Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an “eicosanoid and cytokine storm.” AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.

SummaryDuring an immune response, the duration of T cell residence in lymphoid and non‐lymphoid tissues likely affects T cell activation, differentiation, and memory development. The factors that govern T cell transit through inflamed tissues remain incompletely understood, but one important determinant of T cell exit from tissues is sphingosine 1‐phosphate (S1P) signaling. In homeostasis, S1P levels are high in blood and lymph compared to lymphoid organs, and lymphocytes follow S1P gradients out of tissues into circulation using varying combinations of five G‐protein coupled S1P receptors. During an immune response, both the shape of S1P gradients and the expression of S1P receptors are dynamically regulated. Here we review what is known, and key questions that remain unanswered, about how S1P signaling is regulated in inflammation and in turn how S1P shapes immune responses.

In this elegant study, Evrard et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210116) find that sphingosine 1-phosphate receptor 5 (S1PR5) powerfully impairs tissue-resident memory T cell (TRM) formation, and that tissue-derived TGF-β limits S1pr5 expression by infiltrating T cells.

Sulforaphane (SFN) is a compound [1-isothiocyanato-4-(methylsulfinyl)-butane] found in broccoli and other cruciferous vegetables that is currently of interest because of its potential as a chemopreventive and a chemotherapeutic drug. Recent studies in a diverse range of cellular and animal models have shown that SFN is involved in multiple intracellular pathways that regulate xenobiotic metabolism, inflammation, cell death, cell cycle progression, and epigenetic regulation. In order to better understand the mechanisms of action behind SFN-induced cell death, we undertook an unbiased genome wide screen with the yeast knockout (YKO) library to identify SFN sensitive (SFN S) mutants. The mutants were enriched with knockouts in genes linked to vacuolar function suggesting a link between this organelle and SFN's mechanism of action in yeast. Our subsequent work revealed that SFN increases the vacuolar pH of yeast cells and that varying the vacuolar pH can alter the sensitivity of yeast cells to the drug. In fact, several mutations that lower the vacuolar pH in yeast actually made the cells resistant to SFN (SFN R). Finally, we show that human lung cancer cells with more acidic compartments are also SFN R suggesting that SFN's mechanism of action identified in yeast may carry over to higher eukaryotic cells.

Inflammation and angiogenesis are interdependent hallmarks of cancer. Tumor growth is angiogenesis‐dependent and inflammation is a risk factor for many cancers. Inflammation is regulated by endogenous specialized pro‐resolving lipid‐autacoid mediators (SPMs), including resolvins, protectins, and maresins, which are present in multiple tissues. Unlike the majority of anti‐inflammatory agents, SPMs are non‐immunosuppressive, and non‐toxic. These lipid autacoids inhibit angiogenesis and clear cellular debris by macrophages resulting in reduced localized inflammatory cytokines. SPMs mediate their pro‐resolution and anti‐inflammatory activity through at least five known human G‐coupled protein receptors (GPR32, GPR18, ChemR23, GPR37, and LGR6) for resolvin (Rv) D1, RvD2, RvE1, protectin D1, and maresin 1, respectively, as well as a murine RvD1 receptor ALX/FPR2. We show that stimulating resolution of inflammation (RvD4 or RvD5) and anti‐angiogenic therapy (e.g. the thrombospondin (TSP)‐1 peptide 3TSR or anti‐VEGF via DC101) induced synergistic antitumor activity in human xenograft models including ovarian cancer (e.g. 36M2) compared with either treatment alone. The triple therapy 3TSR, anti‐VEGF, and resolvins displayed additive anti‐tumor activity. As the role of SPM receptors in cancer is unknown, we screened various stromal cells in the tumor microenvironment (e.g. macrophages, pericytes, fibroblasts, and neutrophils) for expression of SPM receptors. SPM receptors were expressed in various clinical specimens including breast cancer, head and neck cancer (e.g. oral squamous cell carcinoma), and brain cancer. Flow cytometry and double immunohistochemistry staining confirmed that SPM receptors were expressed in non‐tumor cells in the tumor microenvironment (e.g. macrophages, fibroblasts, pericytes and blood vessels) in vivo. Accordingly, SPMs inhibited tumor cell proliferation in vivo. Thus, SPMs exhibit anti‐tumor activity via the tumor stroma. Loss of SPM receptor expression may be associated with cancer progression in clinical cancer specimens. Notably, resolvins (RvD4 or RvD5) inhibited tumor growth at doses 10,000 times lower than anti‐inflammatory agents such as aspirin and NSAIDs. Thus, stimulating the expression or activity of SPM receptors may enhance current anti‐angiogenic therapy for various cancers.