Diminished apoptosis of cancer cells is important for a number of reasons.
(1) In some cancers decreased apoptosis is the primary cause of tumorous growth, e.g. in follicular B-cell lymphoma and perhaps in early prostate cancer (—>19.1). In these tumors, cells that ought to undergo apoptosis in the course of normal tissue homeostasis survive, which leads to an oversized and progressively disorganized tissue mass.
(2) A diminished rate of apoptosis exacerbates hyperproliferation in many different cancers.
(3) Apoptosis is a fail-safe mechanism in response to 'inappropriate' proliferation signals (as is replicative senescence) and following pronounced DNA damage, e.g. unrepaired double-strand breaks. Therefore, a decreased response to 'internal' pro-apoptotic signals allows cells to proliferate in spite of proliferation signals being inappropriate or in spite of persisting severe DNA damage. This occurs in many cancer types, at the latest during progression.
(4) Cytotoxic T-cells from the immune system which protect against cancer and infections employ induction of apoptosis as a mechanism of cell killing. Decreased responsiveness to 'external' pro-apoptotic signals therefore is one of the mechanisms by which tumor cells evade the immune response (^9.5). This aspect becomes particularly relevant during invasion and metastasis. At an earlier stage of cancer development, some viruses, e.g. Epstein-Barr virus (^10.3) or HHV8 (Box 8.1), express anti-apoptotic factors which diminish apoptosis in response to both internal and external signals, thereby creating a population of cells more susceptible to carcinogenesis.
(5) Many cytotoxic drugs employed in chemotherapy as well as radiotherapy act by inducing apoptosis (^22.2). Decreased apoptotic responsiveness therefore contributes to primary and secondary resistance (^22.2) to chemo- and radiotherapy.
In human cancers, diminished apoptosis can originate from alterations in many different steps of apoptosis by a variety of mechanisms (Table 7.3). Proteins that relay internal or external pro-apoptotic signals can be inactivated, the extrinsic or the intrinsic pathway become deactivated or desensitized, and even the execution stage can be impeded. In one and the same cancer, several different steps can be affected. Moreover, decreased apoptosis in cancer cells is often caused by overactivity of survival signal pathways rather than by primary alterations in apoptotic pathways. Nevertheless, some degree of apoptosis does take place in human cancers, but not at the same rate as would be elicited in normal cells by comparable external and internal signals. Typical changes that diminish the apoptotic rate in human cancer cells include the following.
Desensitization of death receptors: The CD95/CD95L system is inactivated or desensitized in many different human cancers, in hematological cancers as well as in carcinomas. While mutation of the TNFRSF6 gene encoding CD95 is occasionally observed, in most cases down-regulation of receptor expression is the major mechanism responsible. In some cancers, a shift in expression from the transmembrane towards the soluble (decoy) receptor takes place. Altered expression of FADD proteins, decreased expression of Caspase 8, and overexpression of FLIP which inhibits the activation of Caspases at the DISC have been identified as causes of post-receptor defects in some cancers. In each case, the overall consequence is a decreased response to cytotoxic immune cells, but also to chemotherapeutic agents, which induce apoptosis partly through increased expression of both CD95 and its ligand. Other members of the TNFRSF family like the TRAIL receptors are also often inactivated by similar mechanisms.
Table 7.3. Mechanisms causing diminished apoptosis in human cancers
Desensitization of 'death receptor' (initiation and signaling of extrinsic pathway) Counterattack (avoidance of death receptor signaling) Loss of TP53 function
Desensitization or inactivation of the intrinsic pathway
Overexpression of IAPs
Counterattack: Additionally, decreased expression of the CD95/FAS receptor in some cancers is accompanied by increased expression of soluble CD95 ligand. It is thought that secretion of CD95L normally contributes to the establishment of 'immune-privileged' sites in the human body. Immune-privileged sites are established in organs such as the anterior eye chamber or the testes that could not function properly in the presence of lymphocytes and therefore have to keep them out. In consequence, increased production of CD95L may help cancers to prevent immune responses and may even destroy T-cells and other cells that express CD95. This 'counterattack' may account for some tissue damage caused by invasive cancers locally and perhaps even in distant organs like the liver.
