Autophagy as a double-edged sword
Much like a hipster in San Francisco, your body knows how important recycling is and it was doing it before it was cool and even before you were born. About time you knew too! Recycling prevents cancer development, but cancer cells have also learned to take advantage of recycling for their own survival, making it important to increase our understanding of this process.
Have you ever thought about where all the things that we trash end up? They don’t magically disappear from the earth. With time, things get decomposed and get smaller until they eventually are small enough to become part of the environment again to be reused. The problem however, comes when these waste items become too numerous or too difficult to break down. In this case, the trash accumulates and the world becomes less of a healthy place to be.
Luckily, our cells are much smarter than we are, and understood the importance of recycling long time ago. Cells have the unique ability to destroy components that are damaged or useless and turn them into small building blocks that are recycled into new products. This process, called autophagy (meaning self-eating) not only demolishes the trash though; it is also a great energy sensor. If our body is low on energy, say we haven’t eaten in a few hours, it will use autophagy to create building blocks from obsolete structures to satisfy the cells’ requirements. This process can also get rid of viral and bacterial invaders, which makes autophagy not only a metabolic pathway, but an immune one too. Autophagy is happening in your body right now. At this precise moment as you are reading this text your body is breaking down millions of structures in every cell in your body. You might just thank nature for being so wise. To continue the rubbish metaphor, the things that need to be degraded get surrounded by a double membrane (we will call this the “trash bag”) and once it closes it is delivered to the lysosome (the recycling station), which contains the hydrolytic and proteolytic enzymes that will break the sequestered material apart. The proteins and the damaged organelles are degraded into basic building blocks, which are delivered back to the cell.
The fascinating field of autophagy has grown exponentially since the very first discovery of lysosomes by Christian de Duve in 1955, and the identification of the autophagy genes (1993) for which Yoshimori Ohsumi was awarded the Nobel Prize in 2016. Nowadays we have no doubt that autophagy is very important for the well-being and function of our cells.
Just as we can imagine the consequences of a world without recycling, things will start to look very messy in the tiny world that is our cells if autophagy stops working. Defective autophagy can lead to an accumulation of “rubbish” that can be harmful to our body, which can cause causing diseases like Parkinson’s and Alzheimer’s, demonstrating the importance of autophagy.
But wait, what does this have to do with cancer? And how can something so beneficial for our health turn against us? This paradox is why autophagy often is referred to as a “double-edged sword”. In general, autophagy prevents cancer development by removal of harmful components, including damaged mitochondria that if remaining in the cell can cause alterations in cellular metabolism, increased inflammation, DNA damage and oxidative stress, all of which are factors leading to cancer. This means that autophagy constitutes a powerful obstacle against malignant transformation, but if for various reasons our autophagy levels drop, cells can become malignant and get away with it, turning into tumor cells (the figure above illustrates the whole process).
After the malignant transformation, the tumor cells seem to increase autophagy levels and use it for their own benefit. This means that tumor cells have figured out a way to take advantage of autophagy and use it to promote cancer progression. One explanation for this is the fact that autophagy facilitates survival of tumor cells that would otherwise face a shortage of nutrients and oxygen. In other words, degradation and recycling of cellular components makes the tumor cells able to cope with intracellular and environmental stress, thereby facilitating their rapid growth and division. Such fast-growing cells need many nutrients, which autophagy helps to provide. Tumor cells have also developed the ability to increase autophagy in their neighboring cells, the so-called “tumor microenvironment”, further providing tumor growth. Tumor cells have a high glucose consumption rate and all the waste derived from their metabolism leads to an acidic microenvironment outside the cell, which the autophagy seems to help to deal with since chronic exposure to low pH enhances the autophagic machinery. Moreover, elimination of defective mitochondria now would prevent tumor cell death. And last but not least, autophagy can also increase therapy resistance of the cancer cells, meaning that autophagy protects cancer cells from chemotherapy treatment.
There is growing evidence that inhibition of autophagy might be a very effective concomitant treatment with other cancer drugs. Tumor cells have numerous redundant mechanisms to ensure their survival, and tackling several of them at the same time might be the best way to combat tumor development.
So how do we keep autophagy in healthy levels and functioning? Well, this is a bit complex, because there are many actors involved. Nevertheless, autophagy is generally a beneficial pathway, and we can give it a boost by maintaining healthy lifestyle habits, such as exercising, having a healthy diet and not overeating. So next time you skip the gym or trash plastic in the wrong container, think about how important recycling is for life, for yours, our planet’s and your little tiny cells’.
I would like to take this opportunity to emphasize the importance of basic scientific research to understanding the physiological pathways involved in cancer. Knowing how things work is essential for advancing in our crusade against cancer, and that’s exactly what we do at CanCell!
Galluzzi, L., Pietrocola, F., Bravo‐San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., … Kroemer, G. (2015). Autophagy in malignant transformation and cancer progression. The EMBO Journal, 34(7), 856–880.
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