Gram-Negative Pneumonia Augments Non-Small Cell Lung Cancer Metastasis Through Host Toll-like Receptor 4 Activation

Abstract Surgery is essential for cure of early stage non-small cell lung cancer (NSCLC). Post-operative bacterial pneumonias, however, remain high and there is increasing clinical data to suggest that these infectious complications confer an increased risk for metastasis following resection. Toll-like receptors (TLRs) mediate the inflammatory response to infection by recognizing evolutionarily conserved bacterial structures at the surface of numerous pulmonary cell types; yet, little is known about how host TLR activation influences NSCLC metastasis. TLR4 recognizes gram-negative bacterium cell wall lipopolysaccharide (LPS) activating the innate immune system. We demonstrate that gram-negative Escherichia coli respiratory tract infection via TLR4 activation augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice. Additionally, infected C57BL/6 mice demonstrate increased H59 NSCLC in vivo hepatic sinusoidal adhesion compared to negative controls, a response that is significantly diminished in TLR4 knock-out mice. Similarly, intra-tracheal injection of purified TLR4 activating LPS increases in vivo adhesion of H59 cells to murine hepatic sinusoids. Furthermore, H59 cells incubated with bronchoepithelial conditioned media show increased cell adhesion to in vitro extracellular matrix proteins and in vivo hepatic sinusoids through a mechanism dependent on bronchoepithelial TLR4 activation and interleukin-6 secretion. Consequently, TLR4 is a viable therapeutic target for NSCLC metastasis augmented by gram-negative pneumonia.