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Tumor Hypoxia: A Key to Drug Resistance and Metastasis

Stromal tumor.

Cancerous tumors are resilient. With the ability to survive hypoxic—low oxygen—environments that would kill normal tissue, malignancies are able to resist treatment and metastasize. Little has been known about the molecular hallmarks of tumor hypoxia. Researchers have now made significant progress in this area, identifying markers and characteristics that are shared by various hypoxic tumor types.

In these experiments, published in Nature Genetics, 8,000 tumors belonging to 19 different cancer types, were analyzed for hypoxic conditions. In 10 of the 19 hypoxic tumor types, elevated genomic instability—increased tendency toward genome alteration during cell division—was found. Genomic instability is a common feature of cancer cells, and it allows for tumor growth.

In addition, the researchers discovered that hypoxic tumors all share common markers, including characteristic driver-mutation signatures, regardless of cancer type. These markers can help to predict cancer severity and metastasis potential, both of which can be used to determine the best treatment options for patients.

"If we look at any single aspect of cancer, we only gain a partial understanding of this complex disease. But here we've exploited a wealth of human tumor data to gain a more comprehensive understanding," stated the study's lead author, Vinayak Bhandari, PhD candidate at the University of Toronto and researcher at the Ontario Institute for Cancer Research. "By tying together our new understanding of the environment in which tumors develop with detailed evaluation of genetic changes, we created a biological signature that highlights patients who may benefit from more therapy."

Using this research as a foundation, investigators can develop criteria necessary for treatments targeting hypoxia-induced drug resistance and metastasis.

"Hypoxia was previously associated with aggressive disease, but the mechanisms by which it drives this process in human tumors was poorly understood from a genetic angle," remarked the study's senior author, Robert Bristow, MD, PhD, Professor of Cancer Studies, and Director of the Manchester Cancer Research and CRUK Manchester Centres at the University of Manchester."We can now start to exploit these findings into novel clinical trials to target hypoxia and abnormal genetics at the same time."

For More Information

Bhandari V, Hoey C, Liu LY, et al (2019). Molecular landmarks of tumor hypoxia across cancer types. Nat Genet. [Epub ahead of print] DOI:10.1038/s41588-018-0318-2

Image courtesy of CoRus13

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