APR 02, 2016 08:21 AM PDT

Cancer's Trick to Thriving in Low Oxygen

WRITTEN BY: Xuan Pham
Image credit: Pixabay.com
 

In cancer, scientists note a strange correlation: tumors that had low oxygen seemingly couldn’t cope and died off, but patients with these types of tumors fared the worst. A recent investigation by Johns Hopkins scientists shed light on this conundrum and could point to new therapeutic targets. As it turns out, cancer has a trick whereby it survives and thrives in low oxygen levels by adopting the same mechanisms used by embryonic stem cells.
 
Stem cells are those that have the capacity to divide indefinitely and differentiate into many types of cells in the body. These unique abilities are what make stem cells so attractive in regenerative medicine. But unfortunately, cancer cells have learned how to exploit this ability to enhance their own survival when oxygen is scarce.
 
Researchers have known that the oxygen content in tumors, particularly in breast tumor, is quite low at 1.4 percent, compared to the 9 percent in healthy tissues, and 21 percent in the atmosphere that we breathe. In these hypoxic (low oxygen) conditions, cells stimulate the increase of proteins known as HIFs (hypoxia-inducible factors), which then cause a cascade of other genes to be activated. The key gene from this cascade that’s used by cancer cells is NANOG, a quintessential pluripotency factor in stem cell reprogramming.
 
"Chemotherapy may kill more than 99 percent of the cancer cells in a tumor but fail to kill a small population of cancer stem cells that are responsible for subsequent cancer relapse and metastasis," said Gregg Semenza, the C. Michael Armstrong Professor of Medicine, a member of the Johns Hopkins Kimmel Cancer Center, and senior study author.
 
As such, the research team hypothesized that cancer cells in breast tumors survive in hypoxic conditions by using NANOG to revert to embryonic cell states. "The search has been intense to find these cells ‘Achilles heel.’ If we could get cancer stem cells to abandon their stem cell state, they would no longer have the power to keep repopulating tumors," Semenza added. Their suspicions about NANOG were confirmed, as they found that hypoxic conditions increased HIF proteins, which then led to increased NANOG mRNA transcript levels. 
 

 
Cells quiet NANOG expression and suppress their pluripotency states by adding a chemical methyl tag on the gene’s mRNA transcript – a process known as methylation. If NANOG expression is lowered, cells could be forced to abandon their stem cell states and differentiate into other mature cells, potentially those more susceptible to low oxygen conditions.
 
To test this idea, the researchers honed in on another gene, ALKBH5, which acts to decrease methylation of NANOG transcripts, and thus increase NANOG expression. In cell experiments that block ALKBH5’s expression, the team found reduced NANOG levels due to methylation and a subsequent decrease in the number of cancer stem cells. Conversely, they reported increased NANOG levels and more breast cancer stem cells when ALKBH5 levels grew.
 
Taking their results to mice that were injected with 1,000 triple-negative breast cancer cells, the team noticed the same promising trend. That is, mice injected with cells missing ALKBH5 had reduced incidence of tumor growth; 43 percent of mice showed tumor growth. In contrast, all mice injected with unaltered breast cancer cells had tumor growth. "That confirmed for us that ALKBH5 helps preserve cancer stem cells and their tumor-forming abilities," said Semenza.
 
In the next phase, the research team plans to investigate whether the stem cell mechanisms also affect metastasis. They also aim to find other proteins involved in this pathway, which will perhaps point to new therapeutic avenues for breast cancer treatment. "There are still many questions left to answer but we now know that oxygen poor environments, like those often found in advanced human breast cancers serve as nurseries for the birth of cancer stem cells," said Semenza. "That gives us a few more possible targets for drugs that diminish their threat in human cancer."

Additional source: Hopkins Medicine press release

About the Author
  • I am a human geneticist, passionate about telling stories to make science more engaging and approachable. Find more of my writing at the Hopkins BioMedical Odyssey blog and at TheGeneTwist.com.
You May Also Like
NOV 14, 2018
Cancer
NOV 14, 2018
How Cancer's 'Invisibility Cloak' Works
One of cancer’s cunning strategies to evade death is to make itself invisible to the immune system. Now researchers say they’ve identified the...
AUG 07, 2018
Cancer
AUG 07, 2018
Is There a Best Time of Day to Administer Chemo?
A common hematologic cancer chemotherapy agent is looked at for its efficacy on solid tumors and specifically evaluates if delivery time during the day affects is anti-tumor activity....
AUG 07, 2018
Cancer
AUG 07, 2018
Can a Myeloid Marker Be Helpful in B-cell Neoplasm Diagnostic Testing?
A group of US researchers have identified CD13 in certain subtypes of B-cell neoplasms, thereby aiding in a more detailed diagnosis....
AUG 14, 2018
Cancer
AUG 14, 2018
Can Zika Virus Help Neuroblastoma Patients?
Researchers in Florida published the potential for Zika virus to help in the treatment of Neuroblastoma in patients of all ages....
NOV 06, 2018
Genetics & Genomics
NOV 06, 2018
New Gene is Implicated in a Rare Cancer
Rodents are known as common research models, but zebrafish have been gaining ground as an attractive alternative for many reasons....
DEC 04, 2018
Drug Discovery
DEC 04, 2018
Drug Combination May Be Effective for Melanoma
Protein kinase inhibitors have been noted to be the most effective class of drugs in the treatment of melanoma—a deadly skin cancer of the melanocyte...
Loading Comments...