Резистентность к клеточной смерти | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Резистентность к клеточной смерти

Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011

The concept that programmed cell death by apoptosis serves as a natural barrier to cancer development has been established by compelling functional studies conducted over the last two decades. Elucidation of the signaling circuitry governing the apoptotic program has revealed how apoptosis is triggered in response to various physiologic stresses that cancer cells experience during the course of tumorigenesis or as a result of anticancer therapy. Notable among the apoptosis-inducing stresses are signaling imbalances resulting from elevated levels of oncogene signaling, as mentioned earlier, and DNA damage associated with hyperproliferation. Yet other research has revealed how apoptosis is attenuated in those tumors that succeed in progressing to states of high-grade malignancy and resistance to therapy.

The apoptotic machinery is composed of both upstream regulators and downstream effector components. The regulators, in turn, are divided into two major circuits, one receiving and processing extracellular death-inducing signals (the extrinsic apoptotic program, involving for example the Fas ligand/Fas receptor), and the other sensing and integrating a variety of signals of intracellular origin (the intrinsic program). Each culminates in activation of a normally latent protease (caspases 8 and 9, respectively), which proceeds to initiate a cascade of proteolysis involving effector caspases responsible for the execution phase of apoptosis, in which the cell is progressively disassembled and then consumed, both by its neighbors and by professional phagocytic cells. Currently, the intrinsic apoptotic program is more widely implicated as a barrier to cancer pathogenesis.

The “apoptotic trigger” that conveys signals between the regulators and effectors is controlled by counterbalancing pro- and antiapoptotic members of the Bcl-2 family of regulatory proteins. The archetype, Bcl-2, along with its closest relatives (Bcl-xL, Bcl-w, Mcl-1, A1) are inhibitors of apoptosis, acting in large part by binding to and thereby suppressing two proapoptotic triggering proteins (Bax and Bak); the latter are embedded in the mitochondrial outer membrane. When relieved of inhibition by their antiapoptotic relatives, Bax and Bak disrupt the integrity of the outer mitochondrial membrane, causing the release of proapoptotic signaling proteins, the most important of which is cytochrome c. The released cytochrome c activates, in turn, a cascade of caspases that act via their proteolytic activities to induce the multiple cellular changes associated with the apoptotic program. Bax and Bak share protein-protein interaction domains, termed BH3 motifs, with the antiapoptotic Bcl-2-like proteins that mediate their various physical interactions. The activities of a subfamily of related proteins, each of which contains a single such BH3 motif, are coupled to a variety of sensors of cellular abnormality; these «BH3-only» proteins act either by interfering with antiapoptotic Bcl-2 proteins or by directly stimulating the proapoptotic members of this family.

Although the cellular conditions that trigger apoptosis remain to be fully enumerated, several abnormality sensors that play key roles in tumor development have been identified. Most notable is a DNA-damage sensor that functions via the TP53 tumor suppressor; TP53 induces apoptosis by upregulating expression of the Noxa and Puma BH3-only proteins, doing so in response to substantial levels of DNA breaks and other chromosomal abnormalities. Alternatively, insufficient survival factor signaling (for instance inadequate levels of interleukin-3 in lymphocytes or of insulin-like growth factor 1/2 [Igf1/2] in epithelial cells) can elicit apoptosis through a BH3-only protein called Bim. Yet another condition leading to cell death involves hyperactive signaling by certain oncoproteins, such as Myc, which triggers apoptosis (in part via Bim and other BH3-only proteins) unless counterbalanced by antiapoptotic factors.

Tumor cells evolve a variety of strategies to limit or circumvent apoptosis. Most common is the loss of TP53 tumor suppressor function, which eliminates this critical damage sensor from the apoptosis-inducing circuitry. Alternatively, tumors may achieve similar ends by increasing expression of antiapoptotic regulators (Bcl-2, Bcl-xL) or of survival signals (Igf1/2), by downregulating proapoptotic factors (Bax, Bim, Puma), or by short-circuiting the extrinsic ligand-induced death pathway. The multiplicity of apoptosis-avoiding mechanisms presumably reflects the diversity of apoptosis-inducing signals that cancer cell populations encounter during their evolution to the malignant state.

The structure of the apoptotic machinery and program, and the strategies used by cancer cells to evade its actions, were widely appreciated by the beginning of the last decade. The most notable conceptual advances since then have involved other forms of cell death that broaden the scope of “programmed cell death” as a barrier to cancer.

