How does apoptosis influence carcinogenesis

Nature : — RAGE signaling sustains inflammation and promotes tumor development. J Exp Med : — Suppression of tumorigenesis by the p53 target PUMA. Autophagic degradation of active caspase a crosstalk mechanism between autophagy and apoptosis. Autophagy 6 : — Puma is an essential mediator of pdependent and -independent apoptotic pathways.

Cancer Cell 4 : — The receptor for advanced glycation end products RAGE sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ 17 : — The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5 : — Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev 24 : — FLIP-mediated autophagy regulation in cell death control. Nat Cell Biol 11 : — Lindsten T, Thompson CB.

Cell death in the absence of Bax and Bak. Cell Death Differ 13 : — HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells.

Leukemia e-pub ahead of print 7 October High-mobility group box 1 protein HMGB1 : nuclear weapon in the immune arsenal. Nat Rev Immunol 5 : — Self-eating and self-killing: crosstalk between autophagy and apoptosis.

Nat Rev Mol Cell Biol 8 : — Role of autophagy in cancer. Nat Rev Cancer 7 : — Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death Differ 16 : — Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p Mol Cell 7 : — The CD95 receptor: apoptosis revisited.

Cell : — PUMA suppresses intestinal tumorigenesis in mice. Cancer Res 69 : — The hallmark of carcinogenesis as genomic instability arises within a cyclic setting of whole susceptible and dividing cells that project as derived gene amplification and over-expression. Aurora kinases are central determinants in the contrast profiling of apoptosis and of cell cycling in specific dimensions of genomic instability.

The further derived models of a malignant transformation are inductive and further realized in terms of the cell that inherently cycles and determines whole arrayed sets of susceptibility issues in evolving transformation.

Go to Mini Review Abstract Introduction Aurora Kinases Cell Turnover in Tumors Patterns of Distribution Potential Induction Re-Modeling Apoptosis Concluding Remarks References Introduction The amplification and especially over-expression of the Aurora kinases effectively constitute an excellent model concept in the understanding of the malignant transformation of carcinogenesis in multiple organ oncogenesis.

Multi-organ derivation of especially the metastasis phenomenon allow for the development of a spread process of establishment and progression of many tumor types. The inherent dimensions of metastatic neoplasms are paramount consideration in evolving tumor spread in a manner that allows for systemic dissemination of tumors as dictated by systems of attempted restitution of parameters in oncogenesis. CDKN2A drives carcinogenesis by inducing aneuploidy and cell cycle up-regulation [1].

Go to Mini Review Abstract Introduction Aurora Kinases Cell Turnover in Tumors Patterns of Distribution Potential Induction Re-Modeling Apoptosis Concluding Remarks References Aurora Kinases The development of Aurora kinases as modeled systems of disruption of the cell cycle dynamics is exemplified by the inclusion of resistance to immune system action and for the emergence of parametric independence in tumor origin, establishment and progression.

Bacillus Calmette-Guerin combined with Aurora-A inhibition may constitute a new intravesical modality treatment in preventing bladder carcinogenesis [2]. Aberrant cell cycle regulation of human embryonic stem cells is related to centrosome amplification with enhanced chromosomal instability [3]. SIX homeobox 3 acts as a tumor suppressor that directly represses the transcription of Aurora A and Aurora B and thus inhibits astrocytoma tumorigenesis [4].

Defects in resolving kinetochore-microtubule attachment errors during mitosis are linked to chromosome instability associated with carcinogenesis as well as resistance to cancer therapy [5].

The near-timed or consequent cascades in cell signaling realize significance in terms of the cell cycling check-points in further disrupting the integral dimensions of tumor cell evolution. Chromosome instability is due to a deficiency in cell division, including centrosomal amplification and cytokinesis failure and can result in aneuploidy [6]. The activity of Aurora A might be regulated by the ubiquitin-conjugating enzyme 2C that constitutes a key component in the ubiquitin proteasome system by partnering with the anaphase-promoting complex [7].

Go to Mini Review Abstract Introduction Aurora Kinases Cell Turnover in Tumors Patterns of Distribution Potential Induction Re-Modeling Apoptosis Concluding Remarks References Cell Turnover in Tumors The significance of evolving turnover of tumor cells is characteristically a fundamental process for the evolutionary history of the genomic injury as the malignant transformation step progresses as established dys-homeostasis of the cell cycle dynamics. Translational up regulation of Aurora-A by hnRNP Q1 contributes to cell proliferation and carcinogenesis in colorectal cancer [8].

In addition, inhibition of Ras-GAP induces apoptosis specifically in tumor, but not in normal cells, suggesting Ras-GAP as a novel target for cancer therapy Why would these agents induce apoptosis and, moreover, why would they be selective?

The answer is unknown, but it is possible that tumor cells become dependent on survival signaling through the PI-3 kinase pathway, which could be suppressed by Ras inhibition. In circumstances where apoptosis is lost by a recessive mutation, restoring the dysfunctional gene or activity can promote massive cell death.

For example, reintroduction of p53 into p53 mutant tumor cells can directly induce apoptosis or enhance treatment sensitivity in tumor cell lines or in xenographs , Indeed, strategies using this approach are currently in clinical trials As a general rule, tumor cells are inherently more sensitive to p53 inhibition than normal cells, perhaps because mitogenic oncogenes can activate p53 to promote apoptosis Hence, there is some rationale for selectivity of this approach.

