CRACKING THE RIDDLE OF CANCER ANOREXIA

During tumor growth, anorexia and reduced food intake are among the ma jor causes leading to malnutrition and eventually cachexia, which nega tively affect patients' outcome. Consistent evidence from our laborato ries in rats and humans indicates a key role for ventromedial hypothal amic (VMH) serotonergic system in the development of cancer anorexia. Thus, we postulated that during cancer, increased plasma tryptophan le vels (the precursor of serotonin) lead to increased cerebrospinal flui d tryptophan concentrations and increased VMH serotonin synthesis, whi ch then mediates the occurrence of anorexia. However, recent data stro ngly suggest that factors other than tryptophan supplied to the centra l nervous system might be involved in the pathogenesis of reduced food intake during tumor growth. Particularly, a significant role appears to be played by interleukin-1 (IL-1). We recently showed that IL-1 inf usion in normal rats causes changes in food intake and its determinant s, meal number and meal size, similar to those characterizing cancer a norexia, thus supporting the involvement of this cytokine in the devel opment of anorexia. Interestingly, IL-1 and the VMH serotonergic syste m appear to be closely linked: peripherally infused IL-1 increases bra in tryptophan and serotonin concentrations, while intracerebrally infu sed IL-1 increases neuronal firing rate and serotonin release. We ther efore hypothesize that during tumor growth, increased production/secre tion of IL-1 occurs, which facilitates the tryptophan supply to the br ain. IL-1 can then also act on the VHM itself, where IL-1 receptors ex ist, to increase its neuronal activity and serotonin release. In other words, we believe that centrally acting IL-1 increases hypothalamic n euronal firing rate and serotonin release, while peripherally acting I L-1 is critical in supplying the hypothalamus with the precursor, tryp tophan, in order to maintain the high rate of serotonin synthesis. Als o, additional factors recently proposed as mediators of anorexia (incl uding neuropeptide Y- and nitric oxide) appear to be part of the hypot hesized pathogenic mechanism.