Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

Abstract

Accumulating evidence suggests that Toll-like receptor 4 (TLR4), a sensor for danger signals, is expressed not only in immune cells, but also in resident epithelial cells, and appears to participate in tissue homeostasis. To explain the premetastatic microenvironment created by the newly discovered endogenous TLR4 ligands, I propose a hypothesis of homeostatic inflammation that includes the classical danger hypothesis.

Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

“…The S100A8 expression level in naphthalenetreated tumor-bearing murine lungs was similar to that in naphthalene-treated control murine lungs but the SAA3 expression level of naphthalene-treated tumorbearing murine lungs was significantly lower than that of naphthalene-treated control lungs. As measured previously, the peak concentration of serum SAA3 protein in tumor-bearing mice was around 150 ng/ml at 8 days after subcutaneous transplantation of tumor cells (Maru, 2010). Although both SAA3 protein and its mRNA were upregulated in the lungs by naphthalene treatment, the serum SAA3 protein levels remained almost unchanged from the baseline (61-68 ng/ml).…”

“…The true danger is to arrive after it. Thus, we proposed to explain the lung metastatic microenvironment as a deregulation of homeostatic inflammation (Maru, 2009(Maru, , 2010.…”

“…Protein bands were detected using chemiluminescence reagent and an image analyzer (RAS 4000 mini, GE Healthcare). The serum concentration of SAA3 was determined by western blotting with defined amounts of recombinant proteins as a control (Maru, 2010). Measurement of serum TNFa was performed using ELISA (BD Biosciences).…”

Premetastasis

“…Anti-S100A8 neutralizing antibody abrogated the injected tumor cell recruitment in the lungs, but not in liver or kidney indicating that S100A8 is necessary to establish the premetastatic niche in the lungs but not liver or kidney. Both S100A8 and SAA3 levels are increased in the serum during the premetastatic period, 4-14 d after tumor transplantation (Maru 2009(Maru , 2010. Removal of the primary tumor decreased both CD11b+ cell number and those chemokine expressions (Maru 2016).…”

“…In our experimental lung metastasis model, the transplanted tumors secrete VEGF, TNFα, and CCL2, stimulating the lungs in the absence of metastasizing tumor cells. The activated lungs in turn express S100A8 and SAA3 both of which are endogenous ligands of TLR4/MD-2 complex, a molecular sensor for microbial endotoxin or lipopolysaccharide (LSP), and released into the circulation (Maru 2009(Maru , 2010Deguchi et al 2013Deguchi et al , 2016. TLR4/MD-2 is expressed in a variety of cell types including blood cells of myeloid origin, endothelial cells, and tumor cells.…”