Systemic inflammation leads to behavioural changes by affecting central dopamine signalling.
A recent study has proposed how tumour-secreted interleukin-6, a proinflammatory cytokine, affects the brain and causes apathy and cachexia in cancer patients.
Cachexia affects up to 80% of individuals with advanced cancer. Interleukin-6 has been identified as the potential driving factor for cachexia, with animal studies showing the proinflammatory cytokine is secreted by tumours before ultimately leading to wasting of muscle and fat.
But the exact mechanism linking cause and effect had eluded clinicians and scientists alike – until now. New research published in Science uses a mouse model of cancer to describe a neuroimmune circuit that mediates cancer cachexia-associated apathy involving multiple brain regions and dopamine signalling.
“This specialised interoceptive pathway demonstrates that inflammation engages discrete neural circuits rather than causing broad disruption and cumulative neural damage,” the researchers concluded.
“Although this circuit is likely adaptive during acute illness – conserving energy by dampening motivation – its persistent engagement in chronic conditions such as cancer cachexia is detrimental.
“This reveals that psychiatric symptoms such as apathy in cachexia are not secondary effects of physical decline but can arise directly from the same pathological mechanisms driving the illness itself.”
Researchers from the Washington University School of Medicine in Missouri used a preclinical model of colon cancer to induce apathy-like phenotypes (reduced motivation and increased effort-sensitivity) in mice.
Numerous behavioural tasks and paradigms designed to measure effort-related motivation, anhedonia, despair and locomotor activity were used to confirm the apathetic state was separate from other affective states.
Analysing plasma and brain cytokine levels revealed spikes in IL-6 levels occurred during the onset of cachexia, but that inhibiting IL-6 levels delayed its onset. There was also evidence that cachexia was associated with disruptions to the blood-brain barrier, allowing IL-6 to enter the brain.
Mapping what happened at a neuronal level once IL-6 crossed the blood-brain barrier was key to identifying the rest of the circuit. IL-6 activates receptors in the area postrema, which increases excitatory activity in the parabrachial nucleus and the substantia nigra pars compacta.
In turn, the SNpr inhibits dopamine neurons in the ventral tegmental area, which inhibits the release of dopamine in the nucleus accumbens. The lack of dopamine ultimately results in apathetic behaviour.
Associate Professor Louise Cheng, research lead of the cancer cachexia clinical and research integration program at the Peter MacCallum Cancer Centre in Melbourne, felt both the approach and findings were interesting.
“People have previously shown that IL-6 is important in disrupting the blood-brain barrier, so it makes sense that IL-6 can cross the barrier, cause these changes in localised brain areas and affect dopamine control,” said the developmental biologist, whose research uses fruit fly models of cancer cachexia to study how tumour secreted factors lead to muscle and fat wasting.
“The biggest challenge in neurobiology is how do you link behaviour to circuits to a cause – but I think in this case there is some quite convincing evidence that cachexia behaviours are driven by tumour-secreted IL-6, and that therefore inhibiting IL-6 or activating dopamine circuits can improve these symptoms. It’s quite novel.”
The authors of an accompanying perspective were more reserved in their assessment of the findings.
“This explanation is consistent with the role of nucleus accumbens dopamine in decisions that are made on the basis of effort required but is unlikely to explain the full complexity of altered mood and motivational states observed in cancer cachexia in humans,” they wrote.
“Other mechanisms associated with cachexia, including neuroendocrine and circadian changes, also merit attention for the potential contribution to apathy. In particular, growth/differentiation factor 15 – a cytokine that is produced after cellular stress and makes a major contribution to the cachexia phenotype – also stimulates the hypothalamic pituitary neuroendocrine response to physical and psychosocial stress.”
Though mostly positive about the study, Professor Cheng did note that the transplantation model used by the researchers – which involved Colon-26 adenocarcinoma cells – could mean the findings may not translate to other solid tumour types.
“The tumours that [are more commonly associated with] cachexia includes lung and pancreatic cancer, and I believe it has been shown that C-26 is not a great model to mirror the cachexia symptoms caused by pancreatic cancer or lung cancer. So, the findings could be more specific to the colon and not as applicable to others,” she told OR.
Both the researchers and the perspective authors were quick to suggest that therapies targeting IL-6 or its receptor – such as those approved and used for the treatment of rheumatoid arthritis – could be repurposed to prevent cachexia and other psychological symptoms in cancer patients.
“Supporting this view, the IL-6 antibody tocilizumab has shown promise in alleviating cancer cachexia in small-scale human studies,” the perspective authors noted.
However, Professor Cheng was more measured in her views on how the findings in mice could translate to humans.
“[Previous] IL-6 inhibitors have been quite problematic – people have suffered from a lot of side effects because IL-6 is a very general factor involved in inflammation. So, it’s very difficult to target IL-6 without side effects,” she explained.
Attempts to use IL-6 antibodies had been promising in preclinical studies but had also not panned out when tested in clinical settings.
“The researchers argue that anti-IL-6 therapies had failed because they had been used very late in disease progression, and that if they had used it earlier, then perhaps the outcomes would be better,” Professor Cheng said.
“That’s hard to tell, because in this particular case, all the work has been done in mice. How these findings translate to patients is anyone’s guess. But it was an interesting study, and they showed some convincing evidence that this is a circuit that is responsible for these behaviours. This is a great starting point.
“The challenge has always been that when people lose weight, go to the doctor and do a blood test that leads to a cancer diagnosis, the focus is generally on trying to cure the cancer and cachexia is something underappreciated.”
Professor Cheng acknowledged that cachexia, while a significant issue for cancer patients, was often left to the wayside as there was no effective way to treat it. But she felt this study got to the crux of the problem – how to diagnose and potentially treat cachexia at an early enough stage where it hasn’t caused a huge amount of damage.
