These membrane proteins are a breakthrough in waiting, particularly for controlling metastatic disease

Everybody knows somebody with cancer. In fact, one in two men (and one in three women) reading this article will be touched by some kind of cancer during his or her lifetime. This is the price we are paying for living longer, and not always living well. Cheap, low-quality food, lack of exercise, obesity, environmental pollution and, of course, smoking are all contributing to the problem.

So, cancer incidence keeps rising. There were approximately 14 million new cases and 8.2 million cancer related deaths globally in 2012; these statistics are expected to rise by about 70% over the next two decades! The good news is that a lot can be done for cancer, especially if detected early. There are many therapies that work. The problem is, they come with limitations. Chemotherapy and radiotherapy have well-known undesirable side effects and cannot be applied beyond a certain time; biological therapies, including hormone treatment, suffer from eventual onset of resistance etc., etc. The recent excitement about ‘immunotherapy’ overshadows the fact that it can also be very expensive, a thousand times the cost of gold, and will need to stand the test of time. So, new treatment modalities are urgently needed. Interestingly, recent work suggests that ion channels could be the breakthrough in waiting.

Ion channels – some basics

Every cell in the human body has a membrane potential associated with ion channels. Even red blood cells that do not have nuclei still possess these. The membrane potential is equivalent to some 10 million volts per metre and represents a huge force that could impact upon every protein in the cell membrane. When a typical voltage-gated ion (e.g. sodium) channel opens, ions permeate at an incredible rate of some 10,000 in a millisecond. These are extremely well-designed, cellular characteristics that, until recently, have been overlooked in cancer.

Many channels are expressed in cancers

Cancer cells have plasma membranes that exhibit electrochemical properties that are markedly different from normal cells. The membrane potential and ion channels play a range of key roles in cellular activities integral to the cancer process, from early gene expression to whole-cell behaviours like secretion and motility. The membrane voltage is a driving force even for the fundamental RAS-RAF-MAPK signalling cascade which is responsible for a number of cell behaviours associated with cancer, including growth, malignant transformation and drug resistance. Human lung adenocarcinoma stem cells downregulate their stemness and differentiate when their membrane potential is hyperpolarized. Furthermore, ion channel expression occurs early and is regulated by hormones and growth factors, well-known to be mainstream cancer mechanisms. It may not be surprising, therefore, that all major types and subtypes of ion channels are expressed in cancer cells. These include voltage-gated potassium, sodium, calcium and chloride channels, “transient receptor potential” (Trp) channels, and some ligand-gated ion channels.

Metastasis, the biggest problem in cancer

As far as ion channels are concerned, cancer is like the nervous system— all the channels are there, depending on the type and the stage of the cancer. So, the question is: Which ion channel would be best to target for controlling cancer? Inherent to this question is the crucial need to ensure that the ion channel(s) in question is sufficiently cancer-specific.

We have asked the question: Which ion channel is key to metastasis? This is the process by which cancer cells escape from the tumour, somehow enter the circulation and spread to distant organs. Metastatic disease is the main cause of death from cancer. There are significant differences between cancer cells of strong versus weak metastatic ability. Amongst these is de novo expression of voltage-gated sodium channels (VGSCs). Inhibiting VGSC expression/activity suppresses cancer cell invasiveness in vitro and metastasis in vivo. Importantly, the VGSC in some cancers is expressed as a neonatal splice variant, in line with the dedifferentiated nature of cancer. In breast and colon cancer, the neonatal VGSC (Nav1.5) differ from their adult counterpart by several extracellular amino acids around the gating region. Thus, the neonatal channel can be targeted (and blocked) selectively using small-molecule pharmacological agents or an antibody. Independently of this, the VGSC develops a ‘persistent current’ under hypoxic conditions well known to occur in growing tumours. There is evidence that it is mainly this current that underlies the metastasis-promoting role of the VGSC. Fortunately, also, the persistent current can be blocked using selective drugs whilst allowing nerve and muscle including cardiac functioning, dependent on the transient component of the VGSC current, to continue normally.

The challenges and the future

A number of challenges remain in exploiting ion channels in cancer. The main challenge is how to target cancer ion channels without affecting those in other tissues. Here, VGSCs tick all the boxes. The fact that the VGSC is neonatal with a pharmacology distinct from the normal adult counterpart elsewhere in the body is a distinct advantage. Another advantage is provided by the persistent current which is significant only under the pathologic hypoxic conditions of growing tumours. These are manageable challenges and add to the many advantages provided by ion channels, especially their expression early in cancer. Clearly, therefore, ion channels, in particular neonatal VGSCs, can be the next breakthrough in cancer. Already, there are many channel drugs to test against cancer and more will be developed. These will be non-toxic and free from the kinds of side effects associated with the current treatment modalities, so it should be possible to use them long-term. Thus, once we control metastasis, we could live with cancer, gain time to get rid of the primary tumour as well, and be cancer-free!

How to cite:

Djamgoz, Mustafa B. A., Ion Channels in Cancer. Eureka blog. Mar 30, 2016. Available: http://eureka.criver.com/exploring-ion-channels-in-cancer/