Macrophage-mediated Bystander Effect Triggered by Tumor Cell Apoptosis

Abstract

Restoration of apoptosis is an important therapeutic strategy for cancer, but bystander effects may be crucial to treatment success. We examined the involvement of bystander effects in the outcome of pro-apoptotic treatments and investigated the role of macrophages. Using a murine N202 breast cancer chamber model and intravital microscopy, we observed bystander apoptosis in vivo in mixed spheroids consisting of bystander N202 cells plus modified N202 cells overexpressing the p14ARF N-terminal region, which promotes p53-mediated apoptosis. The effect was not observed in cocultures in vitro, and could not be transferred through conditioned medium from modified N202 cells. However, if macrophages were also included in the N202 co-cultures, bystander apoptosis was restored, and correlated with elevated surface expression of phosphatidyl serine, a macrophage recognition molecule, on the modified N202 cells. Bystander killing was not observed in cocultures of N202 cells plus macrophages plus cisplatin-treated or 5-fluorouracil-treated N202 cells, where apoptosis induction in the target cell population was inefficient, suggesting that specific activation of macrophages by apoptotic tumor cells was required. The results suggest that pro-apoptotic therapies benefit both from the intrinsic vulnerability of cancer cells to apoptosis and from an innate immune response that amplifies the therapeutic effect.

The dialogue between died and viable cells: in vitro and in vivo bystander effects and 1H-NMR-based metabolic profiling of soluble factors

“…In fact, of about 25 % of THP-1 cells emit filopodia on cell surface and consequently the cells change the culture modality (the number of THP-1 cells attached to the substrate increased about 9 fold respect the THP-1 cells cultured in RPMI 1640 fresh medium). A similar bystander-based communication has been demonstrated in mouse bone marrow derived macrophages cultured in the presence of N2O2 tumor spheroids [43] and in J774.2 macrophages cultured in the presence NIH3T3 fibroblasts [44].…”

Retrospective analysis of the preparation and application of immunotherapy in cancer treatment (Review)

“…As ADCs are formed from maytansinoid drugs which are derivatives of maytansine and huC242, humanised mAbs which bind to the CanAg antigen expressed on colorectal tumours, pancreatic tumours and certain NSCLCs, huC242-maytansinoid conjugates can be disintegrated with the influence of lysosomal acidic conditions in order to release the maytansinoid, which contributes greatly to the antitumour effect of conjugates and the bystander effect ( 214 ). If the released payload is permeable, a bystander effect is produced, which means that the internalised payload enters and kills adjacent tumour cells, showing the effect of apoptotic tumour cells on bystander tumour cells ( 215 ). Although ADCs cannot directly kill the adjacent antigen-negative tumour cells, they can kill the antigen-positive tumour cells in order to indirectly kill the adjacent tumour cells by the bystander effect ( 216 ).…”

“…Not only do ADCs damage the growing tumour, they can also disrupt the structure supporting tumour growth, such as tumour stromal cells and tumour vessels, in order to enhance the antitumour effect ( 217 ). More importantly, it was proposed that the activation of bystander effects by apoptotic tumour cells may be crucial to achieving the permanent eradication of tumours ( 215 ).…”

Targeting tumor stemness switch phenotype by activating pathogen induced stem cell niche defense

“…Apoptosis reinstatement has been a promising anti-cancer strategy; bystander apoptosis incurred by activated macrophages, if suitably courted, could be significant to treatment success [12].…”

“…Cancer cells undergoing apoptosis may activate macrophage mediated innate immune mechanism of phagocytosis leading to bystander apoptosis of cancer cells [12]. However, CSCs may suppress the macrophage mediated cancer cell killing [13].…”