BACKGROUND & AIMS Inflammation may contribute to formation, maintenance, and expansion of cancer stem cells (CSCs), which have the capacity for self-renewal, differentiation, and resistance to cytotoxic agents. We investigated the effects of the inflammatory mediator prostaglandin E2 (PGE2) on colorectal CSC development and metastasis in mice and the correlation between levels of PGE2 and CSC markers in human colorectal cancer (CRC) specimens. METHODS Colorectal carcinoma specimens and matched normal tissues were collected from patients at the Mayo Clinic (Scottsdale, AZ) and analyzed by mass spectrometry and quantitative PCR. Human primary CRC cells and mouse tumor cells were isolated using microbeads and flow cytometry and analyzed in sphere-formation and flow cytometry assays. LS-174T cells were sorted by flow cytometry (for CD133+CD44+ and CD133−CD44− cells) and also used in these assays. NSG mice were given cecal or subcutaneous injections of LS-174T or human primary CRC cells. ApcMin/+ mice and NSG mice with orthotopic cecal tumors were given vehicle (controls), PGE2, celecoxib, or/and Ono-AE3-208. PGE2 downstream signaling pathways were knocked down with small hairpin RNAs, expressed from lentiviral vectors in LS-174T cells, or blocked with inhibitors in human primary CRC cells. RESULTS Levels of PGE2 correlated with colonic CSC markers (CD133, CD44, LRG5, and SOX2 mRNAs) in human colorectal carcinoma samples. Administration of PGE2 to ApcMin/+ mice increased tumor stem cells and tumor burden, compared with controls. NSG mice given PGE2 had increased numbers of cecal CSCs and liver metastases, compared with controls, after intracecal injection of LS-174T or human primary CRC cells. Alternatively, celecoxib, an inhibitor of prostaglandin-endoperoxide synthase 2 (PTGS2 or COX2), reduced polyp numbers in Apc Min/+ mice, liver metastasis in NSG mice with orthotopic tumors, and numbers of CSCs in ApcMin/+ and NSG mice. Inhibitors or knockdown of PGE receptor 4 (PTGER4 or EP4), PI3K p85α, ERK1, or nuclear factor (NF)-κB reduced PGE2-induced sphere formation by and expansion of LS-174T and/or human primary CRC cells. Knockdown of ERK1 or PI3K p85α also attenuated PGE2-induced activation of NF-κB in LS-174T cells. An EP4 antagonist reduced the ability of PGE2 to induce CSC expansion in orthotopic tumors and to accelerate formation of liver metastases. Knockdown experiments showed that NF-κB was required for PGE2 induction of CSCs and metastasis in mice. CONCLUSIONS PGE2 induces CSC expansion by activating NF-κB, via EP4–PI3K and EP4–MAPK signaling, and promotes formation of liver metastases in mice. The PGE2 signaling pathway might therefore be targeted therapeutically to slow colorectal cancer progression.
Mammals exhibit multiple adaptive mechanisms that sense and respond to fluctuations in dietary nutrients. Consumption of reduced total dietary protein or a protein diet that is deficient in 1 or more of the essential amino acids triggers wide-ranging changes in feeding behavior and gene expression. At the level of individual cells, dietary protein deficiency is manifested as amino acid (AA) deprivation, which activates the AA response (AAR). The AAR is composed of a collection of signal transduction pathways that terminate in specific transcriptional programs designed to catalyze adaptation to the nutrient stress or, ultimately, undergo apoptosis. Independently of the AAR, endoplasmic reticulum stress activates 3 signaling pathways, collectively referred to as the unfolded protein response. The transcription factor activating transcription factor 4 is one of the terminal transcriptional mediators for both the AAR and the unfolded protein response, leading to a significant degree of overlap with regard to the target genes for these stress pathways. Over the past 5 y, research has revealed that the basic leucine zipper superfamily of transcription factors plays the central role in the AAR. Formation of both homo- and heterodimers among the activating transcription factor, CCAAT enhancer-binding protein, and FOS/JUN families of basic leucine zipper proteins forms the nucleus of a highly integrated transcription factor network that determines the initiation, magnitude, and duration of the cellular response to dietary protein or AA limitation.
Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E 2 (PGE 2 ), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE 2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE 2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.colorectal cancer | COX-2/PGE 2
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