Loss of TP53: While downregulation or mutation of CD95 inactivate external pro-apoptotic signaling, inactivation of TP53 may be the most common alteration that compromises internal pro-apoptotic signaling. TP53 mediates induction of apoptosis in response to DNA damage as well as to hyperproliferation (^6.6). Some think that loss of its pro-apoptotic function may be the most important consequence of TP53 inactivation.
Intrinsic pathway inactivation: The most varied assortment of alterations affect the intrinsic apoptotic pathway. BCL2 was discovered as an oncogene protein activated by the most characteristic translocation in follicular lymphoma (^4.3). It is also over-expressed in a wide range of other cancers, including different types of carcinoma, prominently breast and prostate cancer (^18.4, ^19.2). Alternatively to BCL2, cancers contain high levels of BCL-Xl, which is induced a.o. by the NFkB pathway (^6.9). Conversely, pro-apoptotic members of the BCL2 family such as BAD or NOXA (Table 7.2) are down-regulated in a variety of cancers, in some cases by promoter hypermethylation, and cannot be induced by activated TP53 or other signals. The most generally down-regulated member of the family may be BAX, perhaps due to its effector function at the mitochondria. An even stronger block to apoptosis may ensue when APAF1 expression is down-regulated, typically by promoter hypermethylation (^8.3). In summary, in almost all cancers the balance between pro-apoptotic and anti-apoptotic members of the family is tilted. The overall result of this imbalance is a decreased sensitivity towards apoptotic signals, particularly those elicited by hyperproliferation and aneuploidy, but also by chemotherapy.
IAP overexpression: Both the intrinsic and extrinsic pathway are affected by overexpression of IAP proteins which block signaling through caspases as well as the actual execution caspases, e.g. caspase 3. Survivin, e.g., is expressed at high levels during fetal development, but almost undetectable in normal resting tissues. Some expression is found associated with normal proliferation and regenerative processes such as wound repair. However, in many human cancers the levels of this IAP protein are so strongly and consistently increased that it is being developed as a tumor marker. IAPs may also be expressed or be induced by viruses present in a tumor cell such as EBV (^10.3) or HBV (^16.3). The overexpression of IAPs that block the execution phase can result in chaotic situations within a cancer cell, viz. partial activation of caspases which is not sufficient for execution of cell death. Consequences of such partial activation could be altered cell morphology and adhesion as well as genomic instability. Overexpression of other IAPs or of c-FLIP impede primarily the signaling phase of the extrinsic pathway by inhibiting the signal from FADD to caspase 8 or 10.
Activation of antiapoptotic pathways: The defects in the actual apoptotic signaling and execution cascades occurring in cancer cells are almost regularly complemented by increased activity of pathways that convey survival signals. Perhaps the most important ones in this regard are the PI3K (^6.3) and the NFKB (^■6.9) pathways. The PI3K pathway is activated in many cancers, indirectly by growth factors, oncogenic mutation of receptor tyrosine kinases, or RAS mutations, or directly by inactivation of negative regulators in the pathway like PTEN or by oncogenic overexpression of PI3Ka. The pathway does stimulate proliferation and particularly the growth of cells, but in many cancers, the main importance of its activation may lie in the ensuing inhibition of apoptosis. This is mediated through activity of AKT/PKB which phosphorylates BAX preventing it from activating the intrinsic apoptotic pathway. The kinase also phosphorylates and activates the forkhead transcription factor FKHR-L1, which counteracts apoptosis at the level of transcription. Activation of the PI3K pathway also diminishes the effect of cancer chemotherapy. Compared to the PI3K pathway, the NFKB pathway is less frequently subject to direct activation by mutation in human cancers. However, in many cell types, it limits the extent of induction of apoptosis resulting from activation of TNFRSF death receptors. Therefore, its indirect activation in tumor cells, which can be achieved by a variety of cytokines and stress signals, contributes to the resistance towards induction of apoptosis by external signals such as TNFa or CD95L.
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