December 5, 2021

I, Science

The science magazine of Imperial College

Cancer has been a monumental target for medical research – in the West it’s a leading cause of death, and is highly feared. But this reputation isn’t necessarily earned.

A large number of patients arrive in clinic with the secret apprehension that it could be the ‘big C’ despite the fact heart disease is the single biggest killer and very few of us really take steps to mitigate the damage with diet and exercise. High blood pressure is another silent killer, and one that doesn’t inspire the same terror as the word tumour.

Possibly part of the problem is that people feel cancer happens to us; a random unlucky event. A bigger problem to tackle is the view that there is “no cure”. Cancer is also a large label splashed across a multitude of different organ-specific diseases with vastly different disease courses, victims and outcomes. There are forms of skin cancer that would take more than a lifetime to kill a person, and brain tumours that take merely weeks. There is both a general and expert lack of understanding about the nature of the illness, which has thrown a cog into research and terrifies patients.

At its most basic, cancer is a disease of rapid cell division and a loss of cell specialised roles: it’s basically chaos.

We are multicellular organisms. This state of unified harmony requires cells to a) not compete with each other; b) to sacrifice self sufficiency to perform a niche role; and c) to die on request.

For example, the body regulates blood flow and nutrients so that highly metabolic tissues receive a greater allocation of resources. At times this might be a healing wound, it might be the brain, it might be skeletal muscle. If you put two bacterial cells together they will fight to death over the resources available. When they do have resources they divide like crazy to spawn a generation of successful offspring. In human cells this desire to reproduce is held in check in order to balance the organism as a whole; so that tissues renew in a time-appropriate manner; replacing damaged goods, but no more than that.

Cells of the human body are also highly specialised; brain cells require a particular local environment with certain chemicals packaged and delivered to them by support cells. Goblet cells lining the lungs create mucus as a barrier against infection; however they are useless for oxygen exchange. Heart muscle works tirelessly for decades however its contraction response lacks the explosive power of skeletal muscle. Red blood cells eject their nucleus – their hub of genetic material – in order to bear oxygen round the body, and must be renewed every few months. Meanwhile white blood cells flare up and divide to fight infection, but must be put down days later to avoid wide-spread damage, though a carefully selected few will linger on for decades to provide lasting immunity.

But sometimes cells fail to achieve these objectives; they can’t perform their role in life, or they divide at dangerous rates without respecting the metabolic needs of their neighbours and far-flung relatives, or they become a reservoir of infection. In all these cases they are earmarked for destruction – either by patrolling immune cells or they wave a flag of their own accord, leading to ‘apoptosis’ or programmed cell death. Even in the most symbiotic relationships in the wild, one species rarely goes as far as to die for the other, but in the human body, these cells will do.

However, all of these things go awry in cancer. The first step is usually cell damage and uncontrolled cell division. This can happen spontaneously; over thousands of cell divisions, DNA copying does go wrong. It can happen as a result of toxic exposure; sunlight, smoking, chemicals. Or it can be the result of a genetic predisposition – though few genes deliver cancer 100% of the time

The problem is a slippery slope. Once cell division runs amok (usually carefully guarded by sentry proteins that refuse to let a cell divide when DNA damage is evident) the usual checks on DNA integrity are lost. This means the cells gradually lose their identity. All cells possess exactly the same genes as one another, and it is only the permutation of which genes are switched on and off that specifies cell-type, thus cancer cells can take on weird and wonderful job roles, whilst rudely quitting the employment for which they were destined.

Certain lung cancers may produce ACTH, a hormone usually produced by the pituitary gland. It ramps up the stress response, working on the adrenal glands to produce vast amounts of steroid hormone. Some tumours can produce ectopic insulin causing very low blood sugars. Breast cancers may produce a hormone called Parathyroid hormone-releasing protein, which cause huge quantities of calcium to be released into the bloodstream. This is toxic to the nervous system, the heart and beyond, causing an emergency situation.

