From tumor to torment: The neurobiology of depression in cancer

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Anthony Tao

Cancer is a debilitating disease in more ways than one. Its devastation arises predominantly from its parasitic nature, siphoning the host body’s nutrients and space for tumor growth. Predictably, this leaves victims feeling tired and worn down, with muscle weakness and malnutrition. Altogether, this cancer-associated weakening and wasting is known as cachexia.

Beyond physiological wasting, cachexia is also characterized by its psychiatric consequences—namely depression and apathy. It’s certainly easy to attribute these mood disturbances to the overwhelming psychological burden of a cancer diagnosis and the fear of a disintegrating quality of life. However, emerging data may suggest that cancer directly manipulates circuits in the brain to drive depressive symptoms.

In a recent publication, researchers at Washington University School of Medicine attempted to determine how cancer can directly influence psychiatric health, specifically using mouse models. They implanted colon cancer cells into mice and, as expected, observed the development of cachectic features, including weight loss and weakness. This development happened within just a few short weeks of the cell transfer. 

Notably, these mice also exhibited motivational defects, indicative of a depressive and apathetic state. For instance, in one of their behavioral experiments, researchers trained mice to poke their nose through a port—an action which was rewarded with a food pellet. However, every subsequent nose poke elicited diminishing amounts of the food pellet. At a certain point, once the effort of nose poking outweighed the food reward, the mice gave up. The point at which this occurred reflected the mice’s internal motivational state. In mice with cancer, as cachexia progressed, the mice became increasingly quick to abandon this food reward.

Next, the researchers wondered if systemic inflammation might play a role in this cachectic demotivation. The development of most cancers is accompanied by a systemic inflammatory response involving multiple immune cells attempting to attack the cancer. Though this inflammation can have deleterious effects on normal tissues, it often plays an important role in keeping cancer progression at bay. One of the mechanisms by which immune cells accomplish this is through the secretion of cytokines, which are signaling molecules in the blood. One particular cytokine known as interleukin-6 (IL-6) has been proven to affect many body systems in the presence of systemic inflammation. In cachectic mice, researchers found that the levels of IL-6 were significantly elevated in the blood and brain. Furthermore, when they counteracted the effects of IL-6 using an antibody (anti-IL-6 antibody), they improved the cachexia-associated demotivating behavior in the food reward task. These findings suggested that cancer promotes psychiatric depression through the induction of IL-6.

The question remained as to how a cytokine like IL-6 acts on the brain? Is there a neural circuit in the brain that senses IL-6 and drives depression? To address this question, the researchers broadly screened various brain regions for changes in neuronal activity upon the development of cachexia. To accomplish this, they measured the expression of a protein—cFos—which is associated with high levels of neuronal activation. Of the many regional changes in the brain, the authors found that activity was substantially decreased in the ventral tegmental area (VTA) and increased in the area of the medulla oblongata known as the area postrema.

The VTA is a famously described region of the midbrain that encodes reward behavior and motivation (Figure 1). Reduced activity in this area has been associated with depression, while increased activity has been associated with addiction. Of note, when a reward is experienced (such as food), the VTA releases the signaling molecule dopamine into a brain area known as the nucleus accumbens (NAc), resulting in the sensation of reward and motivation. Researchers found that less dopamine was released in the NAc of cachectic mice owing to impairments in VTA activity. Furthermore, when anti-IL-6 antibodies were administered, VTA activity and NAc levels of dopamine were restored to normal despite cachexia.

Lastly, the researchers were curious to know how IL-6 affects the VTA-NAc neural circuit. They focused on the area postrema due to its increased activity in their cFos experiment. Additionally, the area postrema has previously been described to sense IL-6 and mediate the physiological features of cachexia. Furthermore, the area postrema acts on another brain region called the substantia nigra, which sends inhibitory signals to the VTA, dampens VTA activity, leading to reduced dopamine release (Figure 1). Indeed, when the researchers deleted the IL6 sensing gene in the area postrema, mice showed improvements in motivation levels and increases in dopamine released from the VTA, despite their cachexia. Furthermore, when the neurons in the area postrema were directly stimulated with light, a technique known as optogenetics, VTA activity was inhibited. In summation, these findings reveal an IL-6-responsive neural-circuit (Figure 1) whereby inflammation is sensed by the area postrema via IL-6 signaling, and in turn inhibits the production of dopamine in the VTA thereby promoting depressive and apathetic symptoms.

These findings highlight a unique neurobiological relationship between cancer, inflammation, and psychiatric depression. The VTA-mediated dopamine signaling appears pivotal in driving the depression that accompanies cachexia, suggesting that dopamine-enhancing therapies may be useful in cancer-associated mood disturbances. Yet, traditional dopamine agonists are well-known to carry a side-effect burden that may compound the challenges faced by cancer victims. An alternative strategy could involve targeting IL-6 with tocilizumab, a widely used antibody for numerous autoimmune diseases. However, suppressing IL-6 may blunt anti-tumor immunity, which is important for controlling disease progression. Regardless of therapeutic potential, the true value of this work lies in its elucidation of tangible neurobiological mechanisms that further demystify the complex topic of psychiatric illness, especially within the context of chronic, debilitating diseases like cancer.

Header Image Source: Creators: Pablo Peiker, Ullisses Soares, Rafael Folk, Mykael Sobreira;  Copyright: CC BY-NC-ND 4.0 (a Creative Commons license) (Accessed here: https://nuscimagazine.com/beyond-relief-the-neurobiology-of-mdma-therapy-and-its-implications-for-mental-health/)

Figure 1 Source: Created by author, using Biorender.com

Edited by Brittane Strahan

References

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Sun, Q., van de Lisdonk, D., Ferrer, M., Gegenhuber, B., Wu, M., Park, Y., Tuveson, D. A., Tollkuhn, J., Janowitz, T., & Li, B. (2024). Area postrema neurons mediate interleukin-6 function in cancer cachexia. Nature Communications, 15(1), 4682. https://doi.org/10.1038/s41467-024-48971-1