Children with cancer and their misunderstood endocannabinoid system

Conventional cancer treatments, especially radiation and chemotherapy, put a strain on the body. But for children, conventional treatments can become unbearable. The ban hides how the endocannabinoid system (ECS) behaves in children with cancer. Unfortunately, childhood and ECS are two subjects that are rarely explored together.

Adolescent cancer is indeed a rare disease, although it is the second leading cause of death in children. A recent study drew attention to this fact and the misunderstood ECS. Beyond endocannabinoids, scientists focused on the system’s relationship to nutrition and metabolism in relation to childhood cancer. (1)

Acute lymphoblastic leukemia, brain tumors, lymphoma and solid tumors are among the most common types of cancer in children.

Fat endocannabinoids and nutrition

Endocannabinoids are a type of fat made from omega-3 fatty acids found in food. But there are many reasons why diet and metabolism are crucial in regulating the entire endocannabinoid system in the treatment of childhood cancer. Conversely, the system is crucial in regulating metabolism and nutrition.

A previous report on CLN discussed the role of the ECS in energy homeostasis. Fat metabolism increases leptin levels, which compete with the ECS. However, the previous report did not explain how leptin inhibits endocannabinoids.

Leptin increases fatty acid amide hydrolase (FAAH), an enzyme that breaks down anandamide. (2) Essentially, lipid metabolism knocks down the endocannabinoid and CB1 partial receptor agonist known as anandamide.

Why Does Cancer Digest Glucose Poorly?

There is an important link between diet, energy homeostasis and cancer. Even in children, cancer inefficiently uses glucose as a form of food that endocannabinoids could help control. (1) Remember that complications can arise with endo-cannabinoids. (3) And at the end of the day, regulation is key.

The Warburg effect occurs when cells use up glucose in an oxygen-poor environment. (4) Solid tumor cells in the colon use this type of glucose metabolism to reduce reactive oxygen species (ROS), according to the findings of researchers at Harvard Medical School. (5,6) ROS further contributes to cancer progression while the ECS keeps reactive species in check. However, with or without endogenous human cannabinoids, regulation or inhibition of the Warburg effect must be coupled with inhibition of ROS to treat cancer.

In fact, endocannabinoids were absent from Harvard Medical School research on glucose metabolism in certain cancers and solid tumors. In their more recent study, however, the researchers indirectly cited fatty acid metabolism in the context of colorectal cancer. Fat loss affects a protein that stem cells express, which are vital for regeneration.

Young immune systems and the monitoring ECS

Four immune cells can counterintuitively defend cancer against most cellular immune attacks. With finesse, monoclonal antibodies can dampen one of the four defense signals. Eat me signals (macrophages) can then be introduced to kill cancer cells with much less disruption. It would be easy, except that no two types of cancer are the same. For this reason, treating cancer through the immune system is a personal matter. (7)

In adults, the ECS regulates specific cancer signals rather than controlling or inhibiting them. And on-demand capabilities within the ECS respond separately for each person, preventing the disease on a personal level. However, children have a developing immune system that fuels highly unique immune responses.

Children also have far fewer immune checkpoints for therapies and endocannabinoids to target. Therefore, it is not valid to extrapolate the role of the endocannabinoid system in adults to children, especially in diseases like cancer. In summary, the current field of research on childhood endocannabinoid systems is uncomfortably bleak.

Sources

1. Schab, M.; Skoczen, S. The role of nutritional status, gastrointestinal peptides, and endocannabinoids in the prognosis and management of children with cancer. international J Mol Science. 2022, 23, 5159.G
2. Balsevich G, Sticht M, Bowles NP, et al. Role of fatty acid amide hydrolase (FAAH) in leptin-mediated effects on nutrition and energy balance. Proc Natl Acad Sci US A. 2018;115(29):7605-7610. doi:10.1073/pnas.1802251115
3. Marino S, de Ridder D, Bishop RT, et al. Paradoxical effects of JZL184, a monoacylglycerol lipase inhibitor, on bone turnover in healthy and cancerous mice. EBioMedicine. 2019;44:452-466. doi:10.1016/j.ebiom.2019.05.048
4. K. Xu, N. Yin, M. Peng et al. Glycolysis drives phosphoinositide 3-kinase signaling to boost T cell immunity. Science. 2021;371(6527):405-410. doi:10.1126/science.abb2683
5. Sebastian C, Ferrer C, Serra M et al. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the gut. Nat Commun 13, 1503 (2022). https://doi.org/10.1038/s41467-022-29085-y
6. Choi JE, Sebastian C, Ferrer CM, et al. A unique subset of glycolytic tumor-propagating cells drives squamous cell carcinoma. Nat Metab. 2021;3(2):182-195. doi:10.1038/s42255-021-00350-6
7. Tseng D, Volkmer JP, Willingham SB, et al. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages elicits an effective antitumor T cell response. Proc Natl Acad Sci US A. 2013;110(27):11103-11108. doi:10.1073/pnas.1305569110