Cancer cells lose their selflessness and become self-serving, competition over resources means only the wiliest cells continue to reproduce. Often this means cells start producing chemicals like VEGF, which encourages blood vessel growth, securing more resources for the growing body of cells; the tumour. Some cells may start to produce TNFs to kill off their competitors, making victims of local normal cells. Tumour cells start producing proteins in such rapid quantities in such chaotic environments that the immune system is triggered to see them as foreign invaders. However not only are cancer cells harder to kill – they often helpfully remove the receptors that immune cells stick to – this means any normal cells expressing the proteins the tumour cells have churned out in such controversial amounts are attacked by the body’s own immune system. Autoimmune disease and cancer has a long-standing association. Examples include Lambert-Eaton syndrome where antibodies are produced against receptors on skeletal muscle, causing partial paralysis. A further example is pemphigus, where skin is shed like a snake as a result of an immune attack on the proteins stitching the skin layers together.

Tumours cause local disease by literally invading organs and stealing their blood supply. This naturally impairs function; in the lung it reduces surface area for gas exchange, in the brain it cause pressure changes that damages vital areas, in the heart it impairs pumping, in the kidney it reduces excretion, in the liver it reduces filtering, in the bowel it causes obstruction, in bone it causes fractures. And everywhere it can cause pain as a result of tissue oxygen deprivation, nerve impingement and an inflammatory response.

Localised tumours can be nasty but they tend to have a higher cure rate. They can either be shrunk to reduce symptoms, or they can be surgically removed. We aren’t yet able to restore the organs the tumour destroys but we make do. Bowel can be removed and the ends stitched together, bone can be replaced with a bone graft or a metal prosthesis, liver may regenerate, heart can be aided with valves, blocked blood vessels can be stented, oxygen can be given to patients with lung damage.

However we are able to eradicate the original tumour, which we call the primary tumour, tumour cells may have detached and spread elsewhere. The idea is always to catch cancer before this occurs, because this spread, called metastasis, is much harder to manage. Some tumours may never spread – we call these benign, and they are not defined as cancer, some take years like basal cell carcinoma, some are very rapid like malignant melanoma. It is not usual cell behaviour to detach from one’s peers and float around the body, thus cancer and DNA damage must be fairly advanced before metastasis happens.Typically spreading happens via the bloodstream or lymphatic system. Lymph nodes are very valuable tools in assessing cancer and are also often removed to achieve better clearance. Nodes in the armpit may catch breast cancer; a node just above the collarbone may catch stomach cancer.

Research has indicated that different cancer types metastatise differently. For example bone metastases showing up on x-rays immediately prompt medical staff to look for primary tumours in the lung, prostate, thyroid and breast. Prostate and breast cancer find the spine. A lot of cancers spread to lung and liver due to the fact these organs have a huge blood supply and act as filters.

While surgical removal of a primary tumour can actually be considered a cure, it is not always possible. Radiotherapy and chemotherapy are also excellent ways of reducing symptoms, extending life, and potentially even ‘curing’ some kinds of cancer. They target rapidly diving cells by damaging DNA or inhibiting cell division. But the side effects are severe and so these treatments are more often used on organs that renew frequently; the liver, the gut lining, hair cells, sperm. Quite often we can cure the cancer – by eradicating every last mutated cell in the human body – but not without causing significant harm. Furthermore even once tumours have gone, they leave damage behind in the places they inhabited. Bone will be weaker, and organ parts may have died.

As we age, mutations become more likely. Mutations happen constantly, but in our prime the immune system is much more effective at rooting it out early. This is why the risk of lung cancer is drastically increased when one smokes past middle age. It is also why immuno-suppressed patients are much more likely to develop malignancy.

Thus surviving one type of cancer does not preclude another tumour developing – it is simply a game of chance. Medicine tries to outrun cancer by catching it early – we screen at risk populations, and there are special emergency referral processes when clinicians suspect malignancy is present. But often patients only present themselves to doctors at late stages of disease, when symptoms are evident. Thus we should not all sit back and wait for ‘a cure’ to happen. Treatments are there, and they work very well. They will be improved and refined over the years to come. However the greatest cure lies in prevention and awareness – being aware of a family history, reducing risk factors like sunburn and cigarettes, participating in screening programmes, and knowing which symptoms should spark an urgent visit to the GP. There will always be rare, aggressive types that elude capture, but in time cancer will hopefully lose its terrifying status.

Cancer survival rates are better than ever. This is not due to revolutionary treatments (though there have been a few), but rather, mainly to screening. If the general populace has enough of a basic understanding to ‘self-screen’ their symptoms, we will save a lot of money, a lot of anguish, and a lot of lives.

IMAGE: Human Melanoma cell dividing, Wellcome images.