Tumor associated macrophages br Tumor angiogenesis br Purpos
Purpose: Elevated catecholamines in the tumor microenvironment often correlate with tumor development. However, the mechanisms by which catecholamines modulate lung cancer growth are still poorly understood. This study is aimed at examining the functions and mechanisms of catecholamine-induced macrophage polar-ization in angiogenesis and tumor development.
Experimental design: We established in vitro and in vivo models to investigate the relationship between ca-techolamines and macrophages in lung cancer. Flow cytometry, cytokine detection, tube formation assay, im-munofluorescence, and western blot analysis were performed, and animal models were also used to explore the underlying mechanism of catecholamine-induced macrophage polarization and host immunological response. Results: Catecholamines were shown to be secreted into tumor under the control of the sympathetic nerve system to maintain the pro-tumoral microenvironment. In vivo, the chemical depletion of the natural catecholamine stock with 6OHDA could reduce the release of catecholamines within tumor tissues, restrain the function of alternatively activated M2 macrophage, attenuate tumor neovascularization, and inhibit tumor growth. In vitro, catecholamine treatment triggered the M2 polarization of macrophages, enhanced the expression of VEGF, promoted tumor angiogenesis, and these catecholamine-stimulated eﬀects could be reversed by the adrenergic receptor antagonist propranolol. In addition to regulating tumor-associated macrophages (TAM) recruitment, decreasing catecholamine levels could also shift the immunosuppressive microenvironment by decreasing myeloid-derived suppressor cells’ (MDSCs) recruitment and facilitating dendritic cells’ (DCs) activation, po-tentially resulting in a positive antitumor immune response.
Conclusion: Our study demonstrates the potential of adrenergic stress and catecholamine-driven adrenergic signaling of TAMs to regulate the immune status of a tumor microenvironment and provides promising targets for anticancer therapies.
Nerve system is one important component of the tumor micro-environment. The local extension of cancer CCCP uncoupler along nerves is a fre-quent clinical finding and denervation of the primary tumor is reported to suppress cancer metastasis, suggesting that the nerve system is not a bystander during tumorigenesis (Boilly et al., 2017; Zhao et al., 2014). Nerve-related cancer progression is also believed to be the result of elevated neurotransmitters and growth factors in local microenviron-ments, so that the neurochemical changes of continuous exposure to
stress are able to create a setting conducive for tumor initiation up to progression (Amit et al., 2016). Chronic activation of the sympathetic nerve system (SNS) has become increasingly recognized as a critical factor associated with the poor survival in cancer patients (Cole et al., 2015). Stress-induced SNS activation leads to the elevated levels of catecholaminergic neurotransmitters, which is mainly norepinephrine (NE), contributing to the growth, dissemination, and metastasis of cancer by promoting tumor invasion and remodeling tumor micro-environment (Cole et al., 2015; Eng et al., 2014; Saloman et al., 2016; Magnon et al., 2013). Stress-induced neurotransmitters and hormones
can enter tumor tissue through vasculature, innervation, or even in-directly through immune cell production to manipulate the behaviors of tumor cells (Eng et al., 2014; Saloman et al., 2016; Jobling et al., 2015; Gabanyi et al., 2016). Apart from the systematic eﬀect of EPI through blood circulation, data from mounting studies also show that sympa-thetic nerves infiltrate into the vicinity of cancer and locally release NE to mediate the pro-tumoral eﬀects of activated SNS by acting on the corresponding receptors expressed on tumoral and stromal cells (Scanzano and Cosentino, 2015). Finally, adrenergic stimulation of immune cells regulates the activation state of the immune system and modulates their functional capacity (Bellinger and Lorton, 2014). Conversely, nerve ablation has an inhibitory impact on disease pro-gression, including the delayed development of precancerous lesions, decreased tumor growth, and metastasis. Inhibition of the neuro-transmitter receptor seems to facilitate the anticancer eﬀects of che-motherapy and targeted therapy. In addition, patients taking antago-nists of adrenergic receptors have improved prognosis in various cancers (Barron et al., 2011; Wang et al., 2013; Jansen et al., 2014), and preclinical research have identified β-blockers as having the ability to potentiate the anti-tumor eﬃcacy of chemotherapy agents (Pasquier et al., 2011). All these findings highlight a significant role of cancer-nerve communication in tumor growth and metastasis.