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

August 8, 2016
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

Scientists develop novel 'dot' system to improve cancer detection

August 24, 2017
Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have developed a proof-of-concept nanosystem that dramatically improves the visualization of tumors. Published today in Nature Communications, the platform ...

Study provides insight into link between two rare tumor syndromes

August 22, 2017
UCLA researchers have discovered that timing is everything when it comes to preventing a specific gene mutation in mice from developing rare and fast-growing cancerous tumors, which also affects young children. This mutation ...

Retaining one normal BRCA gene in breast, ovarian cancers influences patient survival

August 22, 2017
Determining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little ...

Study identifies miR122 target sites in liver cancer and links a gene to patient survival

August 22, 2017
A new study of a molecule that regulates liver-cell metabolism and suppresses liver-cancer development shows that the molecule interacts with thousands of genes in liver cells, and that when levels of the molecule go down, ...

Zebrafish larvae could be used as 'avatars' to optimize personalized treatment of cancer

August 21, 2017
Portuguese scientists have for the first time shown that the larvae of a tiny fish could one day become the preferred model for predicting, in advance, the response of human malignant tumors to the various therapeutic drugs ...

Scientists discover vitamin C regulates stem cell function, curbs leukemia development

August 21, 2017
Not much is known about stem cell metabolism, but a new study from the Children's Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then ...

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.