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| Tumor Biology |
Cancer cells behave as independent cells, growing without control to form tumors. Tumors grow in a series of steps. The first step is hyperplasia, meaning that there are too many cells resulting from uncontrolled cell division. These cells appear normal, but changes have occurred that result in some loss of control of growth. The second step is dysplasia, resulting from further growth, accompanied by abnormal changes to the cells. The third step requires additional changes, which result in cells that are even more abnormal and can now spread over a wider area of tissue. These cells begin to lose their original function; such cells are called anaplastic. At this stage, because the tumor is still contained within its original location (called in situ) and is not invasive, it is not considered malignant - it is potentially malignant. The last step occurs when the cells in the tumor metastasize, which means that they can invade surrounding tissue, including the bloodstream, and spread to other locations. This is the most serious type of tumor, but not all tumors progress to this point. Non-invasive tumors are said to be benign.
The type of tumor that forms depends on the type of cell that was initially altered. There are five types of tumors.
- Carcinomas result from altered epithelial cells, which cover the surface of our skin and internal organs. Most cancers are carcinomas.
- Sarcomas result from changes in muscle, bone, fat, or connective tissue.
- Leukemia results from malignant white blood cells.
- Lymphoma is a cancer of the lymphatic system cells that derive from bone marrow.
- Myelomas are cancers of specialized white blood cells that make antibodies.
Although tumor cells are no longer dependent on the control mechanisms that govern normal cells, they still require nutrients and oxygen in order to grow. All living tissues are amply supplied with capillary vessels, which bring nutrients and oxygen to every cell. As tumors enlarge, the cells in the center no longer receive nutrients from the normal blood vessels. To provide a blood supply for all the cells in the tumor, it must form new blood vessels to supply the cells in the center with nutrients and oxygen. In a process called angiogenesis, tumor cells make growth factors which induce formation of new capillary blood vessels. The cells of the blood vessels that divide to make new capillary vessels are inactive in normal tissue; however, tumors make angiogenic factors, which activate these blood vessel cells to divide. Without the additional blood supplied by angiogenesis, tumors can grow no larger than about half a millimeter.
Without a blood supply, tumor cells also cannot spread, or metastasize, to new tissues. Tumor cells can cross through the walls of the capillary blood vessel at a rate of about one million cells per day. However, not all cells in a tumor are angiogenic. Both angiogenic and non-angiogenic cells in a tumor cross into blood vessels and spread; however, non-angiogenic cells give rise to dormant tumors when they grow in other locations. In contrast, the angiogenic cells quickly establish themselves in new locations by growing and producing new blood vessels, resulting in rapid growth of the tumor.
How do tumors begin to produce angiogenic factors? An oncogene called BCL2 has been shown to greatly increase the production of a potent stimulator of angiogenesis. It appears, then, that oncogenes in tumor cells may cause an increased expression of genes that make angiogenic factors. There are at least fifteen angiogenic factors and production of many of these is increased by a variety of oncogenes. Therefore, oncogenes in some tumor cells allow those cells to produce angiogenic factors. The progeny of these tumor cells will also produce angiogenic factors, so the population of angiogenic cells will increase as the size of the tumor increases.
How important is angiogenesis in cancer? Dormant tumors are those that do not have blood vessels; they are generally less than half a millimeter in diameter. Several autopsy studies in which trauma victims were examined for such very small tumors revealed that thirty-nine percent of women aged forty to fifty have very small breast tumors, while forty-six percent of men aged sixty to seventy have very small prostate tumors. Amazingly, ninety-eight percent of people aged fifty to seventy have very small thyroid tumors. However, for those age groups in the general population, the incidence of these particular cancers is only one-tenth of a percent (thyroid) or one percent (breast or prostate cancer). The conclusion is that the incidence of dormant tumors is very high compared to the incidence of cancer. Therefore, angiogenesis is critical for the progression of dormant tumors into cancer.