Аутофагия опосредует и выживаемость, и гибель опухолевых клеток

Autophagy represents an important cell-physiologic response that, like apoptosis, normally operates at low, basal levels in cells but can be strongly induced in certain states of cellular stress, the most obvious of which is nutrient deficiency. The autophagic program enables cells to break down cellular organelles, such as ribosomes and mitochondria, allowing the resulting catabolites to be recycled and thus used for biosynthesis and energy metabolism. As part of this program, intracellular vesicles termed autophagosomes envelope intracellular organelles and then fuse with lysosomes wherein degradation occurs. In this fashion, low-molecular-weight metabolites are generated that support survival in the stressed, nutrient-limited environments experienced by many cancer cells.

Like apoptosis, the autophagy machinery has both regulatory and effector components. Among the latter are proteins that mediate autophagosome formation and delivery to lysosomes. Of note, recent research has revealed intersections between the regulatory circuits governing autophagy, apoptosis, and cellular homeostasis. For example, the signaling pathway involving the PI3-kinase, AKT, and mTOR kinases, which is stimulated by survival signals to block apoptosis, similarly inhibits autophagy; when survival signals are insufficient, the PI3K signaling pathway is downregulated, with the result that autophagy and/or apoptosis may be induced.

Another interconnection between these two programs resides in the Beclin-1 protein, which has been shown by genetic studies to be necessary for induction of autophagy. Beclin-1 is a member of the BH3-only subfamily of apoptotic regulatory proteins, and its BH3 domain allows it to bind the Bcl-2/Bcl-xL proteins. Stress-sensor-coupled BH3 proteins can displace Beclin-1 from its association with Bcl-2/Bcl-xL, enabling the liberated Beclin-1 to trigger autophagy, much as they can release proapoptotic Bax and Bak to trigger apoptosis. Hence, stress-transducing BH3 proteins (e.g., Bid, Bad, Puma, et al.) can induce apoptosis and/or autophagy depending on the physiologic state of the cell.

Mice bearing inactivated alleles of the Beclin-1 gene or of certain other components of the autophagy machinery exhibit increased susceptibility to cancer. These results suggest that induction of autophagy can serve as a barrier to tumorigenesis that may operate independently of or in concert with apoptosis. Accordingly, autophagy appears to represent yet another barrier that needs to be circumvented during tumor development.

Perhaps paradoxically, nutrient starvation, radiotherapy, and certain cytotoxic drugs can induce elevated levels of autophagy that are apparently cytoprotective for cancer cells, impairing rather than accentuating the killing actions of these stress-inducing situations. Moreover, severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy. This survival response may enable the persistence and eventual regrowth of some late-stage tumors following treatment with potent anticancer agents. Thus, in analogy to TGF-β signaling, which can be tumor suppressing at early stages of tumorigenesis and tumor promoting later on, autophagy seems to have conflicting effects on tumor cells and thus tumor progression. An important agenda for future research will involve clarifying the genetic and cell-physiologic conditions that dictate when and how autophagy enables cancer cells to survive or causes them to die.

Некроз обладает провоспалительным и опухоль-промотирующим потенциалом

In contrast to apoptosis, in which a dying cell contracts into an almost-invisible corpse that is soon consumed by neighbors, necrotic cells become bloated and explode, releasing their contents into the local tissue microenvironment. Although necrosis has historically been viewed much like organismic death, as a form of system-wide exhaustion and breakdown, the conceptual landscape is changing: cell death by necrosis is clearly under genetic control in some circumstances, rather than being a random and undirected process.

Perhaps more important, necrotic cell death releases proinflammatory signals into the surrounding tissue microenvironment, in contrast to apoptosis and autophagy, which do not. As a consequence, necrotic cells can recruit inflammatory cells of the immune system, whose dedicated function is to survey the extent of tissue damage and remove associated necrotic debris. In the context of neoplasia, however, multiple lines of evidence indicate that immune inflammatory cells can be actively tumor promoting, given that such cells are capable of fostering angiogenesis, cancer cell proliferation, and invasiveness. Additionally, necrotic cells can release bioactive regulatory factors, such as IL-1α, which can directly stimulate neighboring viable cells to proliferate, with the potential, once again, to facilitate neoplastic progression. Consequently, necrotic cell death, while seemingly beneficial in counterbalancing cancer-associated hyperproliferation, may ultimately do more damage than good. Accordingly, incipient neoplasias and potentially invasive and metastatic tumors may gain an advantage by tolerating some degree of necrotic cell death, doing so in order to recruit tumor-promoting inflammatory cells that bring growth-stimulating factors to the surviving cells within these growths.





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