Stress Induced Tumor Formation: The Interaction Between Rasv12, JNK Signaling, and Stress
Previous cancer research has shown that multiple mutations are needed to spawn tumor development. In the past, it was believed that these alterations needed to be in the same cell. Today, Dr. Tian Xu, Yale Professor of Genetics, has flipped this idea on its head. Utilizing the fruitfly Drosophila melanogaster, his lab has found that tumors need not derive from mutations in a single cell but can form with the mutations present in different cells, increasing the probability that cancerous tumors can develop. They also have found that with just a single mutation of the oncogenic protein Rasv12, stress signals can induce tumor growth as well.
Experimental Procedure and Findings
The main components of interest in Xu’s study are Rasv12, scribble, JNK signaling, and the JAK/STAT signaling pathway. Mutations in the Ras oncogene are the most prevalent cancer alterations, occurring in more than 30% of human cancers. The exact same mutations, e.g. RasV12, were mimicked in the fly model to provide a comparison to humans. Scribble is a tumor suppressor gene, while JNK signaling is a form of stress signaling that releases cytokines that then activate the JAK/STAT pathway. The experiment has shown that the JAK/STAT signaling pathway helps maintain tissue homeostasis by means of compensatory proliferation. All of these mechanisms are also present in human cells.
In Xu’s study, the scribble gene was mutated (Figure 1.A). Because this mutated cell is aberrant, the cell undergoes apoptosis—programmed cell death. The defective scribble cell activates the JNK signaling, which signals neighboring cells and regulates the expression of cytokines that activate the JAK/STAT signaling pathway. The JAK/STAT signaling in the neighboring cells stimulates them to undergo compensatory proliferation to restore tissue homeostasis. Therefore, the scribble mutation alone causes tissue damage that can later be restored.
Xu performed experiments in which a Rasv12 mutation and a scribble mutation were induced in the same cell. The activation of the JNK and the JAK/STAT signals resulted in cell proliferation as opposed to cell death, showing that the interaction between scribble and Rasv12 causes tumor growth (Figure 1.B). But it was also found that if the scribble mutation and Rasv12 mutation are in different adjacent cells, the signal can propagate horizontally, with the cytokines activating that cell’s JAK/STAT pathway and causing the Rasv12 cell to proliferate (Figure 1.C). This parlays the importance of both JNK signaling and the JAK/STAT pathway in tumor growth.
The possibility that the tissue damage could cooperate with Rasv12 was later tested. These studies indicated that tissue damage activates JNK stress signaling which, like in the case of the scribble mutation, causes tumor proliferation through the JAK/STAT pathway.
It was previously thought that multiple mutations were required within one cell for cancer to occur. Xu’s results show that if you have one mutation in one cell and a different mutation in another cell, the stress signal travels between the cells to cause cancer development. The findings also prove that another mutation is not needed to activate the JNK signaling—if a person has a stress condition such as a physical wound, then the signal travels. If there is a cell that has the Ras mutation and the JAK/STAT pathway is activated by that stress signal, it will develop into a tumor.
These findings show that cancer can occur much more easily and through a more diverse variety of stimuli than was previously thought. For instance, the probability that mutations can occur in different cells is much greater than the probability that they all happen in the same cell, making cancer more likely. More importantly, the JNK signaling can be activated not just by tissue damage but also by many other forms of stress, such as inflammation, infection, or by other stressful environmental conditions such as extreme dryness, crowdedness, heat shock, and osmotic pressure. This means that all of these different conditions, in the presence of a mutated oncogene, could cause tumor proliferation.
The implications of this are profound. For example, it is known that stress conditions such as chronic inflammation increases cancer likelihood. Both experimental studies and epidemiological data have demonstrated this, but people didn’t understand why and how this happened. The Xu lab has shown that if a stress signal is activated, that signal can promote a Ras cell to develop into a tumor. While it is unfortunate to know that cancer can form so easily, understanding the mechanism offers a way to combat the cancer.
These findings also help to elucidate how, after a primary cancerous tumor is removed, the tumor can come back. Previously, people didn’t understand this mechanism, believing that the cells just accumulated more mutations. That theory is inaccurate because the cells already have enough mutations to develop into tumors in the first place. The more likely explanation is that tumor growth actually depends on where the cells are left in the body and on what environmental conditions different patients are exposed to. They may have stress conditions that could, if a mutation exists, trigger tumor cells to redevelop later. This stress could derive from inflammation caused by an autoimmune disease, a wound, or some other source.
Looking forward, it is of the utmost importance that studies are done on human and other mammalian cells to see how this process works. Xu says, “I think it would be fair to say that this is just a study using animals to trigger us to change the concept of thinking how humans develop tumors but [we] still need studies in humans for not only verification but to really look to see what happens.” According to Xu, human cells are “so much more complicated” than fly cells, so inspection on this front would be quite revealing.
What can we do to move forward? For one, we can follow the recommendations of the medical community today: reduce stress, avoid stressful conditions, and avoid carcinogens. We can also look into developing medicines to inhibit the JNK and JAK/STAT signaling in tumor cells, which can strongly suppress tumor proliferation.
Over 500,000 Americans die of cancer each year. While this number is astonishing, the scientific community has underestimated how easy it is for the human body to develop cancer. Xu’s research provides us with insight into the phenomenon of cancer in hope of finding a treatment to reduce stress-induced tumors.
In the future, the Xu lab would like to study the interactions between different mutant cells that cause the tumor to occur. They will explore how the stress signal travels between cells and more importantly how stress can activate the signal. Despite the fact that the stress conditions are very diverse, they all can activate the signal. Xu believes that looking into how environmental stress conditions could activate the signal processes in the cell will be a very fundamental step in understanding how cancer works. Additionally, they plan to explore how the stress signal itself is self-sustained, as even with the initial stress condition removed the cells still keep going to make tumors.
The work by Tian Xu, Ming Wu and Jose Carlos Pastor-Pareja has shown that the interaction between scribble and Rasv12 can cause tumor growth and that these mutations need not be in the same cell to induce tumor proliferation. They also have found that a variety of stress conditions can activate JNK signaling and cause tumors to form. While it may be easier to develop cancer than previously thought, this team of Yale researchers has identified new areas to target in our fight against one of the deadliest diseases in the world today.
About the author: Sudhakar Nuti is a freshman in Trumbull College. He is a prospective Classics major who is infatuated with science
Acknowledgements: The author would like to thank Tian Xu and Ming Wu for their time and help.