Of note, strategies to counter recessive anti-apoptotic mutations need not rely on gene or protein therapy. In some instances, inactivation of a pro-apoptotic gene might actually promote cell survival by relieving inhibition of a downstream death suppressor e. PTEN loss de-represses Akt. In such instances, the downstream effector may be a more suitable drug target Although mutations in death receptors are rare events in human tumors, changes accompanying tumorigenesis can alter the regulation of these pathways.

Through an unknown mechanism, the expression of the decoy receptor 1 seems to be widely lost on tumor cells, making them exquisitely susceptible to TRAIL-mediated cell death. Because DR5 is a presponsive gene, combination therapy with TRAIL and classic cytotoxic agents may be particularly effective in treating tumors with functional p53 This protein is responsible for the cytopathic effects of CAV and induces apoptosis in tumor cells but not normal cells Although its mechanism of action remains unknown, apoptin-induced apoptosis is independent of p53 and is enhanced by Bcl-2 , At the very least, the remarkable effects of apoptin underscore the point that selective induction of apoptosis in tumor cells is achievable.

Basic studies suggest that it is possible to directly harness the pro-apoptotic forces produced by certain oncogenic mutations to selectively kill tumor cells. As mentioned earlier, oncogenes like c- myc and inactivation of tumor suppressors such as Rb force proliferation but at the same time promote apoptosis, presumably as a cellular safe-guard against tumorigenesis.

In principle, these E1A mutants, or small molecules which mimic their action, may provide tumor-specific anticancer agents by exploiting the fact that the Rb pathway is disrupted in the majority of human cancers. Rb mutations lead to increased E2F activity, and this promotes both proliferation and apoptosis 91 — It has been suggested that simultaneous inactivation of Rb and cdk2 would be particularly pro-apoptotic, and produce a synthetic lethal effect in cells with a mutant Rb pathway Consistent with this hypothesis, cell-permeable peptides that interfere with cdk2 activity readily induce apoptosis in tumor cells while having little effect on normal cell lines Interestingly, although E2F-induced apoptosis is potentiated by p53 91 , these peptides can induce apoptosis in pdeficient tumor cell lines.

Therefore, this strategy has widespread potential. As indicated above, the propensity of certain tissues e. Since most advanced solid tumors have lost p53 function, these inhibitors should not interfere with cell death of most tumor cells. Several caveats exist with respect to p53 inhibition in patients. First, the premise is based on animal studies, and it is not yet known the extent to which p53 contributes to anticancer agent toxicity in humans.

Secondly, although the protective effects in mice are striking, the magnitude of the protective effect over repeated doses and time is unknown. Thirdly, p53 inhibition may promote mutations by allowing the survival of mutated cells. However, transient inhibition of p53 may be less mutagenic In any case, most current anticancer agents are directly mutagenic, and it is not clear whether p53 inhibitors which would only indirectly promote mutations would be worse.

At the very least, this strategy warrants further consideration. The last decade has seen an extraordinary increase in our understanding of apoptosis, and its contribution to cancer and cancer therapy.

Furthermore, the molecular mechanisms that control and execute apoptotic cell death are coming into focus. Although there is much more to learn, our current understanding of apoptosis provides new avenues for cancer diagnostics, prognosis and therapy. In the coming years, it seems likely that rational strategies to manipulate cell suicide programs will produce new therapies that are less toxic and mutagenic than current treatment regimens.

Oncogene-induced apoptosis. Oncogenes such as E1A and c- myc induce apoptosis through pdependent and independent pathways, and both pathways may facilitate cytochrome c release from mitochondria. Components of the oncogene-induced cell-death program that are mutated in human tumors are shown in black, candidate tumor suppressors are shown in gray.

Anticancer agents induce apoptosis. Hematoxylin and eosin staining of lymph nodes from lymphoma-bearing mice B cell lymphoma left untreated A or isolated 5 h after treatment with cyclophosphamide B. Apoptotic cells are identified by their reduced size and by the presence of highly condensed chromatin. Massive apoptosis occurs in response to cyclophosphamide.

To whom correspondence should be addressed E-mail: lowe cshl. The authors apologize to those investigators whose work was not cited due to an oversight or space constraints.

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Open in new tab Download slide. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Google Scholar Crossref. Search ADS. Google Scholar PubMed. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Bcl-2 prevents death of factor-deprived cells but fails to prevent apoptosis in targets of cell mediated killing. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice.

Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 CPP32 -like protease activation. Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia. VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia.

Tissue expression and subcellular localization of the pro-survival molecule Bcl-w. Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium.

Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of pinduced apoptosis. Slug antagonizes pmediated apoptosis of hematopoietic progenitors by repressing puma.

Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. High levels of expression and nuclear localization of interleukin-1 beta converting enzyme ICE and CPP32 in favorable human neuroblastomas.

Prognostic relevance of c-Myc and caspase-3 for patients with non-small cell lung cancer. Relationship between the expression of caspase-3 and the clinical outcome of patients with non-small cell lung cancer.

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The potential tumour suppressor role for caspase-9 CASP9 in the childhood malignancy, neuroblastoma. Allelic imbalance on 12q in serum circulating DNA of melanoma patients predicts disease outcome. Allelic imbalance of 12q associated with APAF-1 locus correlates with poor disease outcome in cutaneous melanoma. Apoptosis protease activator protein-1 expression is dispensable for response of human melanoma cells to distinct proapoptotic agents. Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis.

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Association of a common variant of the CASP8 gene with reduced risk of breast cancer. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals. Issue Section:. Download all slides.