Serial transplants of DMBA-induced mammary tumors in Fischer rats as a model system for human breast cancer - VI. The role of different forms of tumor-associated stress for the regulation of pineal melatonin secretion

Previous studies on human breast cancer patients showed a decline in circul ating melatonin levels corresponding to primary tumor growth and an increas e when relapse occurred. The aim of the current investigation was to study in an experimental model possible mechanisms involved. Inbred female F344 F ischer rats were used for serial passages derived from a chemically induced mammary adenocarcinoma. Animals with slow-growing carcinosarcomas at passa ge 2 showed a significant elevation of nocturnal urinary melatonin (23.00-0 7.00 h; +50%, p < 0.05) and a nominal increase in plasma melatonin (+41%; 0 2.00-03.00 h). By contrast, these parameters were significantly depressed i n animals with fast-growing sarcomas (urinary melatonin: -22%, p < 0.025; p lasma melatonin: -56%, p < 0.01.). At passage 2 nocturnal pineal N-acetylse rotonin (02.00-03.00 h) was significantly enhanced (+62%, p < 0.05) probabl y due to an increased activity of serotonin-N-acetyltransferase (SNAT, +45% ), the rate-limiting step of pineal melatonin biosynthesis converting serot onin to N-acetylserotonin. The activation of SNAT may be due to a stimulati on of the sympathetic nervous system (urinary noradrenaline; NA: +243%, p < 0.005) when the cellular immune system responded towards tumor growth (uri nary biopterin, +214%, p < 0.005). At passage 12 SNAT and N-acetylserotonin were unaffected but a depletion of plasma tryptophan (-34%, p < 0.0001), t he precursor amino acid of melatonin, was found. The marginal decline in pi neal serotonin (-18%, p < 0.05) disputes that the drastic depletion in circ ulating melatonin (-56%, p < 0.01) can be exclusively explained by a reduce d availability of tryptophan. Therefore, the involvement of an additional m echanism has to be postulated, such as a degradation of melatonin via indol eamine 2,3-dioxygenase, an extrahepatic enzyme which has been detected in t umor tissue and is related to tryptophan 2,3-dioxygenase (TDO). TDO occurs only in the liver, is highly specific for L-tryptophan and is induced by gl ucocorticoids which would account for the observed depletion of plasma tryp tophan resulting from a tumor-associated activation of the hypothalamo-pitu itary-adrenal axis (urinary corticosterone +208%, p < 0.01). These findings present first explanations for the previously observed modulation of melat onin levels in cancer patients but also illustrate the high degree of compl exity of mechanisms involved in the interactions between tumor growth and t he immuno-neuroendocrine system.