Neural plasticity of the uterus: New targets for endometrial cancer?

Abstract

Endometrial carcinoma is the most common gynecological malignancy in Western countries and is expected to increase in the following years because of the high index of obesity in the population. Recently, neural signaling has been recognized as part of the tumor microenvironment, playing an active role in tumor progression and invasion of different solid tumor types. The uterus stands out for the physiological plasticity of its peripheral nerves due to cyclic remodeling brought on by estrogen and progesterone hormones throughout the reproductive cycle. Therefore, a precise understanding of nerve-cancer crosstalk and the contribution of the organ-intrinsic neuroplasticity, mediated by estrogen and progesterone, of the uterine is urgently needed. The development of new and innovative medicines for patients with endometrial cancer would increase their quality of life and health. This review compiles information on the architecture and function of autonomous uterine neural innervations and the influence of hormone-dependent nerves in normal uterus and tumor progression. It also explores new therapeutic possibilities for endometrial cancer using these endocrine and neural advantages.

Keywords: autonomic nervous system; endometrial cancer; nerve plasticity; nerve-cancer; neuroreceptor; neurotherapy; neurotransmitter; sex hormones signaling.

Figure 1.

Autonomic innervation in the uterus: (a) Autonomic innervation distribution in the uterus. (b) Uterus anatomy: layers, nerves, and vessels. Neural control of the uterus is provided mutually by SNS and PSNS fibers creating a visceral co-regulation. The origin of SNS pre-ganglionic fibers initiates from the thoracolumbar region [T10-L2] of the CNS. SNS ganglia, where synapse is produced, are mainly located along the paravertebral sympathetic chain that runs parallel to the spinal cord. The post-ganglionic fibers finally join the spinal nerves to innervate the uterus. PSNS comes from the craniosacral region [S2–S4]. The PSNS ganglia and origin nerve roots are situated close to the uterus where shorter fibers make up the pelvic splanchnic nerves that innervate the uterus (a). Red: sympathetic nervous system; Blue: parasympathetic nervous system; Green: visceral afferents; Continuous line: pre-ganglionic fibers; Dotted lines: post-ganglionic fibers. In detail, uterine anatomy is composed of three layers and an exceptional vessel network that interacts with the autonomic nervous system (b).

Figure 2.

Nerve-cancer cell and sex hormone crosstalk: (a) Tumor progression. (b) Recurrence. Cancer cells can attract nerve fibers and stimulate nerve outgrowth by the paracrine secretion of neurotrophic factors (NF) in a process called neuroneogenesis. NFG contributes to the process and stimulates angiogenesis and inflammation. Tumor-associated macrophages also play an important role by secreting pro-inflamatory cytokines (IL-1, IL-6, IL-8, and TNF-α) that aid the tumor in circumventing antitumor responses. Conversely, nerve fibers secrete neurotransmitters (NE, E, ACh) that bind neuroreceptors in cancer and stromal cells (immune and endothelial cells) to stimulate tumor growth. Furthermore, estrogen has two effects, the induction of tumor growth by increasing estrogen signaling in cancer cells and the disruption of the sympathetic fibers, thereby giving prevalence to parasympathetic signaling (a). After surgical intervention, sex hormone levels are reduced and both sympathetic and parasympathetic signaling are active (b).