The therapeutic effect of death: Newcastle disease virus and its antitumor potential

Abstract

Programmed cell death is essential to survival of multicellular organisms. Previously restricted to apoptosis, the concept of programmed cell death is now extended to other mechanisms, as programmed necrosis or necroptosis, autophagic cell death, pyroptosis and parthanatos, among others. Viruses have evolved to manipulate and take control over the programmed cell death response, and the infected cell attempts to neutralize viral infections displaying different stress signals and defensive pathways before taking the critical decision of self-destruction. Learning from viruses and their interplay with the host may help us to better understand the complexity of the self-defense death response that when altered might cause disorders as important as cancer. In addition, as the fields of immunotherapy and oncolytic viruses advance as promising novel cancer therapies, the programmed cell death response reemerges as a key point for the success of both therapeutic approaches. In this review we summarize the research of the multimodal cell death response induced by Newcastle disease viruses (NDV), considered nowadays a promising viral oncolytic therapeutic, and how the manipulation of the host programmed cell death response can enhance the NDV antitumor capacity.

Keywords: Apoptosis; Autophagy; Necroptosis; Newcastle disease virus; Oncolytic virus; Programmed cell death; Recombinant virus; Tumor therapy.

Fig. 1. Apoptosis induction by Newcastle disease virus. Morphological hallmarks

Confocal microscopy images of HeLa cells infected with the recombinant rNDV-B1/Fas virus (Cuadrado-Castano et al., 2015). Left: composite Z-stack of six optical slices showing Hela-infected cells undergoing apoptosis; highlighted are different stages of the apoptosis response observed among the cell population identified accordingly to the morphological changes observed during the progression of apoptosis cell death: pre-apoptosis stage (lack of morphological changes); active apoptosis (A) showing cellular shrinkage and DNA fragmentation. Advance apoptosis (B) displaying extensive membrane blebbing and DNA fragmentation. Late apoptosis (C) showing apoptotic bodies scale bar 100 µm. Right plots: single stacks and magnification of morphological features, observed in the main left panel: DNA fragmentation (A), membrane blebbing (B) or C (apoptotic bodies). Scale bar 10 µm. For the propose of this image, the cells were infected at an MOI of 1 PFU/cell, fixed 20 h after infection, and stained with monoclonal anti-human Fas antibody (red), polyclonal anti-NDV serum (green) and Hoechst for nuclear contrast. Confocal laser scanning was performed using a Zeiss LSM 190 510 Meta (Carl Zeiss Microimaging, Thornwood, NY) fitted with a Plan Apochromatic 63×/1.4 191. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).

Fig. 2

NDV-induced apoptosis: overview of the cell death response. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article)