Targeting inflammatory pathways for tumor radiosensitization

Abstract

Although radiation therapy (RT) is an integral component of treatment of patients with many types of cancer, inherent and/or acquired resistance to the cytotoxic effects of RT is increasingly recognized as a significant impediment to effective cancer treatment. Inherent resistance is mediated by constitutively activated oncogenic, proliferative and anti-apoptotic proteins/pathways whereas acquired resistance refers to transient induction of proteins/pathways following radiation exposure. To realize the full potential of RT, it is essential to understand the signaling pathways that mediate inducible radiation resistance, a poorly characterized phenomenon, and identify druggable targets for radiosensitization. Ionizing radiation induces a multilayered signaling response in mammalian cells by activating many pro-survival pathways that converge to transiently activate a few important transcription factors (TFs), including nuclear factor kappa B (NF-κB) and signal transducers and activators of transcription (STATs), the central mediators of inflammatory and carcinogenic signaling. Together, these TFs activate a wide spectrum of pro-survival genes regulating inflammation, anti-apoptosis, invasion and angiogenesis pathways, which confer tumor cell radioresistance. Equally, radiation-induced activation of pro-inflammatory cytokine network (including interleukin (IL)-1β, IL-6 and tumor necrosis factor-α) has been shown to mediate symptom burden (pain, fatigue, local inflammation) in cancer patients. Thus, targeting radiation-induced inflammatory pathways may exert a dual effect of accentuating the tumor radioresponse and reducing normal tissue side-effects, thereby increasing the therapeutic window of cancer treatment. We review recent data demonstrating the pivotal role played by inflammatory pathways in cancer progression and modulation of radiation response.

Fig. 1

Conceptual framework of the topics discussed in this review. Radiation therapy induces pro-inflammatory responses in the tumor (which are largely mediated through activation of NF-κB). In turn, NF-κB can up-regulate the pro-survival, angiogenic, invasive and anti-apoptosis pathways which confer a radioresistant phenotype on tumor cells (beneficial to the tumor, detrimental to the patient) and/or it can trigger a pro-inflammatory network of cytokines which mediate radiation-induced early and late side effects in normal tissues (detrimental to the normal tissues and to the patient). By inhibiting these divergent pro-inflammatory responses in tumors and normal tissues, it may be possible to simultaneously achieve enhanced tumor kill and reduced toxicity.

Fig. 2

Simplified depiction of cellular signaling events triggered by clinically relevant doses of radiation. Exposure to clinically relevant doses of ionizing radiation can elicit cellular signaling at two distinct sites - a) Nuclear - The damaged DNA activates the DNA repair machinery which includes activation of ATM, ATR, DNA-PKcs and other repair proteins which arrest the cell cycle b) Cytoplasmic - Radiation-induced disturbance of cellular redox homeostasis by generation of reactive oxygen species (ROS) can activate receptor tyrosine kinases (RTKs) [through inhibition of protein tyrosine phosphatases (PTPases)], which initiate downstream pro-survival signaling pathways mediated through multiple proteins such as Akt. These signaling cascades finally converge upon a small cadre of transcription factors such as NF-κB and STATs which regulate the expression of effector gene products.

Fig. 3

NF-κB as the central mediator of inflammation, carcinogenesis and tumor radioresistance. NF-κB can be activated by microbial components or other pro-inflammatory cytokines which can positively modulate the host immune response by synthesizing chemokines and antimicrobial peptides or can lead to local inflammation. Similarly, NF-κB can be induced by anticancer therapeutics and genotoxic stress, and this activated NF-κB promotes cell survival, which forms the basis of carcinogenesis. However, the most peculiar feature of NF-κB is its ability to be transiently activated by anticancer therapeutics (such as ionizing radiation), which elicits a plethora of pro-survival signaling in the irradiated tumor cells. Thus, activated NF-κB could be beneficial to the host (indicated by solid green arrow) or be detrimental to the host (favoring tumor growth; pathways indicated by dotted red arrows).