292 results on '"DuBois RN"'
Search Results
2. Colon cancer cell growth inhibition by treatment with a selective cox-2 inhibitor
- Author
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Goldman, AP, primary, Williams, CS, additional, Williams, VP, additional, and DuBois, RN, additional
- Published
- 1998
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- View/download PDF
3. A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells
- Author
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Sheng, GG, primary, Shao, J, additional, Sheng, H, additional, Hooton, EB, additional, Isakson, PC, additional, Morrow, JD, additional, Coffey, RJ, additional, DuBois, RN, additional, and Beauchamp, RD, additional
- Published
- 1997
- Full Text
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4. Elevated cyclooxygenase-2 levels in Min mouse adenomas
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Williams, CS, primary, Luongo, C, additional, Radhika, A, additional, Zhang, T, additional, Lamps, LW, additional, Nanney, LB, additional, Beauchamp, RD, additional, and DuBois, RN, additional
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- 1996
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5. Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors
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DuBois, RN, primary, Radhika, A, additional, Reddy, BS, additional, and Entingh, AJ, additional
- Published
- 1996
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6. Accelerated paper. Coordinate regulation of cyclooxygenase-2 and TGF-β1 in replication error-positive colon cancer and azoxymethane-induced rat colonic tumors.
- Author
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Shao, J, Sheng, H, Aramandla, R, Pereira, MA, Lubet, RA, Hawk, E, Grogan, L, Kirsch, IR, Washington, MK, Beauchamp, RD, and DuBois, RN
- Abstract
Evidence is accumulating which indicates that cyclooxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)-induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-β1 staining pattern in these human and rat tumors was similar to that observed for COX-2. The role of TGF-β in RER adenocarcinomas is complex because of the increased mutation rate of TGF-β type II receptors. Northern analysis showed abundant TGF-β1 mRNA in AOM-induced tumors, but not in paired mucosa. TGF-β1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6). Chronic TGF-β1 treatment caused a TGF-β-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1). TGF-β1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence. [ABSTRACT FROM PUBLISHER]
- Published
- 1999
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7. Meloxicam inhibits the growth of colorectal cancer cells.
- Author
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Goldman, AP, Williams, CS, Sheng, H, Lamps, LW, Williams, VP, Pairet, M, Morrow, JD, and DuBois, RN
- Abstract
Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7) and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells. [ABSTRACT FROM PUBLISHER]
- Published
- 1998
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8. Accelerated paper. Nuclear translocation of β-catenin in hereditary and carcinogen-induced intestinal adenomas.
- Author
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Sheng, H, Shao, J, Williams, CS, Pereira, MA, Taketo, MM, Oshima, M, Reynolds, AB, Washington, MK, DuBois, RN, and Beauchamp, RD
- Abstract
The physical interaction between β-catenin and the adenomatous polyposis coli (APC) gene, and the ability of APC to regulate cytoplasmic levels of β-catenin suggest a role for β-catenin in colorectal carcinogenesis. In this study, we found that β-catenin immunoreactivity was detected exclusively in the cell membrane and cytoplasm of morphologically normal intestinal epithelial cells with predominant distribution in the differentiated non-proliferative cell population. In contrast, β-catenin was localized predominantly in the nucleus of adenomas from Min/+ mice and transgenic mice expressing a mutant truncated form of the APC gene (ApcΔ716 mice). β-catenin was expressed predominantly at the cell membrane and cytoplasm of the nontransformed rat intestinal epithelial (RIE-1) cells in culture, whereas predominantly nuclear localization of β-catenin was observed in the human colon cancer cell line SW480. In the azoxymethane (AOM) treated rats, overexpression and nuclear localization of β-catenin was observed in all adenomas. Previous studies have indicated the incidence of APC mutations amongst AOM-induced tumors to be 15% or less. These results demonstrate that nuclear localization of β-catenin is a common event in colorectal tumorigenesis. [ABSTRACT FROM PUBLISHER]
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- 1998
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9. The nuclear eicosanoid receptor, PPARγ, is aberrantly expressed in colonic cancers.
