Cancer is not a single disease rather it is a general term used to describe various malignant tumours that affect all forms of higher organisms including plants and animals. More than a hundred types and sub types of cancer are known to affect the human beings. Cancer can be defined as an abnormal growth of cells in any tissue or organ of body. Cancer cells have potential to spread and grow in other parts of body. Cancer preys on the host and continues to grow indefinitely competing with normal cells of the body for nutrition.
Cancer had its origin since the evolution of multicellular organisms. Our knowledge of cancer goes back to the dawn of civilisation. The evidence of cancer has been found in skeletons of pre historic animals and Egyptian mummies. The earliest written records on cancer have been traced to the ancient Egyptian, Greek and Indian writings. The word Cancer has its origin from the Latin word Cancrum (Greek: Karkinos), which means crab. Ancient Indian surgeon, Sushruta, who used to cauterise the tumours with red hot iron rods, described various types of tumour in his text ‘Sushruta Samhita’ written in circa 600 B.C. Ancient Egyptians tried fire drill (insertion of heated metallic stick into the tumour) to treat cancer. It is believed that the Greek surgeon, Leonides, was the first to operate upon cancer with a knife.
"What causes Cancer?" was the most debatable topic during the twentieth century. After a prolonged era of confusion over the genesis of cancer, this was finally established by end of the century that cancer is caused by mutations in the growth regulatory genes & pathways including oncogenes and tumour suppressor genes.
Robert Weinberg & Douglas Hanahan, both cancer biologists, published an article “The Hallmarks of Cancer” in January 2000 that explains how a normal cell is transformed into a cancer cell by activation of oncogenes (ras, N-myc, c-myc, HER-2/neu, etc); inactivation of tumour suppressor genes (p53, Rb, Ret, WT-1, APC, etc); dysregulation of certain pathways (ras, Rb, myc, etc), evasion of apoptosis; acquisition of tumour angiogenesis; acquisition of ability to migrate, invade and colonise in other tissues and organs (metastasis); and activation of specific pathways that make cancer cells immortal.
Normal cell division (mitosis) in our body is a highly regulated mechanism, controlled by genes (made up of DNA) through growth regulatory pathways. A prolonged exposure to carcinogens damages the DNA and induces mutations in growth regulatory genes including oncogenes and tumour suppressor genes and pathways leading to loss of control over normal cell division. The mutated cells go haywire and proliferate indiscriminately (pathological mitosis), usually forming a mass, known as a neoplasm or a malignant tumour or in simple words, a Cancer.
As the time passes, the cancer cells go on accumulating further mutations and acquire more evil characteristics such as ability to invade & move into the adjoining tissues, travel through lymph and blood vessels, lodge and grow in other parts of the body to form colonies (metastasis), create their own blood vessels (tumour angiogenesis) for their nurtition, evade the process of programmed cell death (apoptosis) and acquire the ability of limitless replication, making the cancer cells immortal.
By the time most of the cancers are finally diagnosed, they have already added many mutations, for example ALL (a type of blood cancer) has been found to have 5 to 10 mutations at the time of diagnosis. Pancreatic cancer has shown 50 to 60 mutations while Breast & Colon cancers have 50 to 80 mutations at the time of diagnosis. Similarly most of the cancers have 11 to 15 aberrant (mutated) pathways at the time of diagnosis.
Further exposure to radiation emitted by X-rays, CT scans, PET scans, Bone scans, etc. during investigation may induce a few more mutations in the cancer cells making them more aggressive. Similarly radiotherapy, chemotherapy, targeted chemotherapy, hormonal therapy during treatment may induce further mutations in the cancer cells making them resistant or refractory to the therapy, which leads to progression or recurrence of cancer.
Genesis of Cancer
To understand genesis of the 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 into 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 osteo-sarcoma); 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 get accumulated, which eventually affects the oncogenes and tumour suppressor genes, thus helping the development of cancer. The 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 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 Initiated cell, which has the highest risk to become 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 proof reading 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 these 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 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 so 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 body for a couple of weeks. The chronic stress leads to production of stress hormone (cortisone), which suppresses immune system of the body, thus causing cancer.
Types of Cancer
Each and every living cell in the human body that is capable of cell division has the potential to become cancerous (malignant). Since there are many type of cells in the body, there could be as many types of cancers. About 200 cancers are already known to affect the human beings. A generic name is usually given to a group of cancers, depending on the type of the cells of their origin such as carcinoma, sarcoma, myeloma, leukaemia and lymphoma.
