Cancer is a group of many related diseases that have to do with cells. Cancer occurs when cells that are not normal grow and spread very fast. Unlike normal cells, cancer cells just continue to grow and divide out of control and don’t die when they are supposed to die. The cells that undergoes abnormal and uncontrolled division causes cancer. Cancer cells grow in an uncontrolled manner, invading normal tissues and organs and eventually spreading throughout the body. The generalized loss of growth control exhibited by cancer cells is the net result of accumulated abnormalities in multiple cell regulatory enzymes.

Classification of cancer:

Cancer can result from abnormal proliferation of different kinds of cells in the body, so there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment. When the normal cells continue multiplying when the body doesn’t need them, the result is a mass of growth, also called as tumor. The tumors are classified in two types:

1) Benign tumor:

A benign tumor such as a common skin wart remains confined to its original location, neither invading neither surrounding normal tissue nor spreading to distant body sites. Benign tumor can be removed surgically.

2) Malignant tumor:

A malignant tumor is capable of both invading surrounding normal tissue and spreading throughout the body via circulatory or lymphatic systems. Only malignant tumors are properly referred to as cancers and it is their ability to invade and metastasize, that make cancer so dangerous. The spread of malignant tumors to distant body sites frequently makes them resistant to such localized treatment.

Both benign and malignant tumors are classified according to the type of cell from which they arise. Most cancers fall into one of the three main groups:

a) Carcinomas:

Carcinomas include approximately 90% of human cancers. They are malignancies of epithelial cells.

b) Sarcomas:

These are rare in humans. They are solid tumors of connective tissues, such as muscle, bone, cartilage and fibrous tissue.

c) Leukemia and lymphomas:

They account for approximately 8% of human malignancies. Leukemia arises from the blood flowing cells and lymphoma arises from cells of immune system.

Causes of cancer:

Substances that cause cancer are called as carcinogens. Many factors may affect the likelihood that cancer will develop and it is overly simplistic to speak of single cause of most of the cancers. Nevertheless, many agents including radiation, chemicals of viruses, have been found to induce cancer in both experimental animals and humans.

Radiations and many chemical carcinogens act by damaging DNA and inducing mutations. These carcinogens are generally referred to as initiating agents, since the induction of mutations in the target genes is thought to be the initial event leading to cancer development. Some of the initiation agents that contribute to human cancers include solar ultraviolet radiation, carcinogenic chemicals in tobacco smoke and aflatoxin, a potent liver carcinogen produced by some molds that contaminate improperly stored supplies of peanuts and other grains. The carcinogens in tobacco smoke are the major identified causes of human cancer. Other carcinogens contribute to cancer development by stimulating cell proliferation, rather than by inducing mutations. Such compounds are referred to as tumor promoters, since increased cell division they induce is required for the outgrowth of a proliferative cell population during early stages of tumor development. The esters that stimulate cell proliferation by activation of protein kinase are classic examples. Their activity was defined by studies of chemical induction of skin tumors in mice.

Hormones, particularly estrogens, are important as tumor promoters in the development of some human cancers. The proliferation of cells of uterine endothelium is stimulated by estrogen and exposure to excess estrogen significantly increases the likelihood that a woman will develop endometrial cancer. In addition to chemicals and radiations, some viruses also induce cancer both in experimental animals and humans. The human cancers caused by viruses include linear cancer and cervical carcinogens which together account for 10-20% of world wide cancer incidence.

Properties of cancer cells:

A primary distinction between cancer cells and normal cells in culture is that normal cells display density-dependent inhibition of cell proliferation. Normal cells proliferate until they reach a finite cell density, which is determined in part by availability of growth factors added to the culture medium. They then cease proliferation and become quiescent, arrested in the G0 stage of cell cycle. The proliferation of most cancer cells, however, is not sensitive to density dependent inhibition. A related difference between normal cells and cancer cells is that many cancer cells have reduced requirements for extra cellular growth factors.

The growth factor requirements of many tumor cells are reduced compared to their normal counterparts, contributing to the unregulated proliferation of tumor cells both in vitro and in vivo. In some cases, cancer cells produce growth factors that stimulate their own proliferation. Cancer cells are also less stringently regulated than normal cells by cell-cell and cell matrix interactions. Most cancer cells are less adhesive than normal cells, often as a result of reduced expression of cell surface adhesion molecules.

Tumor cells continue moving after contact with their neighbors, migrating over adjacent cells and growing in disordered and multilayered patterns. Not only the movement but also the proliferation of many normal cells is inhibited by cell-cell contact and cancer cells are characteristically insensitive to such contact inhibition of growth.

Development of cancer:

One of the fundamental features of cancer is tumor colonailty. The development of tumors from single cell origin of many tumors has been demonstrated by analysis of X-chromosome inactivation.

One member of the X-chromosome pair is inactivated. It occurs randomly during embryonic development, so one X-chromosome is inactivated in other cells. Thus if female is heterozygous for an X-chromosome gene, it will be expressed in different cells. Normal tissues are composed of mixtures of cells with different inactive X-chromosome, so expression of both alleles is detected in normal tissues of heterozygous females. Tumor tissues generally express only one allele of a heterozygous X-chromosome gene. All the cells constituting such a tumor were derived from a single cell of origin, in which the pattern of ‘X’ inactivation was fixed before the tumor began to develop.

At the cellular level, the development of cancer is viewed as a multi-step process involving mutations and selection for cells with progressively increasing capacity for proliferation, survival, invasion and metastasis.

