Abstract 4751: Brain and plasma choline compounds altered by cancer and cancer-induced cachexia

Introduction: Cancer-induced cachexia has lethal consequences. Cachexia results in lower tolerance to chemotherapy1. Cachectic patients experience a wide range of symptoms affecting the function of organs such as muscle, liver, brain, and heart, causing significant morbidity 2. An altered choline metabolism is one of the hallmarks of cancers. Here, for the first time, we identified changes in brain choline metabolism induced by cachexia-inducing pancreatic cancer xenografts and related these changes to plasma choline levels. Methods: Panc1 or Pa04C cells were implanted in the flank of SCID mice. Snap frozen brains were powdered under liquid nitrogen, weighed, and dual phase extraction was performed3. All 1H MR spectra were acquired on a Bruker Avance III 750 MHz MR spectrometer. Mouse plasma choline was quantified using a fluorometric assay (Choline Assay Kit, BioAssay Systems). Brain and plasma studies were performed with normal mice (n=10), mice with cachexia-inducing Pa04C tumors (n=9) and mice with non cachexia-inducing Panc1 tumors (n=10). Results and Discussion: Cachexia-inducing Pa04C tumors induced significant weight loss in mice compared to Panc1 tumor bearing mice or normal mice3. A significant decrease of brain choline was observed in Pa04C tumor bearing mice compared to control mice as well as Panc1 tumor bearing mice, whereas brain phosphocholine (PC) levels were significantly lower compared to normal mice. Brain glycerophosphocholine (GPC) was significantly lower in both tumor bearing groups compared to normal mice. We observed a significant decrease of plasma choline in Pa04C tumor bearing mice. Plasma choline in Panc1 tumor bearing mice also decreased but not as drastically. The changes in plasma choline levels most likely contributed to the reduction of brain choline, PC and GPC. Reduced plasma choline may represent a risk factor for cancer as choline deficiency is known to result in lymphocyte apoptosis and DNA damage 4 that may compromise the immune response. Normalization of plasma choline using metabolic supplements merits investigation in reducing cancer morbidity and the onset of cachexia. Acknowledgement: This work was supported by NIH R35CA209960 and R01CA193365. References 1. Argiles JM et al., Nature reviews Cancer. 14(11):754-762. 2. Inui A. 2002. CA Cancer J Clin. 52(2):72-91. 3. Winnard PT, Jr., et al., Cancer Res. 76(6):1441-1450. 4. da Costa KA, et al., The American journal of clinical nutrition. 84(1):88-94. Citation Format: Santosh K. Bharti, Paul T. Winnard, Raj Kumar Sharma, Marie-France Penet, Balaji Krishnamachary, Zaver M. Bhujwalla. Brain and plasma choline compounds altered by cancer and cancer-induced cachexia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4751.