Table of contents

Volume 3, Issue 11, pp. 328 - 360, November 2019

Issue cover
Cover: This month in Cell Stress: The role of endothelial cell death after stroke. Image shows developing vascular system of a zebrafish embryonal brain. Image by Caitlin Sedwick, licensed under a Creative Commons CC BY 2.0 license. Modified by Cell Stress. The cover is published under the CC BY 4.0 license. Enlarge issue cover

News and Thoughts

LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent

Dagmar Zweytick

page 328-329 | 10.15698/cst2019.11.202 | Full text | PDF |

Reviews

The impact of endothelial cell death in the brain and its role after stroke: A systematic review

Marietta Zille, Maulana Ikhsan, Yun Jiang, Josephine Lampe, Jan Wenzel and Markus Schwaninger

page 330-347 | 10.15698/cst2019.11.203 | Full text | PDF | Abstract

The supply of oxygen and nutrients to the brain is vital for its function and requires a complex vascular network that, when disturbed, results in profound neurological dysfunction. As part of the pathology in stroke, endothelial cells die. As endothelial cell death affects the surrounding cellular environment and is a potential target for the treatment and prevention of neurological disorders, we have systematically reviewed important aspects of endothelial cell death with a particular focus on stroke. After screening 2876 publications published between January 1, 2010 and August 7, 2019, we identified 154 records to be included. We found that endothelial cell death occurs rapidly as well as later after the onset of stroke conditions. Among the different cell death mechanisms, apoptosis was the most widely investigated (92 records), followed by autophagy (20 records), while other, more recently defined mechanisms received less attention, such as lysosome-dependent cell death (2 records) and necroptosis (2 records). We also discuss the differential vulnerability of brain cells to injury after stroke and the role of endothelial cell death in the no-reflow phenomenon with a special focus on the microvasculature. Further investigation of the different cell death mechanisms using novel tools and biomarkers will greatly enhance our understanding of endothelial cell death. For this task, at least two markers/criteria are desirable to determine cell death subroutines according to the recommendations of the Nomenclature Committee on Cell Death.

Research Articles

LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects

Hsin-Wei Liao, Christopher Garris, Christina Pfirschke, Steffen Rickelt, Sean Arlauckas, Marie Siwicki, Rainer H. Kohler, Ralph Weissleder, Vibeke Sundvold-Gjerstad, Baldur Sveinbjørnsson, Øystein Rekdal and Mikael J. Pittet

page 348-360 | 10.15698/cst2019.11.204 | Full text | PDF | Abstract

LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug’s mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of lymphocytes. The second phase of response, which continues over weeks, is defined by long-term alteration of the tumor microenvironment; the changes induced by LTX-315 are most notably characterized by CD8+ T cell infiltration. We further show that these CD8+ T cells are involved in suppressing melanoma outgrowth in mice and report similar CD8+ T cell infiltration following LTX-315 treatment in melanoma and sarcoma patients. Taken together, these findings reveal LTX-315’s multiple antitumor effects, including disrupting the tumor vasculature and promoting the conversion of poorly immunogenic tumors into ones that display antitumor T cell immunity.

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