Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression

Abstract

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.

Mechanisms of Macrophage Plasticity in the Tumor Environment: Manipulating Activation State to Improve Outcomes

“…During tumorigenesis, genetic mutations can be acquired through exposure to chemical carcinogens (18), radiation (19) or viral infections (20,21). Alternatively, inherited mutations (22,23) or those accumulated during chronic inflammation (24)(25)(26) may also drive carcinogenesis. Cell intrinsic tumor suppressive mechanisms, like DNA repair, senescence or apoptosis (27), often fail to contain tumor cell proliferation, promoting the need for immune-mediated elimination of the aberrant cells.…”

Kidney-Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Inflammation, Oxidative Stress, and Cisplatin-Induced Nephrotoxicity

“…Cisplatin nephrotoxicity is accompanied by increased NADPH oxidase (NOX) activity [ 33 , 34 ]. These previous studies have demonstrated increases in renal NOX4, p47phox, and gp91phox in cisplatin nephrotoxicity [ 33 , 34 , 35 , 36 , 37 , 38 ]. We have previously demonstrated that EET analogs can effectively decrease oxidative stress [ 10 , 13 , 26 ].…”

“…EET and EET analogs have been demonstrated to enhance angiogenesis and there is controversy as to whether or not EET analogs could promote tumor growth [ 14 , 15 , 35 , 36 ]. Our previous study demonstrated that EET-A does not enhance cancer cell proliferation [ 30 ].…”

“…Our previous study demonstrated that EET-A does not enhance cancer cell proliferation [ 30 ]. In addition, anti-cancer actions for sEH inhibitors that results in increased EET levels have been found in colon, pancreatic, and liver cancer animal models [ 35 , 37 , 38 ]. Findings in the current study demonstrate that EET-A failed to enhance human breast cancer cell tumor growth in mice.…”

The Role of Introns for the Development of Inflammation-Mediated Cancer Cell

“…Currently, it is scientifically proven that inflammation promotes all stages of tumor formation as well as the development of cancer where chronic inflammation or non-resolving inflammation is playing a principal role in the initiation, promotion, malignant transformation, invasion and metastasis of cancer [4][5][6][7][8][9]. Interestingly, cancer-related inflammation is representing its 7th position as a cancer hallmark and catching the current research attention in human cancer biology [5].…”