Introduction

It is essential that healthcare professionals understand the underlying biological changes that occur during the development of a disease in order to manage the care of an individual. This chapter helps you to understand how and why cancer develops in order for you to identify health promotion strategies to prevent and detect cancer. It also helps you comprehend the principles of cancer treatments, in order to prevent or manage the side effects patients may experience.

Cancer is a term used to refer to a group of diseases. Each of the 200 or so different types of cancer develops for different reasons, will be treated differently and will have a different outcome. Despite this, they all share a common feature – uncontrolled cellular growth.

Cancer is a genetic disease. This does not necessarily mean that it is inherited from our parents, but that it is the consequence of a number of genetic faults in the deoxyribonucleic acid (DNA) in the cell which result in the uncontrollable dividing and reproducing of cells.

How cells should work

A cell (Fig. 2.1) is the basic building unit of life. All animal cells are similar in their components, although they may have different functions. Similar cells are grouped together to create tissues which carry out specific functions. For example, there are four main types of tissue that make up the human body: muscle, epithelial, nervous and connective tissues.

Fig 2.1 The human cell

All cells have the ability to carry out complex tasks, such as the uptake of nutrients and converting this into energy. They are also able to replicate in order to replace damaged or old cells. All the instructions needed to build and maintain the body’s functions are contained in the DNA. Each instruction is carried on a unique piece of DNA called a gene. Each gene codes for particular proteins which control the function and structure of the individual cell. All the genetic codes make up what is known as the human genome. It is a bit like an instruction manual and the genes are chapters in the book with specific information. Genes can be turned on or off depending on the job a cell needs to do.

Each cell contains a complete copy of our genome in the form of 23 separate pairs of chromosomes (one set from each of our parents) (Fig. 2.2). For each chromosome and each gene, we have two slightly different copies.

Fig 2.2 Human chromosomes

DNA is made up of individual molecules called nucleotides, which are in turn made up of a sugar (deoxyribose), a phosphate and a nitrogenous base. The DNA molecule is comprised of two chains of nucleotide bases, arranged in a double helix (Fig. 2.3). There are four bases which are grouped into two types: purines (adenine (A) and guanine (G)) and pyrimidines (thymine (T) and cytosine (C)). Each base is paired up with another base: A pairs with T and C pairs with G. Each base is a slightly different length which gives the double helix its twisted shape. The bases can occur in any sequence. It is the sequence of the bases that makes up the instruction, a bit like the words of an instruction manual. Depending on the sequence of the bases, a particular protein will be produced. The proteins in turn will enable the cell to function in a particular way, including cell replication.

Fig 2.3 DNA: the double helix

Cell cycle

From the time of conception, all of our cells continue to multiply in order for us to grow into an adult. Once we reach adulthood our cells only divide when there is need to repair and replace old damaged cells and to reproduce. To do this, cells go through a process called the cell cycle (Fig. 2.4). The phases of the cell cycle are:

• G0: resting phase, not in cell division.

• G1 and G2: the cell builds up energy and prepares for the next stage.

• S: DNA doubles by splitting the double helix.

• M: mitosis where the cell splits into two cells.

Fig 2.4 The cell cycle.

(Reproduced with permission from Kearney N, Richardson A (2005) Nursing patients with cancer: principles and practice. Churchill Livingstone (Fig. 5.4, page 78))

By replacing old or damaged cells in a controlled manner, the number of cells in the body remains fairly constant. When cells divide, one cell becomes two. One of these will mature and take on a highly specialised function. The other will rest until it is needed to replicate once again, this is dependent on the cell type. Some cells rarely divide once they are mature; for instance, liver cells divide once every 1 or 2 years. Some cells never divide once they are specialised and are irreplaceable (staying in the G0 phase), such as nerve cells. Some cells can replicate on demand in response to physiological need, for example the endometrium, mammary glands, etc. Others continually replicate, such as blood cells, skin and hair cells, germ cells, bone marrow and the cells lining the stomach (which multiply at least twice a day).

