■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

Epstein-Barr virus.

Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing data sets are fragmented and difficult to analyze systematically. Here we present a pan-cancer resource and meta-analysis of expression signatures from ∼18,000 human tumors with overall survival outcomes across 39 malignancies. By using this resource, we identified a forkhead box MI (FOXM1) regulatory network as a major predictor of adverse outcomes, and we found that expression of favorably prognostic genes, including KLRB1 (encoding CD161), largely reflect tumor-associated leukocytes. By applying CIBERSORT, a computational approach for inferring leukocyte representation in bulk tumor transcriptomes, we identified complex associations between 22 distinct leukocyte subsets and cancer survival. For example, tumor-associated neutrophil and plasma cell signatures emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. This resource and associated analytical tools (http://precog.stanford.edu) may help delineate prognostic genes and leukocyte subsets within and across cancers, shed light on the impact of tumor heterogeneity on cancer outcomes, and facilitate the discovery of biomarkers and therapeutic targets.

The prognostic landscape of genes and infiltrating immune cells across human cancers

BACKGROUND: Inflammation may play an important role in cancer progression, and a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a poor prognostic indicator in several malignancies. Here we quantify the prognostic impact of this biomarker and assess its consistency in solid tumors. METHODS: A systematic review of electronic databases was conducted to identify publications exploring the association of blood NLR and clinical outcome in solid tumors. Overall survival (OS) was the primary outcome, and cancer-specific survival (CSS), progression-free survival (PFS), and disease-free survival (DFS) were secondary outcomes. Data from studies reporting a hazard ratio and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled hazard ratios were computed and weighted using generic inverse-variance and random-effect modeling. All statistical tests were two-sided. RESULTS: One hundred studies comprising 40559 patients were included in the analysis, 57 of them published in 2012 or later. Median cutoff for NLR was 4. Overall, NLR greater than the cutoff was associated with a hazard ratio for OS of 1.81 (95% CI = 1.67 to 1.97; P < .001), an effect observed in all disease subgroups, sites, and stages. Hazard ratios for NLR greater than the cutoff for CSS, PFS, and DFS were 1.61, 1.63, and 2.27, respectively (all P < .001). CONCLUSIONS: A high NLR is associated with an adverse OS in many solid tumors. The NLR is a readily available and inexpensive biomarker, and its addition to established prognostic scores for clinical decision making warrants further investigation.

Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Solid Tumors: A Systematic Review and Meta-Analysis

Biologically active sphingolipids have key roles in the regulation of several fundamental biological processes that are integral to cancer pathogenesis. Recent significant progress in understanding biologically active sphingolipid synthesis, specifically within ceramide and sphingosine-1-phosphate (S1P)-mediated pathways, has identified crucial roles for these molecules both in cancer development and progression. Ceramide — a central molecule in sphingolipid metabolism — in effect functions as a tumour-suppressor lipid, inducing antiproliferative and apoptotic responses in various cancer cells. Conversely, S1P induces responses that, on aggregate, render S1P a tumour-promoting lipid. These discoveries are paving the way for the advancement of anticancer therapies.

Biologically active sphingolipids in cancer pathogenesis and treatment.

https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/84725/1/j.ejca.2009.01.023.pdf

Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03.

Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells.

http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/144476/1/yigar01886.pdf

Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis.

We investigated the possibility of the proapoptotic lipid ceramide as an indicator of chemoresistance in leukemia. Doxorubicin (DOX) increased the ceramide level and apoptosis in drug-sensitive HL-60 cells but not in drug-resistant HL-60/ADR cells, under the condition that the uptake of DOX was not different between the two cell lines. In addition, exogenous N-acetylsphingosine (C2-ceramide) enhanced DOX-induced apoptosis in HL-60/ADR cells without affecting the expression of multidrug resistant-1 protein (MDR 1) and the uptake of DOX. A lower level of ceramide with higher activities of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) was detected in HL-60/ADR cells than in HL-60 cells. In contrast, HL-60/GCS cells, overexpressing GCS, significantly inhibited DOX-induced ceramide increase and apoptosis. These observations suggest the involvement of ceramide regulation in drug resistance of leukemia cells. In vivo, the level of ceramide was lower in chemoresistant leukemia patients (6.4 +/- 1.8 pmol/nmol phosphate; n = 14) than in chemosensitive patients (9.5 +/- 2.7 pmol/nmol phosphate; n = 9), and the activities of GCS and SMS were more than 2-fold higher in chemoresistant leukemia cells than in chemosensitive cells. MDR-1 protein was faintly expressed in one of four chemoresistant patients, but Bcl-2 were clearly detected in four patients. Therefore, it is suggested that a decrease of the ceramide level via activation of GCS and SMS is associated with the chemoresistant condition in leukemia, probably in relation to Bcl-2 but not to MDR-1 expression.

https://clincancerres.aacrjournals.org/content/clincanres/9/1/415.full.pdf

Possible Role of Ceramide as an Indicator of Chemoresistance: Decrease of the Ceramide Content via Activation of Glucosylceramide Synthase and Sphingomyelin Synthase in Chemoresistant Leukemia

Toshiyuki Kitano

Papers

Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03.

Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells.

Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis.

Possible Role of Ceramide as an Indicator of Chemoresistance: Decrease of the Ceramide Content via Activation of Glucosylceramide Synthase and Sphingomyelin Synthase in Chemoresistant Leukemia

Diversity and Complexity of Ceramide Signalling in Apoptosis