Evasion of apoptosis: a hallmark of cancer
The balance between cell proliferation and apoptosis is influenced by genes that contribute to the development of cancer (oncogenes) and those that encode proteins that normally suppress tumor formation (tumor suppressor genes).1 Oncogenes are mutated forms of normal cellular genes known as proto-oncogenes, which typically control key cellular functions such as proliferation, cell cycle, and cell death.1 The mutation of a proto-oncogene is usually an activating mutation, and thereby mutation in one allele is enough to turn a proto-oncogene into an active oncogene.1 Functional tumor suppressor genes reduce the probability that a cell will turn into a tumor cell, and their loss allows cellular functions to proceed with little or no control.1 For most tumor suppressor genes, both alleles must be mutated before an effect is manifested.1 Mutations are often inherited, but additional somatic mutations can be acquired through inaccurate DNA replication, reactive oxygen species, and other environmental genotoxic stresses.1 Genetic stability genes are a specific class of tumor suppressor genes that preserve genome integrity.1 This class of genes does not necessarily drive carcinogenesis, but when altered they allow for increased mutagenesis rates, which then facilitate carcinogenesis.1
Virtually all cancer cells contain mutations that enable evasion of apoptosis.2 Cancer cells bypass apoptosis through a variety of mechanisms involving dynamic interplays between oncogenes and/or mutated tumor suppressor genes. More than 50% of cancers are marked by a mutation in the tumor suppressor gene p53, a key pro-apoptotic regulator which, when mutated, facilitates tumorigenesis.2 Persistent and/or elevated signaling from oncogenes such as Myc, Ras, and E1A drive cellular proliferation. However, studies of Myc overexpression suggest that these oncogenes also may affect apoptosis in different ways, depending on certain circumstances. For example, Myc is a powerful inducer of apoptosis under adverse conditions such as cellular stress, DNA damage, or when levels of survival factors are low.3,4 Myc may in fact enhance tumor cells’ sensitivity to apoptotic signaling via the extrinsic pathway, including signaling through DR4 and DR5.5,6 Yet the pro-apoptotic effects of Myc have been shown to be abrogated by exogenous survival factors such as IGF-1, by forced overexpression of anti-apoptotic factors Bcl-2 and Bcl-XL, as well as by disruption of the FAS death signaling circuit.2 Collectively, the data suggest that although a cell’s apoptotic program can be initiated by an overexpressed oncogene, other compounding factors can attenuate such effects.2
Another means by which cancer cells overcome apoptosis is through upregulation of the anti-apoptotic PI3 kinase (PI3K)-Akt/PKB survival pathway.2 This can be achieved through extracellular factors such as IGF-1/2, EGF, or IL-3, by intracellular signals triggered by the oncogene Ras, or by loss of the tumor suppressor gene PTEN, a phospholipid phosphatase that normally downregulates the Akt survival signal.2 Lastly, cancer cells can escape apoptotic programming by upregulating the expression of a nonsignaling decoy receptor for the FAS ligand which may prevent activation of the FAS receptor.2