Low oxygen, high risk: How tumors adapt to become more aggressive

August 8, 2016, The Wistar Institute
cancer
Killer T cells surround a cancer cell. Credit: NIH

One of the many reasons tumors are so difficult to treat is that they are able to adapt whenever they are exposed to unfavorable conditions. Hypoxia, or a lack of oxygen, is one example of a phenomenon that should weaken the tumor, but instead, the malignant cells are able to compensate and drive more aggressive disease behavior.

Now, scientists at The Wistar Institute have identified a novel mechanism that selectively operates in hypoxic tumors to enable tumor cells to thrive and continue to proliferate despite a low oxygen environment. Dario C. Altieri, M.D., Wistar's President and CEO and lead author of the study, and colleagues showed how the activation of this pathway leads to an unfavorable prognosis for patients with gliomas—a type of brain tumor—and how the pathway could be a valuable therapeutic target in cancer. The findings were published in the journal Cancer Cell.

"Hypoxia is a nearly universal hallmark of aggressive tumor growth, and up until now, we really haven't been able to home in on a pathway responsible for this behavior," said Altieri, who is also director of The Wistar Institute Cancer Center and the Robert & Penny Fox Distinguished Professor. "Our study pinpoints a novel way in which tumor cells not only survive but actually continue to divide in spite of a low oxygen environment. In essence, this provides a much-needed answer for exactly how are able to get the energy they need to persist when faced with unfavorable conditions."

Mitochondria, known as the "powerhouse" of cells because of their role in energy production, are the main source of hypoxia-induced reprogramming in tumors. The Altieri lab showed that the protein Akt, which plays a key role in cell signaling and metabolism, accumulates in mitochondria during hypoxia. When this happens, the protein PDK1 is phosphorylated at a unique site, and a complex responsible for cellular respiration is shut down. The pathway then uses the tumor's metabolism to break down glucose and use its energy to reduce cell death and maintain proliferation.

The mitochondrial signaling between Akt and PDK1 was analyzed in a cohort of 116 patients with gliomas. The activation of this signaling pathway progressively increased in different types of gliomas, with the highest activity seen in patients with glioblastoma, a particularly difficult-to-treat form of brain cancer that represents approximately 15 percent of all brain tumors.

"We are excited about our results because there are drugs that exist that specifically target Akt in cancer. These drugs have produced limited clinical responses to date, but we believe with further investigation that we may be able to repurpose these drugs as a viable approach to impair a tumor's ability to adapt to hypoxia," said Young Chan Chae, Ph.D., an associate staff scientist in the Altieri lab and first author of the study.

Explore further: Mitochondria are exploited in cancer for tumor cell motility and metastatic competence

More information: Cancer Cell, DOI: 10.1016/j.ccell.2016.07.004

Related Stories

Mitochondria are exploited in cancer for tumor cell motility and metastatic competence

July 7, 2016
As the powerhouse of the cells, mitochondria are critical for every organism because of their role in producing energy while also controlling survival, but how they function in cancer is still not completely known. This is ...

Treatment with PI3K inhibitors may cause cancers to become more aggressive and metastatic

June 29, 2015
The enzyme phosphatidylinositol-3 kinase (PI3K) appears to be exploited in almost every type of human cancer, making it the focus of considerable interest as a therapeutic target, with many PI3K-inhibiting drugs currently ...

Signaling pathway suppresses brain tumors

December 4, 2015
Researchers at the University of Basel took a close look at a signaling pathway present in most organisms and found that it suppresses the formation of specific types of brain tumor. Their results have been published by the ...

Breast cancer cells use newfound pathway to survive low oxygen levels in tumors

June 20, 2016
Researchers have identified a new signaling pathway that helps cancer cells cope with the lack of oxygen found inside tumors. These are the results of a study published in Nature Cell Biology on June 20, and led by researchers ...

Study reveals how cancer cells thrive in oxygen-starved tumors

February 4, 2014
A new study identifies the molecular pathway that enables cancer cells to grow in areas of a tumor where oxygen levels are low, a condition called hypoxia.

'Rewired' mice show signs of longer lives with fewer age-related illnesses

July 31, 2014
While developing a new cancer drug, researchers at The Wistar Institute discovered that mice lacking a specific protein live longer lives with fewer age-related illnesses. The mice, which lack the TRAP-1 protein, demonstrated ...

Recommended for you

Single-cell study in a childhood brain tumor affirms the importance of context

April 20, 2018
In defining the cellular context of diffuse midline gliomas, researchers find the cells fueling their growth and suggest a potential approach to treating them: forcing their cells to be more mature.

Aggressive breast cancer already has resistant tumour cells prior to chemotherapy

April 20, 2018
Difficult to treat and aggressive "triple-negative" breast cancer is chemoresistant even before chemotherapy begins, a new study by researchers from Karolinska Institutet and the University of Texas MD Anderson Cancer Center ...

Mechanism that drives development of liver cancer brought on by non-alcoholic fatty liver disease discovered

April 19, 2018
A team of researchers from several institutions in China has found a mechanism that appears to drive the development of a type of liver cancer not caused by alcohol consumption. In their paper published in the journal Science ...

Discovery adds to evidence that some children are predisposed to develop leukemia

April 19, 2018
St. Jude Children's Research Hospital researchers have made a discovery that expands the list of genes to include when screening individuals for possible increased susceptibility to childhood leukemia. The finding is reported ...

Scientists identify 170 potential lung cancer drug targets using unique cellular library

April 19, 2018
After testing more than 200,000 chemical compounds, UT Southwestern's Simmons Cancer Center researchers have identified 170 chemicals that are potential candidates for development into drug therapies for lung cancer.

Chip-based blood test for multiple myeloma could make bone biopsies a relic of the past

April 19, 2018
The diagnosis and treatment of multiple myeloma, a cancer affecting plasma cells, traditionally forces patients to suffer through a painful bone biopsy. During that procedure, doctors insert a bone-biopsy needle through an ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.