Abstract
The 1990s were the decade of the brain (a “biological universe”) and we learnt a lot about how neurons work individually and in networks. With techniques like patch-clamp recording, we could follow the activities of even individual ion channel proteins in living cells in real time. In parallel, cancer biologists, in part, armed by the outcome of the Human Genome Project, have been trying to decipher how and why normal cells become cancerous! Indeed, cancer proved to be a “pathological universe”! For years, these two juggernauts of fields have been moving in parallel with hardly any interaction, apart from the obvious case of brain tumors. We have even seen big pharma companies with their neuroscience and oncology arms working on different continents. Increasingly, however, the gap between them has been getting narrower and a new term has emerged—”cancer neuroscience”—and this is getting increasing attention!1–3 Although brain tumors would be expected to maintain some form of their basic neuronal characteristics, the situation is much more surprising for carcinomas, cancers of epithelial tissues.
Cancer neuroscience comes in various forms. First, and perhaps the oldest, is the fact that carcinomas express genes normally associated with neurons and the more aggressive a carcinoma the more neuronal it seems to become, as exemplified by small-cell lung cancer. Regarding genes, the best known example of this is probably neuron-restrictive silencing factor that also functions as a tumor suppressor. Then there is the whole plethora of voltage-gated ion channels (VGICs), normally associated with “excitable” cells such as neurons and muscles, which carcinomas also express. In fact, according to one hypothesis, it is the de novo expression of functional voltage-gated sodium channels in carcinomas that makes them excitable and hyperactive, ultimately leading to invasiveness and metastasis. 4 Along with VGICs, carcinomas also express several types of neurotransmitter receptors (NTRs). Finally, at least currently, cancer neuroscience manifests itself by the direct innervation of tumors. Activation of NTRs, either by the nerve input and/or through the circulation, can impact significantly upon the different stages of the cancer process. Hodgkin–Huxley type action potentials have been recorded in tumors in vivo, although doubt remained whether the electrical activity came from the tumor and/or the impinging nerve. 5 Nevertheless, tumor innervation would make some sense given that cancer is a defection from morphogenetic cooperation, and nerves are one important conduit by which anatomical control signals propagate across tissue. 6
A possibly lesser appreciated facet of the cancer neuroscience is the immune connection. Immune cells also express VGICs and NTRs and use these in their most basic functioning, such as proliferation and motility, even differentiation and antigen presentation.
There is no doubt that bioelectricity is the bridge connecting all these cells, as well as possibly others including endothelial cells, and their interactions within the tumor microenvironment. Indeed, techniques often thought of as unique to neuroscience, such as optogenetics, are now being used to control carcinogenesis. 7 It would seem only a matter of time, therefore, before bioelectricity approaches generate an integral “systems” understanding of cancer and its progression. The next exciting step would then be marching toward the clinic with truly revolutionary techniques such as electrodiagnosis and electrotherapy of cancer!