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DuBois, RN, Gupta, R, Brockman, J, Reddy, BS, Krakow, SL, and Lazar, MA
- Abstract
Continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the relative risk of colorectal cancer in humans and decreases tumor yield in rodents treated with carcinogens. One well documented target for NSAIDs is prostaglandin endoperoxide synthase (cyclooxygenase) and two isoforms of this enzyme have been identified, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX enzymes produce eicosanoid products, some of which have recently been shown to activate transcription mediated by the nuclear hormone receptor peroxisome proliferator activated receptor γ (PPARγ), whose expression is largely restricted to adipose tissue. The present study was undertaken to determine if PPARγ was expressed in colonic tumors. PPARγ messenger RNA (mRNA) and protein levels were assayed in colonic tumors and normal adjacent mucosa, as well as in a variety of human colon cancer cell lines. There was a marked increase in PPARγ RNA levels in four out of four of the colonic tumors compared to paired normal mucosa, where little expression of PPARγ was detected. Western blotting analysis showed that PPARγ protein was expressed in four out of five colonic tumor samples. PPARγ was also expressed in a subset of polyps, and in certain human colonic cancer cell lines as well. Additionally, we were able to demonstrate that an eicosanoid, 15 deoxy-Δ12,14 PGJ2, transactivated transcription of a PPRE-driven promoter in CaCo-2 cells. Thus, we have shown that PPARγ gene and protein expression is elevated in rodent colon tumors, in selected human colon cancer cell lines and that the PPARγ receptor is functional in CaCo-2 cells. Since PPARγ is a ligand-modulated transcription factor, it may provide a novel target for chemopreventive strategies for colorectal cancer. [ABSTRACT FROM PUBLISHER]
- Published
- 1998
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10. NSAIDs and prostate cancer risk.
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DuBois RN
- Published
- 2006
11. Peroxisome Proliferator-Activated Receptor δ Suppresses the Cytotoxicity of CD8+ T Cells by Inhibiting RelA DNA-Binding Activity.
- Author
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Cen B, Wei J, Wang D, and DuBois RN
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Colorectal Neoplasms metabolism, Colorectal Neoplasms immunology, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Cytotoxicity, Immunologic, DNA metabolism, Interferon-gamma metabolism, Mice, Inbred C57BL, Mice, Knockout, Pore Forming Cytotoxic Proteins metabolism, Pore Forming Cytotoxic Proteins genetics, PPAR delta metabolism, PPAR delta genetics, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, T-Lymphocytes, Cytotoxic drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Granzymes metabolism, Perforin metabolism, Perforin genetics, Transcription Factor RelA metabolism
- Abstract
The molecular mechanisms regulating CD8+ cytotoxic T lymphocytes (CTL) are not fully understood. Here, we show that the peroxisome proliferator-activated receptor δ (PPARδ) suppresses CTL cytotoxicity by inhibiting RelA DNA binding. Treatment of ApcMin/+ mice with the PPARδ agonist GW501516 reduced the activation of normal and tumor-associated intestinal CD8+ T cells and increased intestinal adenoma burden. PPARδ knockout or knockdown in CTLs increased their cytotoxicity against colorectal cancer cells, whereas overexpression of PPARδ or agonist treatment decreased it. Correspondingly, perforin, granzyme B, and IFNγ protein and mRNA levels were higher in PPARδ knockout or knockdown CTLs and lower in PPARδ overexpressing or agonist-treated CTLs. Mechanistically, we found that PPARδ binds to RelA, interfering with RelA-p50 heterodimer formation in the nucleus, thereby inhibiting its DNA binding in CTLs. Thus, PPARδ is a critical regulator of CTL effector function. Significance: Here, we provide the first direct evidence that PPARδ plays a critical role in suppressing the immune response against tumors by downregulating RelA DNA-binding activity. This results in decreased expression of perforin, granzyme B, and IFNγ. Thus, PPARδ may serve as a valuable target for developing future cancer immunotherapies., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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12. Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors.
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Francica BJ, Holtz A, Lopez J, Freund D, Chen A, Wang D, Powell D, Kipper F, Panigrahy D, Dubois RN, Whiting CC, Prasit P, and Dubensky TW
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- Humans, Animals, Mice, Dinoprostone metabolism, Receptors, Prostaglandin E, EP2 Subtype metabolism, Celecoxib pharmacology, CD8-Positive T-Lymphocytes metabolism, Receptors, Prostaglandin E, EP4 Subtype metabolism, Cyclooxygenase 2 Inhibitors, Tumor Microenvironment, Prostaglandins, Neoplasms
- Abstract
While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8
+ T cells in vitro as compared with single EP antagonists. CD8+ T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist., Significance: Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule., (© 2023 The Authors; Published by the American Association for Cancer Research.)- Published
- 2023
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13. The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.
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Anderson KC, Cantley LC, Dalla-Favera R, Dang CV, Diaz LA, DuBois RN, Flaherty KT, Greenberg PD, Loda M, Mardis ER, Platz EA, Pollak MN, Schreiber RD, Siu LL, and Teicher BA
- Subjects
- Humans, Periodicals as Topic
- Published
- 2022
- Full Text
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14. Introducing Cancer Center Director Perspectives on Prevention.
