Tumor progression: the neuronal input

Abstract

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.

Norepinephrine‐CREB1‐miR‐373 axis promotes progression of colon cancer

“…Organisms are continuously exposed to a variety of stresses that cause maladaptation and can even lead to cancer. In addition to changes in humoral immunity, recent studies have shown that the peripheral nerves in TNCs are associated with stress‐induced physiological changes in cancer cells (Arese et al , 2018; Faulkner et al , 2019; Jobling et al , 2015; Magnon, 2015; Mauffrey et al , 2019; Tang et al , 2013). Neurotransmitters are age‐old secreted modulators that are evolutionarily conserved.…”

“…Colorectal cancer (CRC) is a commonly occurring cancer that is densely innervated by autonomic fibers and results in shortened patient survival (Liebl et al , 2013). TNCs consist of sympathetic and parasympathetic nervous system (Arese et al , 2018; Faulkner et al , 2019; Jobling et al , 2015). Activation of the adrenergic system significantly affects stress‐induced cancer progression (Magnon et al , 2013).…”

Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer

“…Hence, new therapeutic algorithms and strategies are needed for better PC control. Although the true impact of microenvironment in PC pathogenesis and progression is not known, it is clear that targeting the stromal components may represent a promising approach for the treatment of PC [17,52].…”

“…The other related topics are molecules involved in tumor-neural TME interactions, with 3 main classes of proteins: neurotrophic factors, axon guidance molecules and NT including neuropeptides. Their sources are cancer cells, tumor-associated neuroendocrine Pathobiology 2020;87:87-99 DOI: 10.1159/000505437 cells, and stromal elements [17]. Experiments on PC cell lines showed that PC androgen-resistant cell culture have their genetic profile consistent with the socalled brain signature in 28% [51].…”

“…During wound healing, nerves sprouting from preexisting nerve fibers form a neural network within the microenvironment [16]. The neural tissue elements, such as axons and neurons of different types, are important components of TME creating specific intra/ peritumoral neural milieu [17][18][19][20]. The knowledge on neural component of TME function and significance is still low but neurobiology of cancer has become a new discipline in oncology.…”