However, all cells have a limited life span, although this varies depending on the cell function and type. Most normal cells divide about 40–60 times before they die of old age. The life span of a cell is controlled by the ends of chromosomes known as telomeres. Each time the cell divides, the telomeres get shorter and eventually the cell cannot divide and dies.

Normal cells only divide when they are needed, such as during growth (from conception to adulthood) and to replace old and damaged cells. This replication is carefully controlled by a number of checkpoints (see Fig. 2.4), which ensure that cell division only occurs when really necessary and occurs accurately. Certain genes control cell division, known as proto-oncogenes. These genes code for proteins and growth factors which signal to the nucleus of the cell to turn the cell cycle on, a bit like an accelerator of a car. There are four main groups of proteins produced by the proto-oncogenes: growth factors, growth factor receptors, signal transducers and nuclear proto-oncogenes and transcription factors.

There are other genes that turn cell division off by coding for proteins that slow everything down, a bit like the brake of a car. These are known as tumour suppressor genes. One of the key tumour suppressor genes is known as the ‘guardian of the genome’ or ‘p53’. This controls whether the cell goes into G0 to rest or starts the active cell division process by entering G1. The tumour suppressor genes and the proto-oncogenes work together in order to keep the cell cycle regulated and ensure that cells only divide when they are needed.

During the cell cycle, natural errors occur and the DNA becomes damaged. Normal cells have the ability to repair small amounts of damage by activating repair genes which make the necessary corrections. However, if the damage is too great then the cell will destroy itself by committing cell suicide or apoptosis. This prevents the mutation being passed on to future cells and causing cancer. This may explain why some people might disregard health promotion messages and base their health belief in personal experience: ‘My granny smoked 50 a day until she was 95 years old and she didn’t develop cancer!’ Smoking may well have caused damage to granny’s DNA but she may have had very good repair genes or genes that initiated apoptosis, removing the damaged DNA – she did not, therefore, develop cancer.

Unfortunately there is no way of knowing which individuals have mutated or missing repair genes and/or whose cells lack the ability to recognise and to commit cell suicide. Therefore, health promotion is extremely important. We need to prevent or minimise damage to DNA/genes in the first place by healthy lifestyle choices. Second, we need to raise awareness so that people know the signs and symptoms of cancer, ensuring early diagnosis.

What goes wrong to allow a cancer cell to develop?

Cancer is uncontrolled cellular growth which results from the loss of normal regulation of cell division. This is caused by a number of errors/mutations in either a single base (A, T, G or C) in the DNA or a segment of a chromosome. These errors might be a deleted, altered or swapped base. Additionally, a whole segment of a chromosome may not be copied properly or is not repaired or detected and removed by cell suicide.

Although DNA can spontaneously become damaged (which explains why some non-smokers develop lung cancer), generally DNA is altered by an external environmental agent. The error(s) can also be inherited from one or both parents, however this only accounts for 5–10% of all cancers. Remember that we have two copies of each gene and even if one copy of a gene gets damaged the other one will continue to control cell division. As we get older and/or are exposed to harmful environmental agents, the second gene may become damaged.

The change in the DNA sequencing results in either less or more or different proteins being produced which then changes the behaviour of the cell.

Since the mapping of the human genome (the entirety of the human hereditary information – length of DNA), a number of genetic mutations resulting in cancer have been identified. This has helped our understanding of how and why cancer develops. For example, 95% of patients with chronic myeloid leukaemia (a type of cancer of the white blood cells – granulocytes) have what is known as a Philadelphia chromosome. This occurs when a bit of chromosome 9 swaps with chromosome 22 (9 gets longer and 22 extra short, which is the Philadelphia chromosome). This then codes extra proteins which in turn increase the production of granulocytes.

Human epidermal receptor 2 (HER2) is another example of a proto-oncogene, which when damaged produces too much protein resulting in breast cells losing control of cell division. HER2 mutation has been found to be present in approximately 30–40% of breast cancers.

It isn’t just proto-oncogenes that are affected; approximately 50% of all cancers have a mutated or missing p53 tumour suppressor gene.