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DuBois RN and Pollak MN
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- 2022
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15. Role of Prostaglandin E2 in the Progression of Gastrointestinal Cancer.
- Author
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Wilson DJ and DuBois RN
- Subjects
- Humans, Inflammation pathology, Signal Transduction, Tumor Microenvironment, Dinoprostone metabolism, Gastrointestinal Neoplasms
- Abstract
Chronic inflammation is a well-established risk factor for several diseases, including cancer. It influences tumor cell biology and the type and density of immune cells in the tumor microenvironment (TME), promoting cancer development. While proinflammatory cytokines and chemokines modulate cancer development, emerging evidence has shown that prostaglandin E2 (PGE2) is a known mediator connecting chronic inflammation to cancerization. This review highlights recent advances in our understanding of how the elevation of PGE2 production promotes gastrointestinal cancer initiation, progression, invasion, metastasis, and recurrence, including modulation of immune checkpoint signaling and the type and density of immune cells in the tumor/tissue microenvironment., (©2022 American Association for Cancer Research.)
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- 2022
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16. The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas.
- Author
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Wei J, Zhang J, Wang D, Cen B, Lang JD, and DuBois RN
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Cyclooxygenase 2 metabolism, Dinoprostone metabolism, Humans, Mice, Phosphatidylinositol 3-Kinases metabolism, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins c-akt metabolism, Receptors, Prostaglandin E, EP4 Subtype metabolism, Adenoma, Colorectal Neoplasms pathology
- Abstract
The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2-derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4-PI3K-Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4-PI3K-Akt-NFκB-PD-1 signaling pathway. In contrast, inhibiting the COX-2-PGE2-EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion., Prevention Relevance: These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs., (©2022 American Association for Cancer Research.)
- Published
- 2022
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17. The First Lady Presses for Cancer Screening to Get Back On Track.
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DuBois LA and DuBois RN
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- COVID-19 virology, Humans, Neoplasms epidemiology, Neoplasms prevention & control, Neoplasms virology, United States, COVID-19 complications, Early Detection of Cancer methods, Early Detection of Cancer standards, Famous Persons, Neoplasms diagnosis, SARS-CoV-2 isolation & purification
- Abstract
The First Lady of the United States, Dr. Jill Biden, visited the Hollings Cancer Center at the Medical University of South Carolina on October 25, 2021. This Commentary remarks on the administration's goal of directing public attention to cancer screening and prevention as part of an overall effort to recover ground lost in the COVID-19 pandemic, particularly in underserved communities., (©2022 American Association for Cancer Research.)
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- 2022
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18. Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer.
- Author
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Wang D, Cabalag CS, Clemons NJ, and DuBois RN
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Cancer-Associated Fibroblasts enzymology, Cancer-Associated Fibroblasts immunology, Cyclooxygenase 2 Inhibitors therapeutic use, Epithelial Cells enzymology, Epithelial Cells immunology, Gastrointestinal Neoplasms drug therapy, Gastrointestinal Neoplasms immunology, Gastrointestinal Neoplasms pathology, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating enzymology, Lymphocytes, Tumor-Infiltrating immunology, Signal Transduction, Tumor-Associated Macrophages enzymology, Tumor-Associated Macrophages immunology, Cyclooxygenase 2 metabolism, Dinoprostone metabolism, Gastrointestinal Neoplasms enzymology, Inflammation Mediators metabolism, Tumor Escape drug effects, Tumor Microenvironment immunology
- Abstract
Chronic inflammation is a known risk factor for gastrointestinal cancer. The evidence that nonsteroidal anti-inflammatory drugs suppress the incidence, growth, and metastasis of gastrointestinal cancer supports the concept that a nonsteroidal anti-inflammatory drug target, cyclooxygenase, and its downstream bioactive lipid products may provide one of the links between inflammation and cancer. Preclinical studies have demonstrated that the cyclooxygenase-2-prostaglandin E
2 pathway can promote gastrointestinal cancer development. Although the role of this pathway in cancer has been investigated extensively for 2 decades, only recent studies have described its effects on host defenses against transformed epithelial cells. Overcoming tumor-immune evasion remains one of the major challenges in cancer immunotherapy. This review summarizes the impacts of the cyclooxygenase-2-prostaglandin E2 pathway on gastrointestinal cancer development. Our focus was to highlight recent advances in our understanding of how this pathway induces tumor immune evasion., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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19. The Urgent Need for Expanded Cancer Screening.
