Most studies have been carried out in relation to breast cancer using 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary cancers as well as serial transplants derived thereof. These experiments demonstrate that nocturnal circulating melatonin is modulated due to the presence of different types and stages of these experimental tumors, as has been observed for the respective human tumors underlining the relevance of these studies. Rats with chemically induced mammary tumors and slow-growing as well as well-differentiated serial transplants containing epithelial cell elements (adenocarcinomas and carcinosarcomas) have an enhanced production of melatonin involving activation of the rate-limiting enzyme of pineal melatonin biosynthesis (serotonin-N-acetyltransferase). This is probably due to an elevation of the sympathetic tone in response to a stimulation of the cellular immune system during malignant growth. In contrast, nocturnal circulating melatonin is depleted in animals with fast-growing mammary tumor transplants when myoepithelial-mesenchymal conversion leads to pure sarcomas. The depletion of melatonin appears to be due to either a reduced availability of the precursor amino acid tryptophan because of a glucocorticoid-induced activation of the hepatic enzyme tryptophan 2,3-dioxygenase or a direct peripheral degradation of melatonin via indolamine 2,3-dioxygenase expressed in tumor and/or other tissues. The significance of these findings is discussed in terms of a possible extrapolation to the clinical situation as well as to increase our theoretical knowledge concerning the mechanisms involved in complex host-tumor interactions within the framework of the neuroimmunoendocrine network.
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