Chapter category: Cell Cycle
Hypoxia and Cell Cycle
Cell Cycle Checkpoints and Cancer
Edited by: Mikhail V. BlagosklonnyISBN: 1-58706-067-1
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Chapter authors:
Rachel A. Freiberg, Susannah L. Green and Amato J. Giaccia
Tumor initiation is dependent on several key changes in the requirements for cell growth. Three of the most important features that distinguish transformed cells from untransformed cells are the loss of senescence, anchorage independent growth, and loss of contact inhibition. Cells that adopt a transformed phenotype based on these criteria typically exhibit rapid growth as they have escaped regulation from both internal and external regulatory signals. This uncontrolled cellular growth leads to an accumulation of cells, which are initially genetically identical, but continued growth results in additional mutations which can lead to the outgrowth of transformed cell variants that possess a survival advantage in the context of the tumor microenvironment. When the tumor is less than 150 mM or approximately ten cells in diameter, the supply of oxygen and nutrients through passive diffusion is sufficient to support growth and metabolism of transformed cells. However, as tumor cells continue dividing unchecked, they exceed their ability to obtain sufficient nutrients and oxygen by diffusion alone from pre-existing blood vessels. As a result, regions of the tumor become hypoxic and start secreting mitogens such as VEGF (vascular endothelial cell growth factor) which can stimulate the migration of microvascular endothelial cells into the tumor region to form new microvessels. However, these new microvessels are often disorganized and malformed, resulting in inefficient oxygen and nutrient delivery. Ultimately, this process results in tumor containing areas that are either poorly perfused or subjected to cycling hypoxia through the opening and closing of blood vessels. Angiogenesis has now been recognized as a critical modulator of tumor cell expansion and angiogenic activity has also been implicated in the development of metastases.1, 2 Transformed cells unable to tolerate the nutrient and oxygen poor microenvironment become necrotic or apoptotic, and the cells that survive are selected to do so by their ability to resist apoptosis and reduce their oxygen requirements by cycling slowly or switching to glycolysis. In this way, hypoxia has been suggested to act as a selective pressure for the expansion of variants resistant to its growth restrictive conditions.
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Hypoxia and Cell Cycle
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Tumor initiation is dependent on several key changes in the requirements for cell growth. Three of the most important features that distinguish transformed cells from untransformed cells are the l...
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