Abstract
Functional imaging has become an important tool in oncology because it not only provides information about the size and localization of the tumour, but also about the pathophysiological features of the tumoural cells. One of the characteristic features of some tumour types is that their fast growth leads to deficient intratumoral vascularization, which results in low oxygen availability. To overcome this lack of oxygen, tumoural cells activate the neoangiogenic program by upregulating the transcription factor HIF-1α. Herein we report a non-invasive in vitro detection method of hypoxia using designed fluorescent peptide probes based on the oxygen-dependent degradation domain of HIF-1α. The fluorescent probe retains the oxygen-sensing capability of HIF-1α, so that it is stabilized under hypoxia and readily degraded by the proteasome under normoxia, thus providing direct information of the cellular oxygen availability.
Highlights
Some tumoural types tend to grow in a rapid and disorganized manner leading to poor intratumoral vascularization and low oxygen availability
The molecular mechanism underlying this stabilization was a subject of great discussion due to the dispute between different models, such as the occurrence of hypothetical O2-binding hemoproteins or oxidases interacting with HIF-115
HIF-1α is rapidly degraded in normoxic cells upon hydroxylation of two proline residues (Pro[402] and Pro564) located in its oxygen-dependent degradation domain (ODD domain)[16,17,18]
Summary
Some tumoural types tend to grow in a rapid and disorganized manner leading to poor intratumoral vascularization and low oxygen availability. We take advantage of what we learned from our previous genetically encodable protein sensors, and describe a compact sensor consisting on a fluorescently-labelled peptide, corresponding to a small fraction of the ODD domain of HIF-1α, that mimics the behaviour of HIF-1α under hypoxia conditions, making possible its application for the monitorization of hypoxic activity with potential clinical applicability.
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