Progressão tumoral em camundongos submetidos ao modelo de depressão por separação materna e transplantados com melanoma na idade adulta: Achados fisiopatológicos

Abstract

Maternal separation (MS) is an early life adversity (ELA) that causes stress, as well as important and long-lasting homeostatic changes. In this context, it promotes hyperactivity of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting in the release of hormones that have negative functions on the immune system and that can cause physiological alterations that have serious consequences, such as the development of type-depression behavior in adulthood of animals, as well as the development of tumors. It is known that depression is more incident in women and is related to a worse prognosis and resistance to chemotherapeutic treatment. In view of the homeostatic changes caused by exposure to ELA, the objective of the present study was to verify how the pathophysiological changes promoted by MS might affect the mechanisms related to the progression of murine melanoma B16F10 in adult females mice of the C57BL/6 lineage. Animals C57BL/6 (18-20 g) were mated and, after the birth of the offspring, the MS protocol was started. At 60 days of life, the resulting females underwent behavioral evaluation (open field, Y-maze, tail suspension and forced swimming test). Then, they were divided into the groups: Control (C), C + Tumor (T), MS and MS + T. The females of the C + T and MS + T groups were inoculated (2.5x104 cells/0.3 mL) with metastatic murine melanoma B16F10 cells in the axillary region of the left front paw. The weight evolution was followed up for 25 days and, at the end of that period, the tumor volume was measured. Afterward, the animals were euthanized and the tumor, lung, liver and adrenal glands were collected by surgical resection, in addition to blood, for further analysis. In adult animals, MS induced a depression-like behavior, observed by the cognitive deficit and increased immobility time in the tail suspension test, without inducing locomotion alteration. Tumor growth was influenced by the pathophysiological changes developed by MS. There was DNA damage in peripheral blood leukocytes as well as increased production of reactive oxygen species in peripheral blood mononuclear cells. MS promoted elevation in the number of circulating monocytes in the MS + T group. Immunohistochemistry performed on tumor tissue from the C + T and MS + T groups revealed increased IL-6 and phosphorylated mTOR expression, reduced IDO-1 expression, as well as resistance to apoptosis (TUNEL assay) and increased cell proliferation (Ki-67 expression) in the MS + T group. There was no difference in the expression of the VEGF and TGF-β cytokines, analyzed by ELISA, in the tumor tissue of these two groups. MS produced long-lasting pathophysiological changes that culminated in increased tumor growth kinetics in adult female mice of the C57BL/6 lineage.