Cancer can be defined as a disease in which a group of abnormal cells grow uncontrollably by disregarding the normal rules of cell division. Normal cells are constantly subject to signals that dictate whether the cell should divide, differentiate into another cell or die. Cancer cells develop a degree of autonomy from these signals, resulting in uncontrolled growth and proliferation. If this proliferation is allowed to continue and spread, it can be fatal. In fact, almost 90% of cancer-related deaths are due to tumour spreading – a process called metastasis.
The foundation of modern cancer biology rests on a simple principle – virtually all mammalian cells share similar molecular networks that control cell proliferation, differentiation and cell death. The prevailing theory, which underpins research into the genesis and treatment of cancer, is that normal cells are transformed into cancers as a result of changes in these networks at the molecular, biochemical and cellular level, and for each cell there is a finite number of ways this disruption can occur.
Phenomenal advances in cancer research in the past 50 years have given us an insight into how cancer cells develop this autonomy. We now define cancer as a disease that involves changes or mutations in the cell genome. These changes (DNA mutations) produce proteins that disrupt the delicate cellular balance between cell division and quiescence, resulting in cells that keep dividing to form cancers.
Cancer is clonal in origin
Current dogma states that cancer is a multi-gene, multi-step disease originating from a single abnormal cell (clonal origin) with an altered DNA sequence (mutation). Uncontrolled proliferation of these abnormal cells is followed by a second mutation leading to the mildly aberrant stage. Successive rounds of mutation and selective expansion of these cells results in the formation of a tumour mass see the figar
Subsequent rounds of mutation and expansion leads to tumour growth and progression, which eventually breaks through the basal membrane barrier surrounding tissues and spreads to other parts of the body (metastasis). Death as a result of cancer is due to the invading, eroding and spread of tumours into normal tissues due to uncontrolled clonal expansion of these somatic cells.
Evidence for the clonal expansion model can be demonstrated with a simple but striking clinical example. The enzyme, glucose-6-phosphate dehydrogenase (G6PD) has two forms, G6PD-A and G6PD-B, which differ from each other by 1 single amino acid. Some people have cells that contain either type A or type B but no cell contains both, hence tissues are a mosaic of cells with these two types. Individuals who develop Chronic Myeloid Leukaemia (CML – a blood cancer) contain cancerous myeloid cells which all contain only one type of the enzyme, either type A or type B, but never both, clearly demonstrating that cancers are clonal in origin.
Insights into cancer
Initiation and progression of cancer depends on both external factors in the environment (tobacco, chemicals, radiation and infectious organisms) and factors within the cell (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). These factors can act together or in sequence, resulting in abnormal cell behaviour and excessive proliferation. As a result, cell masses grow and expand, affecting surrounding normal tissues (such as in the brain), and can also spread to other locations in the body (metastasis). However, it is important to remember that most common cancers take months and years for these DNA mutations to accumulate and result in a detectable cancer.
Cancers arise approximately in one among every 3 individuals. DNA mutations arise normally at a frequency of 1 in every 20 million per gene per cell division. The average number of cells formed in any individual during an average lifetime is 1016 (10 million cells being replaced every second!). It would therefore be logical to assume that human populations anywhere in the world would show similar frequencies of cancer. However, cancer incidence rates (number of individuals diagnosed) vary dramatically across countries. Evidently, some factors seem to intervene to dramatically increase cancer incidences in some populations. The obvious inference is that contributory factors that cause cancer are either hereditary or environmental. It means that either certain populations carry a large number of cancer-susceptibility genes or that the environment in which populations live largely contribute to the cancer incidence rates.
Causes of cancer (aetiology of cancer)
Which of the two – genes or the environment – play a dominant role in developing cancer? While genes are distributed unequally across populations, they do not explain the differences in cancer incidence rates in the world. This is demonstrated by most dramatically in this example. Incidences of stomach cancer are 6–8 times higher among Japanese compared to Americans. However, children of migrant Japanese settled in America show incidence rates of stomach cancer comparable to that of the American population. Therefore, the risk of developing cancer seems largely environmental, accounting for more than 90% of all cancers caused.
Lifestyle and Environment
The first known report linking the influence of lifestyle on cancer was by John Hill, an English physician, who noted the link between nasal cancer and the use of tobacco snuff. In the late 18th century, Sir Percival Pott reported that scrotal cancer in chimney sweeps was linked to poor hygiene and accumulation of cancer-causing agents from soot. The Danish Chimney sweeper’s Guild recommended daily baths and was the most likely reason for the dramatic reduction in scrotal cancer incidence rates in Europe.
In 1950, compelling epidemiological evidence showed that heavy cigarette smokers ran a 20-fold higher risk of developing lung cancer compared to non-smokers. Since then, tobacco and alcohol consumption have been linked to almost ~170,000 mouth and throat cancer deaths per year in the US alone. Over half a million deaths every year are expected to be caused by lifestyle choices such as obesity, physical inactivity, diets (low in vegetables, high in salt or nitrates are linked to stomach and oesophageal cancers whereas high fat, low fibre diets are linked to bowel, pancreatic, breast and prostate cancer).
