Two weeks ago I wrote a post sharing some new work looking into why cancer cells metastasize (why they spread from one localized tumor, to multiple tumors in different organs).

Many questions about this process remain, for example: How do the cancer cells traveling through the circulatory system survive the high oxadative stress environment of our blood stream?

New research published today February 9, 2017 in the journal Nature Communications titled "Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination". Sheds some light on this question and today I would like to briefly share that with you.

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Lets Begin With The Articles Conclusions

• Through use of a technique called RNA-Seq, researchers observed high expression levels of the protein β-globin in tumor cells circulating in the blood stream, this result was unexpected.
• β-globin is expressed in these cells in response to the presence of reactive oxygen species.
• An additional protein called KLF4 was identified as a controlling factor in the generation of β-globin in response to these reactive oxygen species, so there are regulatory mechanisms.
• β-globin increases cancer cell survival in the blood stream and metastasis rate (based on new tumor formation)
• In cancer cells where β-globin expression was knocked down (reduced in its expression level), the addition of an antioxidant "N-acetyl cysteine" restores metastasis rates. AKA if there is less β-globin the oxidative stress kills the cells, but reducing that stress allows the cancer cells to flourish again.

What Is β-globin?

You are all familiar with hemoglobin right? It's the protein in our blood that is responsible for carrying oxygen and delivering it to all of our cells. Hemoglobin is actually a protein complex, composed of two copies of two different protein chains (aka their are 4 pieces in total).

Source

The image above is that of hemoglobin, you can see that there are two different colors red and blue. The red colored portions are the protein α-globin while the blue is the protein β-globin.

So for the sake of this post, think of β-globin as a piece of hemoglobin, that is able to exist on its own, in addition to being a part of the oxygen shuttling complex.

Note both α-globin and β-globin can form complexes with themselves as well and form structures that are similar to the mixed mature hemoglobin.

The Results Of The Research

Expression of β-globin Is Elevated in Cancer Cells Circulating In The Blood

The first thing the researchers noticed was that the amount of β-globin (it's called HBB in the figures) being produced by cancer cells was elevated, and the amount being produced by cancer cells that were circulating in the blood, was elevated even further.

Above are plots of the expression levels observed for two different cancer cell lines, with cells that were either circulating in the blood (CTC), in a solid tumor and not circulating (Tumor), or non cancer cells from the same tissue type (Cell Line). You can see that the CTC cells always show the highest amounts of β-globin.

The Increased Expression Of β-globin Is Controlled By The Protein KLF4 In Response to Reactive Oxygen Species

Researchers found that when treated with a reactive oxygen species (in the case of the figure below hydrogen peroxide (H₂O₂) that expression of β-globin increased.

The researchers also found that through gene knock-down techniques (using small interfering RNA's or siRNA) that if they knocked down a gene responsible for creating a response to reactive oxygen species called KLF4 that the expression of β-globin in response to those reactive oxygen species was eliminated. Compare "ctrl" (control, nothing knocked down) to "KLF4" (KLF4 knocked down) for the two plots, one has H₂O₂ added and the other does not. You can see that when KLF4 is knocked down there is no response to the H₂O₂ addition.

β-globin Protects Cells From Dying Due To Reactive Oxygen Species

Here the researchers created cell lines where the β-globin protein was knocked down, the first figure below shows the amount of β-globin present in the cancer cell lines. shCtrl is the control cell line where β-globin was not knocked down, the other two shHBB01 and shHBB02 are the cell lines where β-globin is knocked down and as you can see the experiment results in low expression levels in those cells.

Now, the researchers exposed the cells to increasing amounts of H₂O₂ and as you can see in the plot to the right, the cells that had the β-globin knocked down (the red and green traces) were not able to live in concentrations of H₂O₂ as high as the control cells (blue trace). This indicates that β-globin is protecting the cancer cells from death by reactive oxygen species when those cells are traveling in the blood.

β-globin Also Assists Tumors In Growing

Researchers also wanted to monitor the effect of β-globin on tumor growth and metastasis. To do this they engineered the tumor cells to express a protein called luciferase. This protein doesn't have anything to do with the devil, rather it produces light. With this, the researchers could monitor the tumors based on detecting the light emitted.

Here we see in the pannel to the left, that a mouse had four different cell lines implanted, the control still expressing β-globin and three β-globin knock down cell lines. You can see that after 27 days of allowing the tumors to grow and spread, that the growth was significantly greater for the control cells still expressing the β-globin, then it was for any of the other three where β-globin was knocked down.

In the figure to the right cells were directly injected into the mouses tail vein. You can see that the cell lines where β-globin was knocked down showed drastically less growth.

TL;DR

Researchers were studying the expression levels of proteins in cancer cell lines that are found traveling in blood. They surprisingly identified that a protein component of hemoglobin (β-globin) is highly expressed in these cells. As it turns out, their research indicates that β-globin is involved in protecting the cancer cells from reactive oxygen species in the blood, and allows for the cells to metastasize and grow more quickly.

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Sources

1. http://www.nature.com/articles/ncomms14344
2. https://en.wikipedia.org/wiki/HBB
3. https://ghr.nlm.nih.gov/gene/HBB
4. https://en.wikipedia.org/wiki/Reactive_oxygen_species
5. https://en.wikipedia.org/wiki/KLF4
6. https://ghr.nlm.nih.gov/gene/HBA1
7. https://ghr.nlm.nih.gov/gene/HBA2

All non Cited Images Are Available Under Creative Commons Licenses
Any Gifs Are From Giphy.com and Are Also Available for Use Under Creative Commons Licences

Articles Published in Nature Communications and Images Contained Therein Are Also Available for Use Under Creative Commons Licences

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If you like my work, please consider giving me a follow: @justtryme90. I am a PhD holding biochemist with a love for science. My future science blog posts will cover a range of topics in the biology/chemistry fields.

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