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DuBois RN
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- Child, Humans, Mass Screening, Public Health, Early Detection of Cancer, Neoplasms diagnosis, Neoplasms epidemiology, Neoplasms prevention & control
- Abstract
On October 20, 2021, I had the privilege of testifying before the House Energy and Commerce Committee, Subcommittee on Health Hearing on Enhancing Public Health: Legislation to Protect Children and Families. This commentary is based on the written testimony I provided to the Subcommittee on issues related to cancer screening and early detection. It highlights the research progress, updated guidelines, and new challenges in this field, emphasizing the importance of screening asymptomatic, at-risk population to detect precancerous lesions or cancer at an early stage., (©2021 American Association for Cancer Research.)
- Published
- 2021
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20. Mutant APC promotes tumor immune evasion via PD-L1 in colorectal cancer.
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Cen B, Wei J, Wang D, Xiong Y, Shay JW, and DuBois RN
- Subjects
- Adenomatous Polyposis Coli Protein immunology, Animals, B7-H1 Antigen biosynthesis, B7-H1 Antigen genetics, CD8-Positive T-Lymphocytes immunology, Colorectal Neoplasms drug therapy, Gene Knockdown Techniques, HEK293 Cells, HT29 Cells, Humans, Mice, Mice, Inbred C57BL, Tumor Escape genetics, Adenomatous Polyposis Coli Protein genetics, B7-H1 Antigen immunology, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology
- Abstract
PD-L1 expression is elevated in various human cancers, including colorectal cancer. High levels of PD-L1 expressed on tumor epithelial cells are one of the potential mechanisms by which tumor cells become resistant to immune attack. However, PD-L1 regulation in tumor cells is not fully understood. Here we demonstrate that mutations in the adenomatous polyposis coli (APC) gene lead to colonic epithelial cell resistance to CD8
+ T cell cytotoxicity by induction of PD-L1 expression. Mechanistically, this occurs as a result of the β-catenin/TCF4 complex binding to the PD-L1 promoter, leading to increased transcription. Our findings not only reveal a novel mechanism by which APC mutations induce tumor immune evasion via an immune checkpoint pathway but also pave the way for developing β-catenin or TCF4 inhibitors as possible new options for immune checkpoint inhibition., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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21. Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting.
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Miller MS, Allen PJ, Brown PH, Chan AT, Clapper ML, Dashwood RH, Demehri S, Disis ML, DuBois RN, Glynn RJ, Kensler TW, Khan SA, Johnson BD, Liby KT, Lipkin SM, Mallery SR, Meuillet EJ, Roden RBS, Schoen RE, Sharp ZD, Shirwan H, Siegfried JM, Rao CV, You M, Vilar E, Szabo E, and Mohammed A
- Abstract
The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented., Competing Interests: CONFLICTS OF INTEREST Drs. Allen, Clapper, Dashwood, Demehri, DuBois, Johnson, Kensler, Khan, Mallery, Miller, Mohammed, Rao, Schoen, Sharp, Szabo, and You have no FCOI to declare. Dr. Brown owns stock in GeneTex, whose products are not discussed in this manuscript. Dr. Chan has previously received grant support and consulting fees from Bayer Pharma AG; consulting fees from Pfizer Inc. and Boehringer Ingelheim. Dr. Disis received grant funding from Pfizer, Precigen, Bavarian Nordisk, and Veanna; is a stockholder in Epithany; and is an inventor with patents held by the University of Washington. Dr. Glynn has received support from research grants to his employer from AstraZeneca, Kowa, and Pfizer. The Brigham & Women’s Hospital holds patents for use of inflammatory biomarkers in cardiovascular disease. The CANTOS trial was funded by Novartis. Dr. Liby is an inventor on patents for synthetic triterpenoids and rexinoids. Dr. Lipkin is PI on grant U01-CA233056 that includes work performed by Nouscom, LLC. Dr. Meuillet is a scientific co-founder and member of the Management Team of PHusis, which is developing PHT-427. Dr. Roden is a co-founder of and has an equity ownership interest in Papivax LLC. Also, he owns Papivax Biotech Inc. stock options and is a member of Papivax Biotech Inc.’s Scientific Advisory Board. Under a licensing agreement between Papivax Biotech, Inc. and the Johns Hopkins University, the University and Dr. Roden are entitled to royalties on an invention described in this article. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Siegfried has a US Patent Pending: #62650892. Dr. Shirwan is a CEO at FasCure Therapeutics, LLC, and has ownership interest (including stocks and patents) in the Company. Dr. Vilar has a consulting or advisory role with Janssen Research and Development, and Recursion Pharma., (Copyright © 2021 Korean Society of Cancer Prevention.)
- Published
- 2021
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22. COVID-19, Cancer Care and Prevention.
