To understand the genesis of human cancer, one should know that an adult human body is made up of approximately 100 trillion cells, which are the structural and functional units of the body. These cells are organised in specialised tissues to form different organs and systems of the body. The origin of all these cells can be traced to a single cell called zygote that is formed by fusion of ovum and sperm during the event of fertilisation. The zygote initially passes through a phase of rapid cell division by mitosis. After this initial phase, some cells undergo changes in their size, shape and contents depending on the specialised work they would undertake later. This phase of specialisation is called phase of cell differentiation, which enables the cells to form different tissues, organs and systems of the body. The process of cell division and differentiation is essential for growth and development of the body. In a fully developed human body, most of the cells do not divide except in those tissues, which require continuous renewal, for example, an adult human body contains about 5 litres of blood and each millilitre of the blood contains about 5 million red blood cells (RBCs). Keeping in mind that the average life span of RBC is 120 days, it is calculated that approximately 2.5 million cells must divide every second in the bone marrow to replace the dying RBCs. Cell division also occurs in other tissues of the body to replace the worn out cells.
The process of cell division in the human body is a well-regulated phenomenon, controlled by genes, made up of deoxyribonucleic acid (DNA). If the specific genes that control the process of normal cell division get mutated (due to damage to the DNA caused by some external or internal factors), they may lose their control over the normal cell division, resulting in unregulated proliferation of cells, forming cancerous cells. The process of conversion of a normal cell into the cancerous (malignant) cell is called malignant transformation. It has been observed that almost in all instances cancer is caused by mutations in the genes. Three different groups of genes are known to play an important role in the development of cancer. These include Oncogenes, Tumour suppressor genes and Mutator genes.
Oncogenes are responsible for transforming a normal cell to the cancerous (malignant) cell. Oncogenes are formed by mutations (due to viral and non-viral factors) in the pre-existing normal genes, called Proto-oncogenes. Oncogenes remain harmless in a cell until they get activated (mutated). The activated oncogenes produce aberrant proteins (growth factors and cellular growth factor receptors), which induce unregulated cell division, forming the cancerous cells. Activation of specific oncogenes leads to the development of a particular cancer. Peyton Rous of the Rockefeller Institute in New York was the first to discover the existence of oncogenes in 1910. He got very late recognition for his work, when he was awarded the Nobel Prize in Physiology and Medicine in the year 1966 at the age of 85 years. So far, more than thirty oncogenes have been identified, which include: ras family of oncogenes (associated with about 50 per cent of all the human cancers); c-myc oncogene (associated with Burkitt’s lymphoma); N-myc oncogene (associated with the neuroblastoma); and HER-2/neu oncogenes (associated with the breast and the ovarian cancers). Researchers believe that a couple of activated oncogenes might exist in a normal cell. It has been observed that at least three oncogenes must get activated in a cell, before it becomes cancerous.
Tumour suppressor genes produce regulatory proteins, which inhibit the process of malignant transformation by suppressing cellular proliferation. If mutation occurs in tumour suppressor genes, it may lose its tumour suppressing action, which could prove an important event in the genesis of cancer. It has been observed that the tumour suppressor genes show a better tumour specificity than the oncogenes. The most important tumour suppressor genes known so far is p53 gene that suppresses uncontrolled proliferation of cells as well as triggers apoptosis (programmed cell death). Mutations in p53 gene are seen in about 50 per cent cases of human cancers. Other tumour suppressor genes include: Rb gene (associated with Retinoblastoma and osteosarcoma); Ret gene (associated with Endocrine cancer); WT-1 (associated with Wilm's tumour); NF-1 (associated with Neurofibromatosis type-1); NF-2 (associated with Neurofibromatosis type-2); APC and DCC (associated with the colon cancer).
Mutator genes are another class of genes that have been discovered recently. The job of mutator genes is to repair the damaged DNA. If mutations occur in mutator genes, the DNA damage may accumulate, which eventually affects the oncogenes and tumour suppressor genes, thus helping the development of cancer. Hereditary non-polyposis colon cancer (HNPCC) is a familial syndrome, which occurs due to mutations in a mutator gene. Five mutator genes have been identified so far.
The risk of developing cancer is increased manifold when a person is exposed to certain physical, chemical or biological agents, collectively known as carcinogens that can cause mutation in the genes by damaging the DNA. When some carcinogen enters a cell, the natural cellular response is to convert it into a harmless substance and eliminate it from the body. Certain enzymes known as detoxifying enzymes carry out this job. The rate of detoxification varies in different individuals. If the process of detoxification occurs slowly (due to lack of detoxifying enzymes), the carcinogen is going to remain in the cell for a longer period, enhancing the chances of DNA damage.
Carcinogenesis is a multi-step process. A large number of carcinogens have mutagenic activity, however all the mutagens are not carcinogenic. The sub-optimal dose of a carcinogen may only alter the affected cell. This altered cell is known as the Initiated cell, which has the highest risk of becoming cancerous. Further exposure of the initiated cell to the same carcinogen or certain other substance (which may or may not be a carcinogen) can transform it to the cancerous cell. The substance that transforms the initiated cell to the cancerous cell is called Tumour promoter.
Although any living cell (that is capable of division) in the human body has the potential to become cancerous, but the malignant transformation is considered as the rarest of rare event, because the DNA chromosomal strands are replicated in each cell with incredible precision and the proofreading process repairs the damaged DNA strands, before the mitotic process is allowed to proceed. In spite of all these precautions taken by Nature, one newly formed cell in every few millions still gets mutated, but the immune cells of the body act as a scavenger by destroying this abnormal (mutated) cell. Ultimately, only a fraction of the mutated cells ever succeed in transforming into the cancerous cell.
Most of the newly formed cancerous cells never grow beyond the microscopic stage because the immune system of the body is capable of nipping these abnormal cells in the bud. The transformation of a normal cell into the cancerous cell is probably not such a critical event in the development of cancer as the body’s inability to destroy the newly formed cancerous cells, when they are few in number. Immune cells of the body normally recognise and destroy the newly formed cancerous cells. This work is executed by cytotoxic T-lymphocytes (T cells), Natural Killer (NK) cells, Lymphokine Activated Killer (LAK) cells and Macrophages. The immune cells produce specific anticancer agents, known as Cytokines (Lymphokines and Monokines), which include Interleukins (IL-1 to IL-15), Interferons (alpha, beta and gamma), Tumour Necrosis Factors (TNF) and Colony Stimulating Factors (CSF). So, the human body is having its own immunotherapeutic regime in the form of Cytokines, which can destroy and eliminate the cancerous cells without harming the healthy cells. Sometimes spontaneous regression of a tumour occurs due to the effect of Cytokines. The risk of developing cancer is multiplied manifold in those persons, whose immune system is suppressed due to any reason, for example, undernutrition, old age, HIV and other viral infections. Immune system of the body also gets suppressed by the frequent, widespread, chronic and habitual use of certain drugs such as antibiotics, corticosteroids, painkillers and the drugs used in chemotherapy. Vaccinations also suppress the immunity of the body for a couple of weeks. The chronic stress leads to production of stress hormone (cortisone), which suppresses the immune system of the body, thus causing cancer.