One of the challenges of cancer is its heterogeneity and rapid capacity to adapt. Notwithstanding significant progress in the last decades in genomics and precision medicine, new molecular targets and therapies appear highly necessary. One way to approach this complex problem is to consider cancer in the context of its cellular and molecular microenvironment, which includes nerves. The peripheral nerves, the topic of this review, modulate the biological behavior of the cancer cells and influence tumor progression, including the events related to the metastatic spread of the disease. This mechanism involves the release of neurotransmitters directly into the microenvironment and the activation of the corresponding membrane receptors. While this fact appears to complicate further the molecular landscape of cancer, the neurotransmitters are highly investigated molecules, and often are already targeted by well-developed drugs, a fact that can help finding new therapies at a fraction of the cost and time needed for new medicines (through the so-called drug repurposing). Moreover, the modulation of tumor progression by neurotransmitters can probably explain the long-recognized effects of psychological factors on the burden of cancer. We begin with an introduction on the tumor-nervous-connections and a description of the perineural invasion and neoneurogenesis, the two most important interaction patterns of cancer and nerves. Next, we discuss the most recent data that unequivocally demonstrate the necessity of the nervous system for tumor onset and growth. We introduce the molecular players of the tumor-nervous-connections by citing the role of three main families: neurotropic factors, axon guidance molecules, and neurotransmitters. Finally, we review the role the most important neurotransmitters in tumor biology and we conclude by analyzing the significance of the presented data for cancer therapy, with all the potential advantages and caveats.

Background: Perineural fibrotic adhesions are among the major complications of

The neuregulin1/ErbB system plays an important role in Schwann cell behavior both in normal and pathological conditions. Upon investigation of the expression of the neuregulin1/ErbB system in vitro, we explored the possibility to manipulate the system in order to increase the migration of Schwann cells, that play a fundamental role in the peripheral nerve regeneration. Comparison of primary cells and stable cell lines shows that both primary olfactory bulb ensheathing cells and a corresponding cell line express ErbB1-ErbB2 and neuregulin1, and that both primary Schwann cells and a corresponding cell line express ErbB2-ErbB3, while only primary Schwann cells express neuregulin1. To interfere with the neuregulin1/ErbB system, the soluble extracellular domain of the neuregulin1 receptor ErbB4 (ecto-ErbB4) was expressed in vitro in the neuregulin1 expressing cell line, and an unexpected increase in cell motility was observed. In vitro experiments suggest that the back signaling mediated by the transmembrane neuregulin1 plays a role in the migratory activity induced by ecto-ErbB4. These results indicate that ecto-ErbB4 could be used in vivo as a tool to manipulate the neuregulin1/ErbB system.

CMC-PEO gel can reduce perineural scar tissue. In histological section, scar tissue was present in both groups, but in the Burned+gel group a gliding surface was identified between scar and nerve.