- Author
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DuBois RN
- Subjects
- Betacoronavirus, COVID-19, Humans, SARS-CoV-2, Coronavirus Infections, Early Detection of Cancer, Neoplasms prevention & control, Pandemics, Pneumonia, Viral
- Abstract
The COVID-19 pandemic has had an enormous impact on our society and healthcare delivery in the United States. Importantly, elective procedures and screening exams for cancer have been delayed or canceled over the past 4-5 months raising concerns over the future incidence and outcomes for those at risk or diagnosed with cancer. It is clear to everyone in the cancer field that the earlier we detect premalignant disease or cancer, the better the clinical outcome is for the patient. Most healthcare institutions have now put safety procedures and guidelines in place, which have dramatically reduced the risk of viral spread during encounters in their healthcare facilities. We must now encourage the public and those individuals at high risk for cancer to resume normal cancer screening., (©2020 American Association for Cancer Research.)
- Published
- 2020
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23. Fibroblasts fuel intestinal tumorigenesis.
- Author
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Wang D and DuBois RN
- Subjects
- Fibroblasts, Humans, Intestines, Carcinogenesis, Cell Transformation, Neoplastic
- Published
- 2020
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24. Prostaglandin E 2 Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.
- Author
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Cen B, Lang JD, Du Y, Wei J, Xiong Y, Bradley N, Wang D, and DuBois RN
- Subjects
- Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Humans, RNA, Long Noncoding metabolism, Tumor Cells, Cultured, Up-Regulation genetics, Colorectal Neoplasms metabolism, Dinoprostone genetics, MicroRNAs metabolism, Neoplasm Metastasis genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Background & Aims: Prostaglandin E
2 (PGE2 ) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE2 on colorectal cancer (CRC) development., Methods: We incubated LS174T colorectal cancer cells with PGE2 or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative polymerase chain reaction, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NOD-scidIL-2Rg-/- mice were given injections of LS174T cells, and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes., Results: We identified miRNA 675-5p (miR675-5p) as the miRNA most highly up-regulated by incubation of colorectal cancer cells with PGE2 . PGE2 increased expression of miR675-5p by activating expression of Myc, via activation of protein kinase B, also known as (AKT), nuclear factor κB, and β-catenin. PGE2 increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE2 formed more liver and lung metastases in mice than control LS174T cells. We identified a 3' untranslated region in the TP53 messenger RNA that bound miR675-5p; binding resulted in loss of the p53 protein. Expression of miR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC., Conclusions: We found that treatment of mice with PGE2 increased CRC cells invasive activity and ability to form liver and lung metastases. PGE2 down-regulates expression of p53 by increasing expression of miR675-5p, which binds to and prevents translation of TP53 messenger RNA. These findings provide insight into the mechanisms by which PGE2 promotes tumor development and progression. Strategies to target PGE2 might be developed for treatment of CRC., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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25. PPARδ Mediates the Effect of Dietary Fat in Promoting Colorectal Cancer Metastasis.
- Author
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Wang D, Fu L, Wei J, Xiong Y, and DuBois RN
- Subjects
- Animals, Colorectal Neoplasms etiology, Colorectal Neoplasms metabolism, Diet, High-Fat adverse effects, HCT116 Cells, Humans, Liver Neoplasms, Experimental secondary, Male, Mice, Inbred NOD, Mice, Mutant Strains, Nanog Homeobox Protein genetics, Neoplastic Stem Cells pathology, PPAR delta agonists, Promoter Regions, Genetic, Thiazoles pharmacology, Xenograft Model Antitumor Assays, Colorectal Neoplasms pathology, Dietary Fats adverse effects, PPAR delta metabolism
- Abstract
The nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPARδ) is a ligand-dependent transcription factor involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Although PPARδ has been shown to promote intestinal adenoma formation and growth, the molecular mechanisms underlying the contribution of PPARδ to colorectal cancer remain unclear. Here, we demonstrate that activation of PPARδ induces expansion of colonic cancer stem cells (CSC) and promotes colorectal cancer liver metastasis by binding to the Nanog promoter and enhancing Nanog expression. Moreover, PPARδ mediated the effect of a high-fat diet in promoting liver metastasis and induction of colonic CSC expansion. Our findings uncover a novel role of dietary fats in colorectal cancer metastasis and reveal novel mechanisms underlying PPARδ-mediated induction of CSCs and those responsible for the contribution of dietary fats to colorectal cancer progression. These findings may provide a rationale for developing PPARδ antagonists to therapeutically target CSCs in colorectal cancer. SIGNIFICANCE: These findings show that PPARδ contributes to colorectal cancer metastasis by expanding the CSC population, indicating that antagonists that target PPARδ may be beneficial in treating colorectal cancer., (©2019 American Association for Cancer Research.)
