Cancer Pathology 821 Cell Biology of Cancer

In the cell cycle, dividing cells undergo one mitosis (M) after another, passing through Gi, S (DNA synthesis phase), and G2 phases. Some cells leave the cycle temporarily, entering a G0 state from which they can be rescued by appropriate mitogenic stimuli. Other cells leave the cycle permanently, entering terminal differentiation.

Any population of cells can grow in number by any one of three mechanisms: shortening the length of the cell cycle, decreasing the rate of cell death, and moving G0 cells into the cell cycle. All three mechanisms operate in normal and abnormal growth. In most tumours, all three mechanisms are important in determining the growth of the tumour, which is best characterized by its doubling time. Doubling time of tumours range from as little as 17 days for Ewing sarcoma to more than 600 days for certain adenocarcinomas of the colon and rectum. However, the fastest growing tumour is probably Burkitt's lymphoma, with a mean doubling time of less than 3 days.

Cancer is a multi-step process in which multiple genetic alterations must occur, usually over a span of years, to have a cumulative effect on the control of cell differentiation, cell division, and growth [3].

As in cancer predisposing syndromes, these genetic alterations are sometimes carried in the germline. Among human tumours, heritable mutations are an exception. Most alterations are acquired in somatic life in the form of chromosomal translocations, deletions, inversions, amplifications or point mutations. Certain oncogenic viruses play important roles in a few human tumours. Examples are human papilloma-virus in cervical cancer and skin tumours, Ep-stein-Barr virus in nasopharyngeal carcinoma and Burkitt's lymphoma, and human T-cell leukaemia viruses (e.g. HTLV-I, HTLV-II) in T-cell leukaemia.

In recent past decades there has been an extraordinary progress in the understanding of the mechanisms of oncogenesis. The application of molecular biological techniques in the field of tumour virology, cytogenetics, and cell biology led to the discovery of the transforming genes of tumour viruses, the genes activated at the breakpoints of non-random chromosomal translocations of lymphomas and leukaemias, the correlation between growth factors or growth factor receptors and certain transforming genes, and the existence of transforming genes that are activated in vivo and in vitro by direct-acting chemical carcinogens [4-6].The transforming genes are collectively called oncogenes. Oncogene products are positive effectors of transformation. They impose their activity on the cell to elicit the transformed pheno-type and can be considered positive regulators of growth. To the transformed cell, they represent a gain in function. Tumour suppressor gene products are negative growth regulators and their loss of function results in expression of the transformed phenotype.

The normally functioning cellular counterparts of the oncogenes, called protooncogenes are also important regulators of biological processes. They are localized in different cell compartments, are expressed at different stages of the cell cycle, and appear to be involved in the cascade of events that maintain the ordered procession through the cell cycle.

The cell cycle is regulated by external mitogens (e.g. growth factors, peptide and steroid hormones, lymphokines), which activate a process called signal transduction by which specific signals are transmitted within the cell to the nucleus. The process is also mediated by non-integral-membrane-associated proteins belonging to the tyrosine kinase, RAS gene families, and members of the MAPK family. Signals generated by mitogenic stimulation can lead to the expression of specific genes coding for proteins localized in the nucleus. Certain members of the nuclear oncogene protein family have been shown to be transactivators of specific RNA transcripts.

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