two distinct mechanisms

• Tumor reoxygenation results in both HIF-1 stabilization

and enhanced translation of HIF targets through the
release of reactive oxygen species

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Radiotherapy
• Effects of HIF on tumor radiosensitivity:
• HIF-1 stabilization promotes:

• Tumor vasculature radioresistance through the release of

proangiogenic cytokines such as VEGF.

• Paradoxically, HIF-1 can also induce tumor radiosensitivity

through the induction of apoptosis.

• Overall, HIF-1 stabilization promotes radioresistance

because HIF-1–deficient tumors are more sensitive to
radiation compared to wildtype tumors.

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