Serial Transplants of DMBA-Induced Mammary Tumors in Fischer Rats as a Model System for Human Breast Cancer

Abstract

Previous studies on human breast cancer patients showed a decline in circulating melatonin levels corresponding to primary tumor growth and an increase when relapse occurred. The aim of the current investigation was to study in an experimental model possible mechanisms involved. Inbred female F344 Fischer rats were used for serial passages derived from a chemically induced mammary adenocarcinoma. Animals with slow-growing carcinosarcomas at passage 2 showed a significant elevation of nocturnal urinary melatonin (23.00–07.00 h; +50%, p < 0.05) and a nominal increase in plasma melatonin (+41%; 02.00–03.00 h). By contrast, these parameters were significantly depressed in animals with fast-growing sarcomas (urinary melatonin: –22%, p < 0.025; plasma melatonin: –56%, p < 0.01). At passage 2 nocturnal pineal N-acetylserotonin (02.00–03.00 h) was significantly enhanced (+62%, p < 0.05) probably due to an increased activity of serotonin-N-acetyltransferase (SNAT, +45%), the rate-limiting step of pineal melatonin biosynthesis converting serotonin to N-acetylserotonin. The activation of SNAT may be due to a stimulation of the sympathetic nervous system (urinary noradrenaline; NA: +243%, p < 0.005) when the cellular immune system responded towards tumor growth (urinary biopterin, +214%, p < 0.005). At passage 12 SNAT and N-acetylserotonin were unaffected but a depletion of plasma tryptophan (–34%, p < 0.0001), the precursor amino acid of melatonin, was found. The marginal decline in pineal serotonin (–18%, p < 0.05) disputes that the drastic depletion in circulating melatonin (–56%, p < 0.01) can be exclusively explained by a reduced availability of tryptophan. Therefore, the involvement of an additional mechanism has to be postulated, such as a degradation of melatonin via indoleamine 2,3-dioxygenase, an extrahepatic enzyme which has been detected in tumor 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 glucocorticoids which would account for the observed depletion of plasma tryptophan resulting from a tumor-associated activation of the hypothalamo-pituitary-adrenal axis (urinary corticosterone +208%, p < 0.01). These findings present first explanations for the previously observed modulation of melatonin levels in cancer patients but also illustrate the high degree of complexity of mechanisms involved in the interactions between tumor growth and the immunoneuroendocrine system.

Melatonin mediates seasonal adjustments in immune function

“…However, when high doses of DMBA were used, there was no significant difference between pinealectomized or sham-operated animals in the incidence of mammary neoplasms [5]. Transplanted DMBA-induced mammary tumors grew more slowly after melatonin treatment as compared to control rats that did not receive melatonin [9].…”

Influence of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil on plasma melatonin and chosen hormones in breast cancer premenopausal patients

“…Investigating any circardian rhythm in MEL secretion may help to confirm or refute this hypothesis. In patients with many types of breast, prostate, colon or uterus cancer, a decrease in night‐time MEL secretion has been reported (4, 8, 16). Bartsch et al .…”

“…Bartsch et al . (8, 16) reported that a growing tumour could modulate MEL biosynthesis. An initial increase is followed by a decrease in MEL biosynthesis, which can indicate neoplastic disease dissemination.…”

“…Several hypotheses have been put forward for explaining how melatonin and the pineal gland may exert an oncostatic effect. These include an immunostimulating action (3, 6–9), a direct antiproliferative action on neoplastic cell growth (10), an inhibitory influence on the action and/or formation of neoplastic cell growth factors (11–13). Interaction between the pineal gland and the endogenous opioid system (6, 7, 14) is indicated.…”

The Effect of E. scaber Extract to TNF-α and TGF-β on Mice under Carcinogen Treatment

“…Based on this results, the researcher assume that cancer induction by carcinogen compounds DMBA and Estradiol for 2 months has not resulted in excessive inflammatory reactions to cause cachexia syndrome. In rats model, DMBA can cause cachexia after 195 days of administration, while in 1 month administration of DMBA was not enough to promote cachexia syndrome [42,43]. TNF-α is cytokines that play major role to cause cachexia syndrom, and the increasing number of TNF-α can be considered as cachexia symtomps, because TNF-α responsible to degradation of myofibrillar and soleus muscle proteins [44].…”