Sunday, December 18, 2022

Oxygen's Role in Growth of Tumors Reconsidered

Good news! Cancer is history (soon)!

"... When tumors start running out of oxygen, they can switch on hypoxia-inducible factor (HIF-1alpha)—a transcription factor, which is a protein that controls the activity of genes. As a result of HIF-1alpha activation, the expression of hundreds of genes can change and dramatically alter the behavior of cancer cells. Although the increase in HIF-1alpha is thought to be steady, the new study ... discovered that the levels of this molecule can also repeatedly rise and fall in small groups of cells, particularly in areas of high cell density. The effects of this oscillation are profound, as it allows cancer cells starving for oxygen to resume division and growth. It can also promote pro-cancer genes and inhibit anti-cancer genes. ...
Cells displaying oscillatory behavior were detected using various fluorescent biosensors. Importantly, the researchers found that the oscillations in HIF-1alpha trigger certain genes within a cell. These oscillation-specific genes were rich in oncogenes, which promote cancer. At the same time, tumor suppressor genes went down. ..."

From the abstract:
"Response to hypoxia is a highly regulated process, but little is known about single-cell responses to hypoxic conditions. Using fluorescent reporters of hypoxia response factor-1α (HIF-1α) activity in various cancer cell lines and patient-derived cancer cells, we show that hypoxic responses in individual cancer cells can be highly dynamic and variable. These responses fall into three classes, including oscillatory activity. We identify a molecular mechanism that can account for all three response classes, implicating reactive-oxygen-species-dependent chaperone-mediated autophagy of HIF-1α in a subset of cells. Furthermore, we show that oscillatory response is modulated by the abundance of extracellular lactate in a quorum-sensing-like mechanism. We show that oscillatory HIF-1α activity rescues hypoxia-mediated inhibition of cell division and causes broad suppression of genes downregulated in cancers and activation of genes upregulated in many cancers, suggesting a mechanism for aggressive growth in a subset of hypoxic tumor cells."

With Discovery, Oxygen's Role in Growth of Tumors Reconsidered | Yale School of Engineering & Applied Science


Graphical abstract:


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