Tumor‐derived semaphorin 3D promoting cancer cachexia via regulating hypothalamic pro‐opiomelanocortin neurons

Cachexia is very common in cancer patients and predicts a poor prognosis; however, the molecular basis for progress in these individuals remains unclear, especially the effect of tumors on the hypothalamus energy regulation center. To investigate the regulatory pathway of tumors associated with hypothalamic pro‐opiomelanocortin (POMC) neurons known as appetite‐inhibiting neurons, we conducted observations both on patients and mice models. Results showed that the highly expressed exocrine semaphorin 3D (SEMA3D) both in cachexia patients and mice was positively related to the expression of POMC and its proteolytic peptide. Compared with the control group, mice inoculated with the SEMA3D‐knockout C26 cell line decreased the activity of POMC neurons resulting in a 1.3‐fold increase in food intake, a 22.2% increase in body weight, and reduced skeletal muscle and fat catabolism. The effect of SEMA3D on cachexia progression can be partially alleviated by knocking‐down POMC expression in the brain. In terms of mechanism, SEMA3D enhances the activity of POMC neurons by activating the expression of NRP2 (membrane receptor) and PlxnD1 (intracellular receptor). Our research revealed the overexpression of SEMA3D in tumors works as an activator of POMC neurons, which may play a vital role in suppressing appetite and promoting catabolic metabolism. SEMA3D is highly expressed in cachexia patients or mice with gastrointestinal tumors. High SEMA3D expression in serum promotes the activity of POMC neurons in the ARC through NRP2 and PlxnD1 receptors, resulting in increased secretion of α‐MSH, β‐LPH, and CLIP. Eventually, cachexia phenotypes of skeletal muscle, adipose tissue, and appetite loss become more severe.