Risk of cancers are also increased by infectious agents including viruses [hepatitis B virus (HBV), human papillomavirus (HPV), human immunodeficiency virus (HIV) – increase risk of nasopharyngeal, cervical carcinomas and Kaposi’s sarcoma] and bacteria such as Helicobacter pylori (stomach cancers). Incidences of skin cancers (melanomas) are on the rise, especially in Australia, due to exposure to high levels of ultraviolet radiation in the sun’s rays and popularity of tanning salons. However the risk of developing some of these cancers can be reduced by changing lifestyles and vaccines (like Gardasil© which reduces the risk of cervical carcinomas).
Initiation and progression of cancer is also due to exposure to cancer-causing agents (carcinogens, mutagens). These are present in food and water, in the air, and in chemicals and sunlight that people are exposed to. Since epithelial cells cover the skin, line the respiratory and alimentary tracts, and metabolize ingested carcinogens, it is not surprising that over 90% of cancers originate from epithelia (‘carcinomas’). In less than 10% of cases, a genetic predisposition increases the risk of cancer developing a lot earlier (E.g. certain childhood leukemia’s, retinal cancers etc.).
Although cancer can occur in persons of every age, it is common among the aging population below pic. Sixty percent of new cancer cases and two thirds of cancer deaths occur in persons > 65 years. The incidence of common cancers (eg, breast, colorectal, prostate, lung) increases with age.
There are several theories as to why cancer incidence increases in the elderly: age-related alterations in the immune system (decreased immune surveillance); accumulation of random genetic mutations or lifetime carcinogen exposure (especially for colorectal and lung cancers); hormonal alterations or exposure; and long lifespans.
Multiple genetic changes are necessary for the development of cancer, most clearly exemplified by the stepwise genetic changes shown by many colon polyps progressing to cancer. The exponential rise in many cancers with age fits with an increased susceptibility to the late stages of carcinogenesis by environmental exposures. Lifetime exposure to estrogen may lead to breast or uterine cancer; exposure to testosterone leads to prostate cancer. The decline in cellular immunity may also lead to certain types of cancer that are highly immunogenic (e.g., lymphomas, melanomas). Accumulation of DNA mutations have to be amplified to constitute a cancer, therefore the longer the lifespan, the higher the risk of developing cancer.
Identification and histopathology of cancers
Why do we need to identify and classify cancers? There are several benefits to identifying and classifying cancers using histological sections and staining methodology
1. Diagnosis: Microscopic observation helps determine whether the tumour tissue is benign (harmless) or malignant (potentially fatal). Gross cellular morphology and tissue specific markers are used to classify cancerous cells.
2. Therapy: Pathology can be used as a confirmation or in prognosis E.g: has the surgeon removed the entire tumour? Or was the treatment effective in eliminating tumours? Or what is the rate of progression of the cancer? Progression can be predicted by histotyping. E.g. Patients with simple hyperplasia in the uterine epithelium have <1% chance of developing cancer compared 82% risk in patients with atypical hyperplasia.
3. Cellular origin (histogenesis): Determining the origins of the tumour by histopathological classification of tissue is useful in a) identifying whether the tumour is a primary or secondary tumour e.g. a liver tumour may have metastasised from elsewhere or b) source of origin of the tumour e.g. lung cancer due to smoking is epithelial (lung carcinoma) but due to asbestos exposure is mesothelial (mesothelioma* or asbestos cancer).
The 6 hallmarks of cancer
DNA mutations result in defects in the regulatory circuits of a cell, which disrupt normal cell proliferation behaviour. However the complexity of this disease is not as simple at the cellular and molecular level. Individual cell behaviour is not autonomous, and it usually relies on external signals from surrounding cells in the tissue or microenvironment. There are more than 100 distinct types of cancers and any specifi organ can contain tumours of more than one subtype. Th s provokes several questions. How many of these regulatory circuits need to be broken to transform a normal cell into a cancerous one? Is there a common regulatory circuit that is broken among different types of cancers? Which of these circuits are broken inside a cell and which of these are linked to external signals from neighbouring cells in the tissue?
The answer to these questions can be summarised in a heterotypic model, manifested as the six common changes in cell physiology that results in cancer (proposed by Douglas Hanahan and Robert Weinberg in 2000). This model looks at tumours as complex tissues, in which cancer cells recruit and use normal cells in order to enhance their own survival and proliferation. The 6 hallmarks of this currently accepted model can be described using a traffic light analogy.
1) Immortality: Continuous cell division and limitless replication
2) Produce ‘Go’ signals (growth factors from oncogenes)
3) Override ‘Stop’ signals (anti-growth signals from tumour suppressor genes)
4) Resistance to cell death (apoptosis)
5) Angiogenesis: Induction of new blood vessel growth
6) Metastasis: Spread to other sites