Depression induced neuropeptide Y secretion promotes prostate cancer growth by recruiting myeloid cells

Purpose: Psychological depression has been shown to dysregulate the immune system and promote tumor progression. The aim of this study is to investigate how psychological depression alters the immune profiles in prostate cancer. Experimental Design: We used a murine model of depression in Myc-CaP tumor bearing immune competent FVB mice and Hi-myc mice presenting with spontaneous prostate cancer. Transwell migration and co-culture assays were used to evaluate myeloid cell trafficking and cytokine profile changes evoked by Myc-CaP cells that had been treated with norepinephrine (NE), a major elevated neurotransmitter in depression. Chemoattractant which correlated with immune cell infiltration was screened by RNA-seq. The chemoattractant and immune cell infiltration were further confirmed using clinical samples of prostate cancer patients with high score of psychological depression. Results: Psychological depression predominantly promoted tumor-associated macrophage (TAM) intra-tumor infiltrations which resulted from spleen and circulating monocytic myeloid-derived suppressor cell (Mo-MDSC) mobilization. Neuropeptide Y (NPY) released from NE-treated Myc-CaP cells promotes macrophage trafficking and IL-6 releasing which activates STAT3 signaling pathway in prostate cancer cells. Clinical specimens from prostate cancer patients with higher score of depression revealed higher CD68+ TAM infiltration and stronger NPY and IL-6 expression. Conclusions: Depression promotes myeloid cell infiltration and increases IL-6 levels by a sympathetic-NPY signal. Sympathetic-NPY inhibition may be a promising strategy for prostate cancer patients with high score of psychological depression.

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