Evaluation of Innate Immune Signaling Pathways in Transformed Cells
Oncolytic viruses, the use of viruses to treat cancer, is emerging as a new option for cancer therapy. Oncolytic viruses, of both DNA and RNA origin, exhibit the ability to preferentially replicate in and kill cancer cells plausibly due to defects in inna
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1. Introduction That natural virus infections occasionally coincided with the regression of certain types of tumors in patients suffering from such maladies is relatively well documented and has led to a spate of studies designed to utilize viruses as oncolytic agents for the treatment of malignant disease (1). However, the mechanisms that favorably enable the replication of viruses in tumor cells compared to normal cells still remain to be clarified. Such reasons could involve the accumulation of genetic mutations in innate signaling pathways important for mediating antiviral activity. In cancer cells, these defects can lead to a reduction or inactivation of the type 1 interferon (IFN-D/E) response, critical for upregulating numerous antiviral genes, making such cells highly susceptible to viral replication and
David H. Kirn et al. (eds.), Oncolytic Viruses: Methods and Protocols, Methods in Molecular Biology, vol. 797, DOI 10.1007/978-1-61779-340-0_15, © Springer Science+Business Media, LLC 2012
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J.F. Heiber and G.N. Barber
subsequent cellular lysis (2). In order to fully explore the mechanisms of oncolytic virus action, it is necessary to understand the architecture of innate immune signaling cascades in normal cells and then evaluate their plausible deregulation in cancer cells. Only in the last few years has it become clear that the host has evolved a number of pathways to detect and respond to foreign pathogens such as viruses and bacteria (3–5). However, it is likely that important components of innate signaling still remain to be identified, which will make the reasons underlining oncolysis potentially elusive for some time. Nevertheless, progress has been made toward understanding these processes, and now these signaling cascades including their components can start to be analyzed in cancer cells. The reasons underlining viral oncolysis are particularly intriguing since numerous virus types replicate in a wide variety of cancer cells, making the responsible defective pathway potentially a major reason behind tumorigenesis (6). These recently unraveled pathways may include the Toll-Like Receptor (TLR) pathway, the RIG-I Like Helicase (RLH) pathway, and recently the STING regulated pathway (SRP), a brief description of which follows. 1.1. Toll-Like Receptor Signaling
The triggering of innate immune responses follows the detection of pathogen specific molecules (pathogen-associated molecular patterns- PAMPS) by cellular pattern-recognition receptors (PRRs). For example, bacteria have cell wall components comprising lipopolysaccharides that can trigger innate immune responses, while viral nucleic acids are also known to be potent PAMPs (5, 7). A key innate immune pathway that is highly conserved and able to recognize a wide array of pathogens is the Toll pathway, first identified in Drosophila melanogaster. Activation of D. melanogaster Toll leads to the fat body cells triggering, via dMyD88, tube, and pelle, the production of antimicrobial peptides (AMPs) and the subsequent secretion of the peptides in
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