- Published
- 2019
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26. Magnetic Resonance Imaging and Bioluminescence Imaging for Evaluating Tumor Burden in Orthotopic Colon Cancer.
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Ravoori MK, Margalit O, Singh S, Kim SH, Wei W, Menter DG, DuBois RN, and Kundra V
- Subjects
- Animals, HCT116 Cells, Humans, Male, Mice, Mice, Nude, Neoplasm Transplantation, Colonic Neoplasms diagnostic imaging, Luminescent Measurements, Magnetic Resonance Imaging
- Abstract
Quantifying tumor burden is important for following the natural history of orthotopic colon cancer and therapeutic efficacy. Bioluminescence imaging (BLI) is commonly used for such assessment and has both advantages and limitations. We compared BLI and magnetic resonance imaging (MRI) for quantifying orthotopic tumors in a mouse model of colon cancer. Among sequences tested, T2-based MRI imaging ranked best overall for colon cancer border delineation, contrast, and conspicuity. Longitudinal MRI detected tumor outside the colon, indistinguished by BLI. Colon tumor weights calculated from MRI in vivo correlated highly with tumor weights measured ex vivo whereas the BLI signal intensities correlated relatively poorly and this difference in correlations was highly significant. This suggests that MRI may more accurately assess tumor burden in longitudinal monitoring of orthotopic colon cancer in this model as well as in other models.
- Published
- 2019
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27. Cancer Prevention: A Message from the New Editors-in-Chief.
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DuBois RN and Pollak MN
- Published
- 2019
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28. AACR White Paper: Shaping the Future of Cancer Prevention - A Roadmap for Advancing Science and Public Health.
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Lippman SM, Abate-Shen C, Colbert Maresso KL, Colditz GA, Dannenberg AJ, Davidson NE, Disis ML, DuBois RN, Szabo E, Giuliano AR, Hait WN, Lee JJ, Kensler TW, Kramer BS, Limburg P, Maitra A, Martinez ME, Rebbeck TR, Schmitz KH, Vilar E, and Hawk ET
- Subjects
- Biomedical Research organization & administration, Congresses as Topic, Health Plan Implementation, Health Status Disparities, Humans, Neoplasms ethnology, Neoplasms etiology, Obesity complications, Primary Prevention methods, Primary Prevention trends, Public Health statistics & numerical data, Public Health trends, Societies, Medical organization & administration, Societies, Medical trends, Societies, Scientific organization & administration, Societies, Scientific trends, United States epidemiology, Biomedical Research trends, Neoplasms prevention & control, Obesity epidemiology, Primary Prevention organization & administration
- Abstract
The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling-from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold "Cancer Interception" initiative., (©2018 American Association for Cancer Research.)
- Published
- 2018
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29. Role of prostanoids in gastrointestinal cancer.
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Wang D and DuBois RN
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- Animals, Carcinogens metabolism, Dinoprostone immunology, Dinoprostone metabolism, Gastrointestinal Neoplasms immunology, Humans, Immune Tolerance, Inflammation Mediators immunology, Inflammation Mediators metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Macrophages immunology, Macrophages metabolism, Metabolic Networks and Pathways, Models, Biological, Prostaglandins immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tumor Microenvironment immunology, Gastrointestinal Neoplasms etiology, Gastrointestinal Neoplasms metabolism, Prostaglandins metabolism
- Abstract
Chronic inflammation is a risk factor for gastrointestinal cancer and other diseases. Most studies have focused on cytokines and chemokines as mediators connecting chronic inflammation to cancer, whereas the involvement of lipid mediators, including prostanoids, has not been extensively investigated. Prostanoids are among the earliest signaling molecules released in response to inflammation. Multiple lines of evidence suggest that prostanoids are involved in gastrointestinal cancer. In this Review, we discuss how prostanoids impact gastrointestinal cancer development. In particular, we highlight recent advances in our understanding of how prostaglandin E2 induces the immunosuppressive microenvironment in gastrointestinal cancers.
- Published
- 2018
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30. CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer.
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Wang D, Sun H, Wei J, Cen B, and DuBois RN
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- Animals, Chemokine CXCL1 immunology, Colorectal Neoplasms immunology, HCT116 Cells, Heterografts, Humans, Liver Neoplasms immunology, Liver Neoplasms metabolism, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Metastasis, Neoplastic Stem Cells immunology, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Stem Cell Niche, Tumor Microenvironment, Chemokine CXCL1 biosynthesis, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Liver Neoplasms secondary
- Abstract
Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655-65. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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31. Krüppel-Like Factor 12 Promotes Colorectal Cancer Growth through Early Growth Response Protein 1.
