| Cells that undergo mutation(s) that disrupt the regulation of cell division will divide without regard to the overall needs of the organism and become apparent as a tumor or neoplasm
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| As long as the neoplastic cells remain as an intact tumor, the tumor is said to be benign, and can be removed surgically. However, if further mutations allow such tumor cells to invade and colonize other tissues, creating widespread secondary tumors or metastases, the tumor is described as malignant, and classified as a cancer. Each cancer is derived from a single cell that has undergone some heritable mutation that allows it to outgrow its surrounding cells: by the time they are first detected, tumors typically contain a billion cells. Cancers are classified according to the tissue and cell type that they are derived from: those from epithelial cells are carcinomas, those from connective tissue or muscle cells are termed sarcomas, and those from the hemopoietic system are called leukemias. About 90% of human cancers are carcinomas, the five most common being those of the lung, stomach, breast, colon/rectum, and uterine cervix.
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| A single mutation is not sufficient to convert a healthy cell to a cancer cell; several rare mutations have to occur together
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| Mutations in DNA occur spontaneously at a rate of 10-6 mutations per gene per cell division (even more in the presence of mutagens). Thus, since approximately 1016 cell divisions occur in the human body over an average lifetime, every human gene is likely to undergo mutation on about 1010 occasions. Clearly then, a single mutation is not sufficient to convert a healthy cell to a cancer cell; several rare mutations have to occur together, as demonstrated by epidemiologic studies showing that, for any given cancer, the incidence increases exponentially with age. Indeed, it has been estimated that three to seven independent mutations are usually required, leukemias apparently needing the fewest mutations and carcinomas the most.
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| Tumor progression can be observed when initial minor disruptions of cell regulation escalate into a full cancer. For example, chronic myelogeneous leukemia (CML) is initially characterized by the overproduction of white blood cells, as a result of chromosomal translocation. This chronic stage of the disease remains stable for several years before transforming into the acute, rapidly progressing phase of the disease, in which the cells have accumulated several other mutations that cause them to proliferate more rapidly. Alternatively, mutations may have arisen such that committed progenitors of the cells continue to divide indefinitely, rather than terminally differentiating and dying after a strictly regulated number of cell divisions as happens to their normal counterparts.
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| Mutations that block the normal development of cells towards an end-differentiated, nondividing cell, or a cell that would normally be programmed to die by apoptosis, have been shown to play an essential part in many cancers
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| Thus drugs that promote cell maturation may turn out to be at least as useful as those targeted to prevent cell proliferation (cytotoxic drugs).
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| THE PAPANICOLAOU OR 'PAP SMEAR' TEST OF THE UTERINE CERVIX |
| The epithelium of the uterine cervix resembles the epidermis of the skin, and comprises a proliferating basal layer that generates cells that differentiate into flat, keratin-rich cells that are eventually shed from the surface. Cancers of the uterine cervix are strongly associated with infection by human papilloma virus types 16 and 18 and arise from mutations in the basal epithelial cells, which are no longer then confined to the basal layer but invade the area normally occupied by the differentiated keratin-rich cells (dysplasia). These proliferating cells are shed at a less mature stage of differentiation than normal. Whereas the differentiated cells are characterized by their large size and highly condensed nuclei, the mutant cells have relatively large nuclei and little cytoplasm so that dysplasia can be identified in the Pap smear test, which simply involves microscopic examination of the morphology of a sample of cells scraped from the cervix. Dysplasia often remains stable or even spontaneously regresses. However, it may progress to a more serious lesion, called carcinoma in situ, in which the epithelium is entirely made up of undifferentiated proliferating cells with nuclei of variable size and shape. This lesion can be completely cured by surgery; however, in 20-30% of cases carcinoma in situ progresses over several years into a malignant cervical carcinoma. |
| Comment. Abnormal nuclear morphology is a key diagnostic tool of pathologists for identifying cancer, and correlates with the destabilization of karyotypes of cancer cells when they are cultured. These unstable karyotypes exhibit genes that become amplified or deleted, and chromosomes that are highly susceptible to loss, duplication, or translocation. These findings suggest that the cells have developed one or more mutations in the mechanisms regulating chromosomal replication, repair, recombination, or segregation, thereby facilitating the accumulation of the multiple mutations required for development of cancer. |
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In order to metastasize, cells in a tumor must be able to escape their adhesion to neighboring cells, invade surrounding tissues, enter the blood or lymph systems, and, finally, invade and colonize a new tissue. The mechanisms involved
are as yet poorly understood, but it appears that, in epithelia, loss of expression of the adhesion molecule, E-cadherin, has a key role in the ability of the cell to leave its parent tumor. Moreover, in order to bind to and traverse the basal lamina, the cells must express specific integrins to bind laminin, and type IV collagenase to digest the lamina.
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