Neuroendocrine Factors in Melanoma Pathogenesis

Abstract

Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects.

Keywords: melanoma; neurohormones; neuropeptides; neurotransmitters; stress.

Figure 1

Neuroendocrine factors produced in different compartments of the skin and their most relevant effects on melanoma cells via specific receptors.

Figure 2

Neuroendocrine factors released by melanoma cells and their effects on the tumor microenvironment.

Figure 3

Role of β-adrenergic modulatory mechanisms in tumor development and progression. Release of catecholamines in the tumor tissue associated with activation of sympathoadrenal system, stimulates β-adrenergic receptors on melanoma and tumor microenvironment cells. In tumor cells it further induces an increase of cAMP formation which, in its turn, activates multiple intracellular signaling pathways, such as GATA1, CREB and ATF, initiating protumorigenic mechanisms. Adrenergic stimulation of tumor infiltrating immune cells (TIICs) increases the production of proinflammatory cytokines and matrix metalloproteinases (MMPs), also favoring tumor growth, invasion and metastasis.