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Kim SH, Park YY, Cho SN, Margalit O, Wang D, and DuBois RN
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- Cell Line, Tumor, Cell Survival drug effects, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Gene Knockdown Techniques, Humans, Prognosis, Promoter Regions, Genetic, Protein Binding, Colorectal Neoplasms genetics, Early Growth Response Protein 1 genetics, Gene Expression Regulation, Neoplastic, Kruppel-Like Transcription Factors metabolism
- Abstract
Krüppel-like factor 12 (KLF12) is a transcription factor that plays a role in normal kidney development and repression of decidualization. KLF12 is frequently elevated in esophageal adenocarcinoma and has been reported to promote gastric cancer progression. Here, we examined the role of KLF12 in colorectal cancer (CRC). Indeed, KLF12 promotes tumor growth by directly activating early growth response protein 1 (EGR1). The levels of KLF12 and EGR1 correlate synergistically with a poor prognosis. These results indicate that KLF12 likely plays an important role in CRC and could serve as a potential prognostic marker and therapeutic target.
- Published
- 2016
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32. The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression.
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Wang D and DuBois RN
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- Animals, Humans, Neoplasms immunology, Prostaglandin-Endoperoxide Synthases metabolism, Tumor Escape
- Abstract
Tumor-associated inflammation can create an immunosuppressive microenvironment allowing tumor cells to escape immunosurveillance. Inhibiting immunosuppression remains one of the major challenges in cancer immunotherapy via checkpoint inhibitors. Recent preclinical data from the Reis e Sousa group may provide a strong rationale for developing new therapeutics to subvert tumor-induced immunosuppression via prostaglandin inhibition., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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33. Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice.
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Wang D, Fu L, Sun H, Guo L, and DuBois RN
- Subjects
- Animals, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Carcinoma genetics, Carcinoma prevention & control, Carcinoma secondary, Cell Line, Tumor, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms prevention & control, Cyclooxygenase 2 Inhibitors pharmacology, Dinoprostone administration & dosage, Gene Expression Regulation, Neoplastic, Genes, APC, Heterografts, Humans, Liver Neoplasms metabolism, Liver Neoplasms prevention & control, Liver Neoplasms secondary, Male, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Mitogen-Activated Protein Kinases genetics, Mitogen-Activated Protein Kinases metabolism, NF-kappa B genetics, NF-kappa B metabolism, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Phosphatidylinositol 3-Kinase genetics, Phosphatidylinositol 3-Kinase metabolism, RNA Interference, Receptors, Prostaglandin E, EP4 Subtype genetics, Receptors, Prostaglandin E, EP4 Subtype metabolism, Signal Transduction, Transfection, Tumor Burden, Tumor Cells, Cultured, Carcinoma metabolism, Cell Movement drug effects, Cell Proliferation drug effects, Colorectal Neoplasms metabolism, Dinoprostone metabolism, Inflammation Mediators metabolism, Neoplastic Stem Cells metabolism
- Abstract
Background & Aims: Inflammation may contribute to the 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 polymerase chain reaction. Human primary CRC cells and mouse tumor cells were isolated using microbeads or flow cytometry and analyzed for sphere-formation and by flow cytometry assays. LS-174T cells were sorted by flow cytometry (for CD133(+)CD44(+) and CD133(-)CD44(-) cells) and also used in these assays. NOD-scidIL-2Rγ(-/-) (NSG) mice were given cecal or subcutaneous injections of LS-174T or human primary CRC cells. Apc(Min/+) mice and NSG mice with orthotopic cecal tumors were given vehicle (controls), PGE2, celecoxib, and/or 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 messenger RNAs) in human colorectal carcinoma samples. Administration of PGE2 to Apc(Min/+) 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, reduced polyp numbers in Apc(Min/+) mice, liver metastasis in NSG mice with orthotopic tumors, and numbers of CSCs in Apc(Min/+) and NSG mice. Inhibitors or knockdown of PGE2 receptor 4 (EP4), phosphoinositide 3-kinase (PI3K) p85α, extracellular signal-regulated kinase 1 (ERK1), or nuclear factor (NF)-κB reduced PGE2-induced sphere formation 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 the 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-mitogen-activated protein kinase signaling, and promotes the formation of liver metastases in mice. The PGE2 signaling pathway therefore might be targeted therapeutically to slow CSC expansion and colorectal cancer progression., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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34. AACR Cancer Progress Report 2015.