Stages of tumor development:

a) The initiation of tumor development begins with mutation. The tumor develops as a result of mutation. The number of mutations involved in different types of tumors may vary. As a result of mutation, tumor begins to develop and the normal cell more likely begins to divide than it normally would divide.

b) This develops a condition called hyperplasia, in which the altered cell and its descendents grow and divide too often. Sometimes, another mutation occurs in one of these cells, thus increasing its tendency to divide.

c) The second mutation develops a condition called as dysphasia, in which mutated cell and its descendents divide rapidly and look abnormal.

d) After a certain period of time, one of the cells experiences another mutation. This mutated cell and its descendents are very abnormal in both growth and appearance. The tumor formed from these cells is contained within its tissue of origin, causing insitu cancer. Insitu cancer remains contained indefinitely.

e) There are chances for some cells to experience additional mutations. These mutations allow the tumor to invade neighboring tissues and shed cells into blood or lymph. This tumor is said to be malignant tumor. The escaped cells then establish new tumors (metastases) at other locations in the body.

Genetics of cancer:

The cancer development involves some important genes. They are broadly classified into two categories depending on their function in cell.

1) Tumor Suppressor Genes:

Tumor suppressor genes represent the opposite side of cell growth control, normally acting to inhibit cell proliferation and tumor development. In many tumors, these genes are lost or inactivated, thereby removing negative regulators of cell proliferation and contributing to the abnormal proliferation of tumor cells.

Identification of tumor suppressor genes:

The first insight into the activity of tumor suppressor genes came from somatic cell hybridization experiments initiated by Henry Harris and his colleagues in 1969. The fusion of normal cells with tumor cells yielded hybrid cells containing chromosome from both parents. The first tumor suppressor genes were identified by studies of retinoblastoma, a rare childhood eye tumor. Provided that the disease is detected early, retinoblastoma can be successfully treated.

In 1971, Alfred Knudson proposed that the development of retinoblastoma requires two nutrients which are now known to correspond to the loss of both the functional copies of the tumor susceptibility gene, the Rb tumor suppressor gene. This gene would be present on homologous chromosome of a diploid cell. The significance of Rb tumor suppressor gene thus extends beyond retinoblastoma, apparently contributing to development of substantial fractions of more common human cancer. The second tumor suppressor gene to have identified is p53, which is frequently inactivated in a wide variety of human cancers including leukemia, lymphomas, sarcomas, brain tumors and carcinomas of many tissues, including breast, colon and lung. In fatal mutations, p53 may play a role upto 50% of all cancer, making it most common target of genetic alterations in human malignancies.

Like p53, the INKa tumor suppressor gene plays a role in several common cancers including lung cancer. The two other tumor suppressor genes Apc and Pccr are frequently deleted or mutated in colon cancers. In addition to being involved in inherited cases of this adult cancer, inherited mutation of Apc gene are responsible for a rare hereditary form of colon cancer called as familial adenomatous polyposis.

Function of tumor suppressor gene product:

The proteins encoded by the NF-I tumor suppressor genes inhibit cell proliferation. Inactivation of tumor suppressor genes therefore leads to tumor development by eliminating negative regulatory proteins. In several cases, tumor suppressor proteins inhibit the same cell regulatory pathways that are stimulated by the products of oncogenes.

The proteins encoded by NF-I tumor suppressor gene is an interesting example of antagonism between oncogenes product and tumor suppressor gene products. The NF-I proteins down regulate the Ras proto oncogenes proteins by acting as a GTPase activating protein. High levels of the active GTP bound form of Ras genes are therefore present in tumor cells in which NF-I have been inactivated and inactivation of tumor suppressor gene appears to stimulate cell proliferation as a result of deregulation of Ras signaling pathway.

Oncogenes:

These are the genes whose protein products enhance cell division and viability of cells. They also contribute to tumor growth by inhibiting cell death.

Cancer results from alterations in critical regulatory genes that control cell proliferation, differentiation and survival. Studies of tumor viruses revealed that specific genes called oncogenes are capable of inducing cell transformation, thereby providing the first insights into the molecular basis of cancer. Therefore in terms of our overall understanding of cancer, it has been critically important that studies of viral oncogenes also led to the identification of cellular oncogenes which are involved in the development of non-virus induced cancers.

Oncogenes in human cancer:

Some of the oncogenes identified in human tumors are cellular homologues to oncogenes that were previously characterized in retroviruses, whereas others are new oncogenes first discovered in human cancer. The first human oncogenes identified in gene transfer assay were subsequently identified as the human homology of rash oncogenes of Harvey sarcoma virus. The closely related members of ras gene family are rash, rasK, rasN. These oncogenes are most frequently encountered in human tumors. These genes are involved in approximately 15%-50% of colon and 25% of lung carcinoma.

The ras oncogenes are not present in normal cell; rather they are generated in tumor cells as a consequence of mutations that occur during tumor development. The ras oncogenes differ from their proto-oncogene by point mutation resulting in single amino acid substitution at critical positions. In animals it ahs been found that mutations that convert ras proto-oncogene to oncogenes are caused by chemical carcinogens, providing a direct link between the mutagenic action of carcinogens and cell transformation. The first characterized example of oncogenes activation by chromosome translocation was the involvement of the C-myc oncogenes in human Burkitt’s lymphomas and mouse plasmocytomas, which are malignancies of antibody producing B lymphocytes. Both of these tumors are characterized by chromosome translocations involving the gene that encode immunoglobulins.