6. Cell Division

Failure of proliferation control

Cancer can arise when the controlling factors over cell growth fail and allow a cell and its descendants to keep dividing at the expense of the organism. Studies of viruses that transform cultured cells and thus lead to the loss of control of cell growth have provided insight into the mechanisms that drive the formation of tumours. Transformed cells may differ from their normal progenitors by continuing to proliferate at very high densities, in the absence of growth factors, or in the absence of a solid substrate for support.

cancer-causing retroviruses

cancer-causing retrovirusesRetroviral insertion can convert a proto-oncogene, integral to the control of cell division, into an oncogene, the agent responsible for transforming a healthy cell into a cancer cell. An acutely transforming retrovirus (shown at top), which produces tumours within weeks of infection, incorporates genetic material from a host cell into its own genome upon infection, forming a viral oncogene. When the viral oncogene infects another cell, an enzyme called reverse transcriptase copies the single-stranded genetic material into double-stranded DNA, which is then integrated into the cellular genome. A slowly transforming retrovirus (shown at bottom), which requires months to elicit tumour growth, does not disrupt cellular function through the insertion of a viral oncogene. Rather, it carries a promoter gene that is integrated into the cellular genome of the host cell next to or within a proto-oncogene, allowing conversion of the proto-oncogene to an oncogene.Encyclopædia Britannica, Inc.

Major advances in the understanding of growth control have come from studies of the viral genes that cause transformation. These viral oncogenes have led to the identification of related cellular genes called protooncogenes. Protooncogenes can be altered by mutation or epigenetic modification, which converts them into oncogenes and leads to cell transformation. Specific oncogenes are activated in particular human cancers. For example, an oncogene called RAS is associated with many epithelial cancers, while another, called MYC, is associated with leukemias.

An interesting feature of oncogenes is that they may act at different levels corresponding to the multiple steps seen in the development of cancer. Some oncogenes immortalize cells so that they divide indefinitely, whereas normal cells die after a limited number of generations. Other oncogenes transform cells so that they grow in the absence of growth factors. A combination of these two functions leads to loss of proliferation control, whereas each of these functions on its own cannot. The mode of action of oncogenes also provides important clues to the nature of growth control and cancer. For example, some oncogenes are known to encode receptors for growth factors that may cause continuous proliferation in the absence of appropriate growth factors.

Loss of growth control has the added consequence that cells no longer repair their DNA effectively, and thus aberrant mitoses occur. As a result, additional mutations arise that subvert a cell’s normal constraints to remain in its tissue of origin. Epithelial tumour cells, for example, acquire the ability to cross the basal lamina and enter the bloodstream or lymphatic system, where they migrate to other parts of the body, a process called metastasis. When cells metastasize to distant tissues, the tumour is described as malignant, whereas prior to metastasis a tumour is described as benign.

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