Abstract
Macrophages are abundant in the tumor microenvironment where they adopt a pro-tumor phenotype following alternative polarization induced by paracrine factors from cancer and stromal cells. In contrast, classically activated macrophages have tumoricidal activities, such that the polarization of tumor-associated macrophages has become a novel therapeutic target. Toll-like receptor 4 engagement promotes classical activation of macrophages, and recent literature suggests TLR4 agonism to prevent metastasis and promote survival in experimental metastasis models. A growing number of studies indicate that TLR4 can respond to opioids, including the opioid receptor-inactive morphine metabolite morphine-3-glucuronide (M3G). We measured the activation of TLR4 in a reporter cell line exogenously expressing TLR4 and TLR4 co-receptors, and confirmed that M3G weakly but significantly activates TLR4. We hypothesized that M3G would promote the expression of classical activation signature genes in macrophages in vitro. We exposed mouse and human macrophage cell lines to M3G or the TLR4 activator lipopolysaccharide (LPS), alone or in combination with interferon gamma (IFN-γ). The classical macrophage activation markers tested were iNOS, CD86, IL-6, or TNF-α in RAW 264.7 cells and IL-6, IL-12, IL-23, TNF-α, CXCL10, and CXCL11 in THP1 cells. Our results show that despite exhibiting TLR4-activation ability, M3G does not elicit the expression of classical activation markers in LPS-responsive macrophages.
Highlights
The possibility that the pain management of cancer surgery patients can be exploited to significantly reduce the risk of local or metastatic recurrence is generating tremendous interest
We tested the ability of M3G to activate TLR4 in this system (Supplementary Figure 1B) and showed at 1 μM and above a modest but statistically significant activation plateauing at ∼150–160% of control with maximal activation at and above 10 μM
There is increasing evidence that the morphine metabolite M3G is active at TLR4 (Hutchinson et al, 2010; Lewis et al, 2010; Due et al, 2012)
Summary
The possibility that the pain management of cancer surgery patients can be exploited to significantly reduce the risk of local or metastatic recurrence is generating tremendous interest. We have unveiled the ability of morphine to modulate the interaction between cancer and noncancer cells important in the tumor microenvironment, including endothelial cells and macrophages (Afsharimani et al, 2014; Khabbazi et al, 2015, 2016). Tumor-associated macrophages (TAMs) are critical determinants of cancer cell invasiveness, their metastatic potential as well as angiogenesis (Noy and Pollard, 2014; Bronte and Murray, 2015). Macrophages display great functional plasticity in response to specific pathological contexts (Murray et al, 2014) and play a key role in the biology of solid tumors where they constitute up to 50% of the cell population (Solinas et al, 2009). Classically activated (M1) macrophages are considered to have anti-tumor properties (Noy and Pollard, 2014). Reprogramming TAMs from an M2-like phenotype to an M1-like, pro-inflammatory phenotype has the potential to induce anti-tumor activity by rendering the tumor immunogenic (Georgoudaki et al, 2016)
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