Effect of IL-6-mediated inflammation on the anti-tumor effect of EGFR inhibitors in head and neck cancer

Interleukin-6 (IL-6) is a pleotropic cytokine with a wide range of biological activities and is well known for its role in inflammation, tumor progression and chemoresistance in HNSCC. Increases in IL-6 expression correlate with poor prognosis in HNSCC patients and patients resistant to chemotherapy have shown significantly higher serum IL-6 levels than those who did respond. In this project we study how EGFR inhibitors increase the expression of IL-6 and how NOX4 –induced oxidative stress may play a role in IL-6 signaling. 

Role of NADPH oxidase 4 (NOX4) and autophagy in the anti-tumor effect of EGFR inhibitors in head and neck cancer

Autophagy is a self-degradation phenomenon activated under conditions of stress including nutrient deprivation, oxidative stress, chemotherapeutic insult and radiation. During this process a double membranous structure is formed which encloses the cytoplasm along with the components targeted for degradation, then fuses with lysosome to form an autophagolysosome where the contents are degraded and recycled for use by the cells under conditions of stress. Autophagy has been implicated as both a tumor suppressor and tumor promoting mechanism depending on the cell model used, type of stress and duration of stimuli. Additionally, autophagy has been implicated in resistance and decreased response to chemotherapeutic agents due to its tumor promoting activity. We have found that the EGFR inhibitor erlotinib may activate autophagy in HNSCC cells as a pro-survival mechanism, and NOX4 may play a role in mediating this effect. Our current goal for this project is to understand how NOX4 activates autophagy.

EGFR inhibitors and inflammasome activation

Interleukin 1β (IL-1β)-driven inflammation has been shown to promote tumor progression and invasiveness in various tumor models. IL-1β secretion is typically known to be a two-step process. First, transcription of pro-IL-1β may be induced by inflammatory stimuli including toll like receptor (TLR) activation. Second, activation of inflammasome assembly by a second stimulus such as reactive oxygen species (ROS) production results in the processing of pro-IL-1β to IL-1β. In this project we study if EGFR inhibitors may stimulate inflammasome activity via TLR activation and NOX4-mediated oxidative stress leading to an IL-1β-driven inflammatory response in head and neck tumor cells.

Welding fume exposure and head and neck cancer development

Exposure to nanoparticles derived from welding fumes is associated with an increased risk of respiratory illnesses, which is likely due to the induction of pro-inflammatory immune responses. It is now known that chronic inflammation generates a microenvironment favoring genomic lesions (via oxidative stress) and survival/proliferative signals (via cytokines) leading to the initiation or promotion of oncogenic transformation. Head and neck epithelia, is the first site of exposure to welding fumes, therefore in this project we study if welders may have an increased risk of head and neck cancer (HNSCC) due to an increased pro-inflammatory immune response.

Activation of toll-like receptors (TLRs) in response to EGFR inhibition

TLRs are known mediators of inflammation that activate immune responses and are present on many types of tumors including HNSCC. Downstream signaling pathways resulting from TLR stimulation include activation of NFκB and AP-1, which are transcription factors necessary for the expression of pro-inflammatory cytokines many of which are involved in tumor growth and survival. In this project we study the effect of EGFR inhibition on TLR activation and if TLR signaling reduces the anti-tumor efficacy of EGFR inhibitors.