Children with cancer and their misunderstood endocannabinoid system



Conventional cancer treatments, especially radio and chemotherapy are harsh on the body. But for children, conventional treatments can become unbearable. Hidden by prohibition is how the endocannabinoid system (ECS) behaves in children with cancer. Childhood and the ECS are sadly two subjects rarely explored in unison.

Adolescent cancer is indeed a rare disease despite being the second most frequent cause of death in children. A recent study drew attention to this fact and the misunderstood ECS. Expanding beyond endocannabinoids, the scientists focused on the system’s relationship with diet and metabolism concerning childhood cancer. (1)

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

Fatty endocannabinoids and diet

Endocannabinoids are a type of fat produced from dietary Omega-3. But many reasons exist why diet and metabolism are critical for regulating the entire endocannabinoid system while treating childhood cancer. In reverse, the system is crucial for regulating metabolism and diet.

A previous report on CLN discussed the ECS’s role in energy homeostasis. The metabolism of fat increases the level of leptin which competes with the ECS. The previous report, however, did not explain how leptin inhibits endocannabinoids.

Leptin boosts Fatty Acid Amide Hydrolase (FAAH), an enzyme that chews up anandamide. (2) So essentially, the metabolism of fat knocks down the endocannabinoid and partial CB1 receptor agonist know as anandamide.

Why does cancer poorly digest glucose?

A major connection exists between diet, energy homeostasis, and cancer. Even in children, cancer inefficiently consumes glucose as a form of food which endocannabinoids might help control. (1) Do keep in mind that complications with endo cannabinoids can occur. (3) And at the end of the day, regulation is the key.

The Warburg Effect occurs when cells consume glucose in an environment deprived of oxygen. (4) Solid tumour cells in the colon use this type of glucose metabolism to reduce reactive oxygen species (ROS), according to discoveries by Havard Medical School researchers. (5, 6) ROS further contributes to cancer progression while the ECS keeps reactive species in check. With or without endogenous human cannabinoids, though, regulation or inhibition of the Warburg Effect must be coupled with the inhibition of ROS to treat cancer.

Endocannabinoids were indeed missing from Harvard Medical School‘s research on glucose metabolism in specific cancers and solid tumours. Indirectly, however, the researchers did cite fatty acid metabolism in regards to intestinal cancers in their more recent study. The breakdown of fat affects a protein that expresses stem cells which are vital for regeneration.

Young immune systems and the surveillant ECS

Four immune cells can counterintuitively defend cancer from most cellular immune offences. With finesse, monoclonal antibodies can reduce one of the four defensive signals. Eat-me-signals (macrophages) can then be introduced to kill cancer cells with far less interference. It would be simple except that no two cancers are identical. For this reason, treating cancer via the immune system is a personal affair. (7)

In adults, the ECS regulates rather than drives or inhibits specific cancer signals. And on-demand functions within the ECS respond separately for each individual, hindering the disease on a personal level. Children, however, have developing immune systems that drive highly unique immune responses.

Children also have far fewer immune checkpoints for therapies and endocannabinoids to target. And so, translating the role of the endocannabinoid system in adults to children is not valid, especially for diseases like cancer. Conclusively, the current field of research regarding childhood endocannabinoid systems is uncomfortably desolate.

Sources

  1. Schab, M.; Skoczen, S. The Role of Nutritional Status, Gastrointestinal Peptides, and Endocannabinoids in the Prognosis and Treatment of Children with Cancer. Int. J. Mol. Sci. 2022, 23, 5159.G
  2. Balsevich G, Sticht M, Bowles NP, et al. Role for fatty acid amide hydrolase (FAAH) in the leptin-mediated effects on feeding and energy balance. Proc Natl Acad Sci U S 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, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice. EBioMedicine. 2019;44:452-466. doi:10.1016/j.ebiom.2019.05.048
  4. Xu K, Yin N, Peng M, et al. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster 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 intestine. 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 tumour-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 primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A. 2013;110(27):11103-11108. doi:10.1073/pnas.1305569110





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