De-stressing stem cells and the Bonnie & Clyde of stem cells

Dr. John Cashman

The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.

Researchers at the Human BioMolecular Research Institute (HBRI) and Stanford University, have reported on a compound that can trigger a cascade of events that create stress and ultimately impact Wnt’s ability to control the ability of cells to repair themselves.

In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”

The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.

“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Speaking of cancer….

Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.

In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.

In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”

So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.

They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.

The study is published in the journal Cell Reports.

One thought on “De-stressing stem cells and the Bonnie & Clyde of stem cells

  1. De-stressing Stem Cells Wnt signaling pathways play important roles in human carcinogenesis and embryonic development. During the embryonic processes, wnt signalling control body axis repatterning, cell fate specifications, cell proliferation and migration. The response of signaling is essential to control proper formation of tissues including bone, heart and muscle. The dysregulation of wnt signalling produces abnormal protein and triggers formation of cancers.

    Recent investigation showed that stress in cell is not only blocking wnt signalling but also preventing cell from migration, replication, differentiation and healing damage tissue. Stress of cells can induce the production of heat shock proteins (HSPs). In response to environmental, physical and chemical stresses, production of cellular HSPs can limit the consequences of cell damaged and facilitate cellular recovery. Therefore, HSPs can promote self-assembly of newly synthesis proteins, transportation through membranes and participation in signal transduction. Evidence proved that HSPs modulated apoptotic signaling cascade to help sustainable of cell survival following damaging stimuli. In contrast, HSPs had been found overexpressed in a wide range of human cancers and implicated in tumor cell proliferation, differentiation, invasion, metastasis, death and recognition by immune system. However, the modulation of HSPs in stress signalling cascade cause negative impacts in wnt signaling and transcriptional activation of cells. Thus, current research identified that PAWI-1 and PAWI-2 are able to modulate stress signalling and transcriptional activation. It is interesting to see how both PAWI-1 and -2 can bypass blockage event caused by HSPs on wnt signalling.

    The Bonnie and Clyde of Stem cells. ADAR1 is adenosine deaminese catalyzed by editing of adenosine to iodine in double standard RNA. RNA editing is essential for survival of mammals. However, its dysregulation results in non-synonymous codon changes in transcripts, yield alternative splicing, disrupt maturation of microRNAs and lead to cancer. ADAR1 is commonly overexpressed in many cancers and promote cancer progression in chronic mylogenous leukemia. The elevation of ADAR1 levels can suppress an innate immunity in response to cancer. In contrast, APOBEC-3C is RNA editing cytidine deaminase encodes proteins that are structurally and functionally related to change of C to U. It play important role in cell growth and cell cycle control.

    Recent investigation showed that APOBEC-3C and ADARI are able to transform pre-cancer stem cells into cancer stem cells. Both enzymes can be activated by inflammatory molecules during body’s immune response to viruses. Clinical results revealed that an increase in ADAR1 levels correlated with low survival rates in patients with multiple myeloma. The increase of both enzymes levels was associated with the progression of leukemia stem cells. In the event of inflammation response, APOBEC-3C promotes proliferation of human pre-leukemia stem cells whereas ADAR1 skewing edited gene expression to support the growth of leukemia stem cells. Therefore, inhibition of ADAR1 is an effective therapeutic tool to prevent the formation of leukemia stem cells.

    Upon astronauts returning to the earth, an increase of inflammatory growth factors and pre-cancer mutations in their bodies which activate both APOBEC-3C and ADAR1 persisted for almost a year. To note that, human’s body always produces abnormal cells during cell proliferation and repairing. Immune systems play roles to eradicate abnormal cells from becoming cancer. The persistent high levels of both enzymes not only activate cancer stem cell generation but also suppress innate immunity of human. The developing of enzyme inhibitors to block both of enzymes is an effective way to mitigate the risk factors generated by astronauts in low-Earth orbit and on deep space missions. In addition, infection of viruses triggers a flood of cytokines and stimulate immune forces. But it is uncertain, different strains of viruses might have different ability to trigger both enzymes into high levels.

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