One of the key genes which allow the cell to self-destruct (apoptosis) is the tumour suppressor gene ‘p53’. If p53 is damaged, the cell’s ability to kill itself is reduced or lost and the cell can continue to divide unregulated.

Usually there is more than one mutation in the DNA. For instance, many individuals who develop cancer will have mutations in a proto-oncogene (when a proto-oncogene becomes damaged it is known as an oncogene), a tumour suppressor gene and a repair gene. These errors will code for different proteins and subsequently the cell will behave differently and cell cycle regulation may be overridden, resulting in uncontrolled growth (Fig. 2.5).

Fig 2.5 The progression of cancer growth

Normal cells divide at different rates, as do cancer cells. The rate of growth of a cancer depends on the cell ‘doubling time’. This is the time it takes for a cell to complete the cell cycle. The time varies from hours to months. For instance, leukaemia (cancer of the white blood cells) may divide very quickly in a matter of hours, and colorectal cancer may divide slowly over approximately 120 days. This has implications for diagnosis and treatment.

There are several other key changes in a cancer cell:

A primary cancer rarely causes a patient to die. It is usually the metastatic disease that causes death and is the most frequent cause of cancer treatment failure. This is because the cells that manage to move and settle somewhere else in the body are usually more mutated and aggressive. Even if 99.9% of cells are killed in a clinically palpable tumour (= 1 billion cells), a significant number of non-responsive cells remain to continue growing and developing. They are more likely to behave and look differently to each other and normal cells.

Patients often misunderstand secondary or metastatic disease, often thinking that they have a second primary cancer. For instance, a patient with colorectal cancer may think that she/he now has liver cancer as well as colorectal cancer, when in fact they have colorectal cancer with liver metastases. It is important to explain the difference between primary and secondary disease as this will affect the treatment plan. Treatment will be selected according to the primary disease, so the patient with colorectal cancer with liver metastases will receive chemotherapy for colorectal cancer, not chemotherapy for liver cancer. This is because the cells from the colorectal region have travelled and settled in the liver, but they remain colorectal cells, however mutated they may become.

Not all cancers metastasise. For instance, glioma and basal cell carcinoma stay at the primary site (original anatomical site). Other cancers metastasise very soon after the initial DNA damage, for instance small cell lung cancer.

Approximately 60% of patients will have metastatic disease when they present initially. Of these, 30% will have metastatic disease that will be detected by investigations (such as scans) and the remaining 30% will have microscopic metastatic disease that cannot be detected even using modern technology.

How cancer cells spread to other parts of the body?

It is incredible that cancer cells manage to metastasise as they have to get into the blood stream or lymphatic system to achieve this. They achieve it by developing their own blood supply in a process known as angiogenesis or neovascularisation and secrete enzymes that dissolve the extracellular matrix. When entering the circulation system, cancer cells have to contend with the body’s immune system and very turbulent conditions in blood vessels. From the large numbers of cancer cells that circulate in the blood stream, only < 0.01% of cells successfully deposit in distant tissues or organs. These few survive by covering themselves in platelets, thus disguising themselves and avoiding being recognised as a foreign object and being attacked by white blood cells.

What causes the DNA to become damaged?

As mentioned previously, some cancers cannot be attributed to any particular factor and may occur spontaneously. Although the exact causations of cancer are unknown, there is well-established evidence that some agents ‘initiate’ or ‘promote’ the development of cancer. These are known as carcinogens. Many are lifestyle-related factors, such as dietary, smoking or sun exposure, and are potentially preventable.

It is not a coincidence that 75% of cancers are epithelial (tissues that line the body inside and out) as these come in contact with environmental agents.

Age is a key risk factor in cancer. As we age, we are increasingly exposed to agents that cause damage to DNA and at the same time our immune system becomes less efficient and our repair genes become less effective.

It is important that causations of cancer are understood by the public so that people are able to appraise their own lifestyle behaviours and identify ways that they can change and reduce their likelihood of developing a cancer.

The following discussion presents current understanding of what are known to contribute to the development of cancer, split into three groups of carcinogens: physical, biological and chemical factors.