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.

Introduction

The functional link between inflammation and cancer was postulated many years ago. In 1863, Virchow [1] noted the presence of leukocytes in the neoplastic tissue and hypothesized that cancers originated from the sites of chronic inflammation. In 1986, Dvorak illustrated that wound healing and tumor stroma formation share several salient features [2]. Since then, the notion that chronic inflammation provides a favorable environment for cancer formation and progression has been widely accepted. Whereas the critical correlation between tumor progression and inflammation is increasingly confirmed by evolving data, it is only recently that the potential significance of these associations has become apparent. The rapid expansion of our understanding of oncogenic molecular signaling pathways has revealed the intricate functional relationships that exist among the inflammatory pathways, tumor progression, invasion and metastasis and resistance of tumors to therapy [3]. These insights have led to the development of new anti-inflammatory therapeutic approaches for cancer treatment [4], [5].

This review portrays the convergence of multiple lines of evidence that inflammatory signaling pathways modulate the response of tumors to radiation therapy (RT). The scope of this review is, however, not to detail the fundamental relationship between inflammatory pathways and tumor progression which has been thoroughly reviewed elsewhere [1], [3], [6], [7] or to elaborate on tumor immunology [8] and/or tumor immunotherapy [9], [10]. Instead, focusing on the intricate interplay between tumor responses to radiation and inflammation, this review offers insights into potential druggable targets to sensitize tumors to RT without significant collateral damage to normal tissue. It is now known that exposure to clinically relevant doses of ionizing radiation (IR) not only induces DNA damage in the nucleus, but also triggers a large network of intracellular signaling events. These include transient activation of pro-survival pathways [receptor tyrosine kinase (RTK) pathways such as the epidermal growth factor receptor (EGFR) pathway and the downstream Ras and phosphoinositide 3-kinase/atypical kinase (PI3K/Akt) signaling], activation of transcription factors [p53, nuclear factor kappa B (NF-κB), activator protein-1 (AP-1)], upregulation of the expression of chemokine receptors (CXC motif receptor 4; CXCR4) [11] and upregulation of the levels of a variety of cytokines [tumor necrosis factor alpha (TNF-α), IL-6, IL-8, urokinase-type plasminogen activator (uPA), transforming growth factor (TGF)-β] [12], [13], [14], [15], all of which are not only crucial mediators of inflammation but also control post-irradiation cell survival responses [16], [17], [18], [19], [20]. Whereas many of these inflammatory downstream responses to radiation are detrimental to normal tissue, they confer a survival advantage to tumor cells. Therefore, unlike many radiosensitization strategies that equally sensitize the tumor cells and the adjacent collaterally irradiated normal cells to RT [21], [22], [23], specific targeting of downstream components of this inducible inflammatory signaling response offer the possibility of seamlessly and simultaneously abrogating radioresistance within tumor cells and blocking deleterious inflammatory responses of normal tissues to RT (Fig. 1).