Addicted to Death

Abstract

The development of an invasive cancer involves a progressive switch from predominantly apoptotic (scheduled) to necrotic (unscheduled) tumor cell death. This switch is associated with chronic and increasing release of intracellular factors that in turn promote reactive angiogenesis and stromal proliferation and mediates the disordered tumor microenvironment associated with local immune suppression. The authors review the relevant immunobiology of these factors, including the nuclear protein HMGB1; the products of purine metabolism (uric acid, ATP, and adenosine); the S100 family members; and the heat shock proteins, which we believe drive futile cycles of cell death followed by reparative cell growth. The authors also present a novel and provocative hypothesis that suggests that most of the derangements that we associate with progression of cancer and the associated immunologic consequences can indeed be ascribed to the consequences of disordered tumor cell death rather than cell growth. Thus the fundamental defect in invasive human cancers, in the authors' view, is not one of cell growth but rather one of disordered cell death, resulting in turn in a tumor microenvironment that encourages tumor growth, progression, and local immunosuppression, a condition the authors have termed "addicted to death." This new understanding could inform and drive the development of more effective biologic therapies for patients with cancer.

Shift from Apoptotic to Necrotic Cell Death during Human Papillomavirus-induced Transformation of Keratinocytes

“…K and HF1 cells were analyzed several times in each of two variations. Samples were treated with CDDP at a fixed concentration (25 M) and removed at various time points (0, 8,12,18, and 24 h); alternately, samples were treated with CDDP at various concentrations (0, 25, and 50 M) for a fixed period of 24 h. HeLa cells were treated with CDDP at a fixed concentration (25 M) and analyzed after 24 h.…”

Role of Autophagy in Cancer: Management of Metabolic Stress

“…By provoking an inflammatory response, necrosis, by analogy with wound healing, may facilitate proliferation and angiogenesis favoring tumor growth. [23][24][25] As defects in both autophagy and apoptosis provide the genetic means to specifically induce necrosis in response to metabolic stress, the contribution of components of the inflammatory response to tumor initiation and progression can be directly tested. Examining the impact of a necrotic rather than apoptotic cell fate on proliferation, angiogenesis, mutagenesis, genetic instability, the cytokine milieu, and the cellular immune response may provide some of the answers.…”

Current insights into the regulation of programmed cell death by NF-κB

“…Apoptotic cells corpses are engulfed by macrophages, a process that does not generate an inflammatory response (reviewed in Leist and Jaattela, 2001;Edinger and Thompson, 2004). In contrast, PCD via necrosis is independent of caspases and is typically associated with breakdown of the plasma membrane, organelle swelling and nuclear degradation that is accompanied by the release of nuclear factors like high mobility group box 1 (HMGB1) that trigger a potent inflammatory response (reviewed in Lotze and Tracey, 2005;Zeh and Lotze, 2005). NF-kB is commonly cytoprotective toward PCD caused by apoptosis or necrosis and its prosurvival activity has been observed in response to a variety of death-inducing stimuli like the proinflammatory cytokine TNFa, ultraviolet (UV) radiation, anticancer agents and B-cell receptor crosslinking (Wu et al, 1996;Grumont et al, 1998;Wang et al, 1998;van Antwerp et al, 1998;Owyang et al, 2001).…”