Microenvironmental Effects of Cell Death in Malignant Disease

Abstract

Although apoptosis is well recognized as a cell death program with clear anticancer roles, accumulating evidence linking apoptosis with tissue repair and regeneration indicates that its relationship with malignant disease is more complex than previously thought. Here we review how the responses of neighboring cells in the microenvironment of apoptotic tumor cells may contribute to the cell birth/cell death disequilibrium that provides the basis for cancerous tissue emergence and growth. We describe the bioactive properties of apoptotic cells and consider, in particular, how apoptosis of tumor cells can engender a range of responses including pro-oncogenic signals having proliferative, angiogenic, reparatory, and immunosuppressive features. Drawing on the parallels between wound healing, tissue regeneration and cancer, we propose the concept of the "onco-regenerative niche," a cell death-driven generic network of tissue repair and regenerative mechanisms that are hijacked in cancer. Finally, we consider how the responses to cell death in tumors can be targeted to provide more effective and long-lasting therapies.

Extracellular Vesicles Arising from Apoptotic Cells in Tumors: Roles in Cancer Pathogenesis and Potential Clinical Applications

“…Less intuitively, aggressive, rapidly growing tumors also display high AIs. Indeed, close association between high AI and high proliferative rate has been reported for multiple aggressive cancers, including colorectal carcinoma, bladder, lung and breast cancers, leukemia, and lymphoma ( 6 ). To place these observations in perspective, it has long been known that in Burkitt’s lymphoma, for example, which displays evidence of both high mitotic and apoptotic indices in standard histological sections, a substantial proportion (around 70%) of the proliferating cells die ( 7 ).…”

Repeated exposure of epithelial cells to apoptotic cells induces the specific selection of an adaptive phenotype: Implications for tumorigenesis

“…of a number of the pro-oncogenic properties of TAMs (19,35,36,77,78). TAMs acquire a phenotype favoring proliferation, angiogenesis, tissue invasion and metastasis, and evasion of immune destruction (19,35,36,71,72,77,78). TAMs are also intimately involved in remodeling of the extracellular matrix and in creating an environment more conducive to tumor growth (19,35,36).…”

“…A striking complexity characterizes the flow of information from apoptotic cells to live cells (1)(2)(3)(4)19). Information can be extracted from multiple death-related variables, including the mode of cell death (e.g.…”

“…This specific adaptation to the pres-ence of apoptotic cells has especial consequence for cancer, in which the post-mortem effects of dead cells are magnified because of the increased rate and persistence of cell death. Like other features of the tumor microenvironment (19,(31)(32)(33)(34)(35)(36), dead cells may play a major role in shaping the neoplastic phenotype.…”

Royal Society Scientific Meeting: Extracellular vesicles in the tumour microenvironment

“…As part of this process, cancer cells can release EVs that may subvert cells of the immune system within the tumour microenvironment [12]. Christopher Gregory (MRC Centre for Inflammation Research, The University of Edinburgh, UK) described how apoptotic cells in the tumour microenvironment can activate endothelial cells (which in turn promote angiogenesis) and macrophages, both of which then support the tumour in what Prof Gregory terms the 'onco-regenerative niche' [18]. Elke Pogge von Strandmann (University of Cologne, Germany) showed that by activating the retinoic acid-inducible gene I in malignant B cells EVs were released with the ability to trigger natural killer cells to kill the tumour cells [19].…”