Currently Disarming Cancer
Channelling new pathways for chemotherapy.
Our understanding of disease processes is constantly in flux and with it, our treatments. Centuries ago, insanity was thought to be caused by bad gases in the blood which would be allowed to escape by cutting a hole in the skull. Next, patients were treated hellishly, in order to flush the demons out. Nowadays, a subtler approach through psychotherapy and medication is approved for the range of mental illnesses that stem from insanity.
Similar examples can be found in other diseases, the most striking of which posits that aggressive cancers can be induced from benign tumours by prolonged electrical stimuli.
Cancers are characterised as having three functional stages:
Initiation occurs when a cell acquires a negative mutation in a tumour-suppressing gene or a positive mutation in an oncogene. This primes the cell for a cancerous takeover, from which multiple mutations usually follow. At this point, the cell is proliferating quickly, establishing a small tumour cluster.
During development, the cluster continues to grow, with different micro-factions competing for local resources such as nutrients and oxygen. As each faction independently evolves, the competition strengthens the overall tumour mass, lending such as immune suppression, vasculature recruitment and localised environmental remodelling to the strongest cell subtypes.
Finally, invasion begins with angiogenesis, where the tumour starts encouraging blood vessels to grow towards it, supporting an even larger overall size. Cells may break away from the central mass, entering the blood stream and migrating to some distant location in the body. At this point, the tumour can be classified as a cancer, with those migratory cells establishing new tumours - ultimately leading to organ closure and death.
Voltage-gated ion channels (VGICs) are now known to play a part in enhancing the invasive abilities of a tumour and subsequently increasing the risk of mortality. VGICs are typically associated in the electrophysiological transduction of information along axonal processes. Further research has also revealed secondary roles in cytoskeletal regulation (for cell structure and integrity), proliferation and migration. Each of these subsidiary processes are deeply ingrained within cancer biology, situating perturbed VGICs function at the precipice for cancerous takeover. The particular VGIC responsible for the cancer-inducing channelopathy is a member of the voltage-gated sodium channel (VGSC) family called Nav1.5 which is expressed in tissues such as the breast.
VGSC’s have a ubiquitous mode of action, mediating the influx of sodium ions against the antagonistic outflux of potassium ions through voltage-gated potassium channels (VGKCs). Depolarisation of the axon membranes elicits a conformational change in VGSCs, opening pores and allowing a flood of positively charged sodium ions to enter the cell cytoplasm by diffusion. At the same time, VGKC pores seal tightly shut, preventing any loss of potassium ions. This continues until a sufficient membrane charge is reached, whereupon the system flips to membrane repolarisation by closure of the VGSCs, simultaneously opening VGKCs until a resting charge level is attained. Cells can then interpret different commands depending on the strength of the signal, the length of the signal, and the pattern of signals.
How then, is the Nav1.5 gene, SCN5A, important for cancer generation? Well, the gene can be processed in two different ways before giving rise to the mature protein. Firstly, during embryonic development, SCN5A is spliced to produce neonatal Nav1.5 (nNav1.5) which remains open for longer during depolarisation, affording a wider window of activity. Thus, signalling lasts for hundreds of milliseconds, as opposed to just a few. Upon maturation, nNav1.5 is replaced by Nav1.5 and signalling is shortened to just several milliseconds, regulating both the strength and length of the sodium signal. However, some cancers deviously rewire their internal circuitry, slipping back to nNav1.5 expression to perturb the signal pattern and lead to responses which are more aligned with their insidious schemes.
Over-expression of nNav1.5 pushes tumour growth by affecting various prolific pathways, such as epidermal growth factor receptors (EGFR), which has been strongly implicated in cancer cell survival and replication. In fact, growth factor receptors are so powerful that entire classes of drugs have been dedicated to disrupting them, most famously with Herceptin that is frequently used as breast cancer treatments.
While less evidence for nNav1.5’s role in development has been recorded, nNav1.5 is one of few major promoters of invasion. Extended electrical stimuli drive causes remodelling of the cytoskeletal structure, transforming the usually cuboidal cells into streamlined vessels which are capable of pushing their way through breast tissue and punching their way into the blood stream, to then be carried away to new areas of colonisation throughout the body. nNav1.5 can also trigger the initial breakage of cellular connections that holds the cell in place, freeing the cells for transport. Finally, the channel helps form cellular protrusions that extend from the central body and reach out in front of the cell. These protrusions then latch onto the surrounding structures and effectively ‘pull’ the cell forward. At the same time, degradation proteins are secreted that eat away these structures, allowing the cell to burrow through the tissue to the blood vessels.
The brutality and effectiveness of cancer is forcing scientists to identifying new means to combat the disease. Adopting an electrophysical approach that targets cancer at its most vulnerable point – the switch to invasion – may be key to stopping disease progression and death. Relatively few invasion mechanisms exist so cancer heterogeneity is bottlenecked. Rather than directly counterattacking, which is often rebuffed by the cancerous cells and promotes retaliation, new techniques are being developed to prevent a metastatic onslaught. In effect, these treatments focus on keeping the cancer ‘happy’, negating the cell competition which drives development.
Thus, these therapies must not be toxic or extremely damaging to the cell. One hypothesis is to subjugate proteins that directly influence the perturbed signalling. For example, if c-Src, a tumour-promoting protein that maintains the extensive nNav1.5 signal via the cytoskeleton can be controlled, then perhaps perturbed proteins will be more willingly obedient.
In any case, the dawn of a new era of cancer therapeutics is rising, with sloppy, direct attacks that may anger cancers being replaced with calming, non-toxic therapies that indorse dormancy. This would help build a world in which living with cancer is possible.
About the Writer: Jack Hopkins
Jack has just started his doctorate, having obtained his Bachelor of Science degree in Biochemistry at the University of Nottingham and a Masters of Research from Imperial College London. His research interests span oncology mixed with a dash of ophthalmology that has led to his study of retinoblastoma.
He has previously written for the student-run newspaper, Felix, and completed a research presentation competition at Imperial College. He wishes to continue bringing the latest developments of biosciences to the people throughout his career.
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