Carcinoma: Cancers arising from the epithelial cells are called carcinomas. This is the single largest group of cancers comprising about 80 per cent of all the human cancers. Carcinomas are further divided into squamous cell carcinomas, basal cell carcinomas and glandular cell carcinomas (adenocarcinomas).
Sarcoma: Cancers arising from the connective tissue (mesenchymal) cells are called sarcomas. The sarcomas include cancers arising from the bone, cartilage, muscle, fatty tissue and fibrous tissue.
Myeloma: Cancers arising from the plasma cells are called myelomas.
Leukaemia: Cancers arising from the blood-forming cells are called leukaemias.
Lymphoma: Cancers arising from the cells of lymphatic tissue are called lymphomas
Similarly, malignant tumours of the central nervous system are named according to the type of cells of their origin; for example, cancer arising from the glial cells is called glioma.
Spread of Cancer
Cancer spreads in the body by local invasion and by metastases. Cancer (malignant tumour) usually grows in size by progressive infiltration and invasion, destroying the adjoining tissues. Although cancer can invade any tissue in the body but the connective tissue is the softest target. After the initial growth, some of the cancerous cells become free from the primary tumour. These cells penetrate the blood vessels, lymphatic channels & body cavities and travel through the respective channels to lodge themselves in different tissues and organs of the body. These migrated cancerous (malignant) cells continue to grow at their new locations, forming secondary growths known as metastases. Most of the carcinomas metastasise through the lymphatic channels. In lymphatic spread, first of all, the local lymph nodes are involved, after which the cancerous cells travel through the natural route of lymphatic drainage. Sometimes the local lymph nodes are bypassed (Skip metastasis). Most of the sarcomas metastasise through the blood stream usually to the lungs, liver and bones. The third common way of metastases is by implantation or seeding in body cavities, usually in the peritoneal cavity. Seeding can occur in the skin or mucous membrane having close contact with the primary cancer. Sometimes, seeding of cancer is seen in post surgery wounds. Some cancers such as renal cell carcinoma have the propensity to invade veins and grow in a snake like fashion upwards in the inferior vena cava, reaching up to the heart.
Stages of Cancer
Staging of cancer is done to describe the extent of cancer, which include size of the primary tumour, its spread to the regional lymph nodes and its status of metastasis. The staging helps in assessing the treatment & prognosis of cancer. There are different staging systems, for example, Dukes & Astler Coller staging system (used to stage a colorectal cancer) and Clark's level staging system (used in malignant melanoma). The most common and globally accepted staging system is "TNM" classification. This staging system describes the size (or number) of the primary tumour (T); involvement of the regional lymph nodes (N); and the status of metastasis (M). The letter (T) is followed by: ‘x’ if the primary tumour is not assessed clinically; ‘0’ if there is no evidence of primary tumour; ‘IS’ if the tumour is in situ; or it is followed by the number 1, 2, 3 or 4, which denotes the size of tumour. The greater the number, the larger is the size of tumour. The letter (N) is followed by: ‘x’ if the involvement of regional lymph nodes is not assessed clinically; ‘0’ if the regional lymph nodes are not involved; or it is followed by the number 1, 2, 3 or 4, which denotes the extent of involvement of regional lymph nodes. The letter (M) is followed by: ‘x’ if the metastasis not assessed clinically; ‘0’ if there is no evidence of metastasis; or ‘1’ if the cancer has metastasised. These numbers are usually translated for convenience of the patient, as Stage I, Stage II, Stage III, etc.
Attributes of Cancer
Cancer has different forms in different tissues but most of the cancers have some common biological properties such as unrestrained cell division; lack of cell maturation; loss of the normal cellular functions; and invasive behaviour of the cells. The four major attributes that differentiate the cancerous cells from normal cells of the body are clonality, autonomy, anaplasia and metastasis.
Clonality: Cancer cells multiply to form clone.
Autonomy: Cancer cells are not regulated by the body.
Anaplasia: Cancer cells do not have cellular differentiation.
Metastasis: Cancer cells can grow in other tissues and organs of the body.
Cancer biologists, Robert Weinberg & Douglas Hanahan published an article “The Hallmarks of Cancer” in January 2000 that identified six essential traits of human cancer cells, which include:
1. Pathological mitosis by activation of oncogenes (such as ras or myc).
2. Inactivation of tumour suppressor genes (such as Rb) that normally inhibit abnormal cell growth.
3. Evasion of programmed cell death (apoptosis).
4. Acquire potential of limitless replication making cancer cells immortal.
5. Tumour angiogenesis
6. Migration to other organs, invade their tissues and colonise these organs (tissue invasion and metastasis).