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Baselga J, Bhardwaj N, Cantley LC, DeMatteo R, DuBois RN, Foti M, Gapstur SM, Hahn WC, Helman LJ, Jensen RA, Paskett ED, Lawrence TS, Lutzker SG, and Szabo E
- Subjects
- Medical Oncology trends
- Published
- 2015
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35. Immunosuppression associated with chronic inflammation in the tumor microenvironment.
- Author
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Wang D and DuBois RN
- Subjects
- Chronic Disease, Humans, Immune Tolerance, Immunosuppression Therapy, Inflammation pathology, Melanoma pathology, T-Lymphocytes pathology, Inflammation immunology, Melanoma immunology, T-Lymphocytes immunology, Tumor Microenvironment immunology
- Abstract
Chronic inflammation contributes to cancer development via multiple mechanisms. One potential mechanism is that chronic inflammation can generate an immunosuppressive microenvironment that allows advantages for tumor formation and progression. The immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is characterized by accumulation of proinflammatory mediators, infiltration of immune suppressor cells and activation of immune checkpoint pathways in effector T cells. In this review, we highlight recent advances in our understanding of how immunosuppression contributes to cancer and how proinflammatory mediators induce the immunosuppressive microenvironment via induction of immunosuppressive cells and activation of immune checkpoint pathways., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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36. The Jeremiah Metzger Lecture: Inflammation, Immune Modulators, and Chronic Disease.
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Dubois RN
- Subjects
- Awards and Prizes, Chronic Disease, Humans, Inflammation epidemiology, Inflammation metabolism, Inflammation Mediators metabolism, Prognosis, Risk Assessment, Risk Factors, Inflammation immunology, Inflammation Mediators immunology, Signal Transduction
- Abstract
Chronic inflammation is a risk factor for many different diseases. It is clear that inflammation is associated with degenerative brain diseases, obesity, metabolic syndrome, cardiovascular disease, diabetes, and cancer. Throughout the past 100 years, changes in the causes of death in the US have been dramatic. The most recent data indicate that cardiovascular disease and cancer are now responsible for 63% of mortality in the US population. Although progression of these diseases is related to diet, lifestyle, and genetic factors, a common but often unrecognized link is the presence of underlying chronic inflammation. As of 2014, 83.6 million people were living with some form of cardiovascular disease, 29.1 million people have been diagnosed with diabetes, 14 million people carried the diagnosis of cancer, and 5.2 million people were living with Alzheimer disease. These diseases are a huge burden on our health care system and all have been associated with chronic inflammation.
- Published
- 2015
37. CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models.
- Author
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Kim SH, Margalit O, Katoh H, Wang D, Wu H, Xia D, Holla VR, Yang P, and DuBois RN
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Cyclooxygenase 2 Inhibitors pharmacology, Dinoprostone metabolism, Furans pharmacology, Humans, Mice, Sulfonamides pharmacology, Xenograft Model Antitumor Assays, Adenoma drug therapy, Antineoplastic Agents therapeutic use, Carcinoma drug therapy, Colorectal Neoplasms drug therapy, Cyclooxygenase 2 Inhibitors therapeutic use, Furans therapeutic use, Sulfonamides therapeutic use
- Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors (COXIBs) can reduce the risk of developing colorectal cancer (CRC) and are being considered for use as adjuvant therapy for treatment of CRC patients. However, long-term use of most NSAIDs, except aspirin, increases cardiovascular risk, hampering use of these drugs in CRC prevention and possibly for treatment. CG100649 is a new member of the COXIB family, which is proposed to inhibit both COX-2 and carbonic anhydrase-I/-II (CA-I/-II) activity. Using mouse models, we show here that CG100649 inhibits premalignant and malignant colorectal lesions in mouse models, partly through inhibiting tumor cell proliferation. These pre-clinical findings suggest a need for further exploration of CG100649 for CRC prevention and treatment. The long-term safety profile of CG100649, particularly regarding its effect on cardiovascular risk, is yet to be determined.
- Published
- 2014
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38. PPARδ and PGE 2 signaling pathways communicate and connect inflammation to colorectal cancer.
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Wang D and DuBois RN
- Abstract
The nuclear hormone receptor peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-dependent transcription factor that is involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Despite decades of research, the role of PPARδ in inflammation and colorectal cancer remains unclear and somewhat controversial. Our recent work presented the first genetic evidence demonstrating that PPARδ is required for chronic colonic inflammation and colitis-associated carcinogenesis. We also found that a PPARδ downstream pathway, namely the COX-2-derived PGE
2 signaling, mediated crosstalk between tumor epithelial cells and macrophages to promote chronic inflammation and colitis-associated tumor genesis. In this brief review, we summarize recent studies on the role of PPARδ in inflammatory bowel disease (IBD) and colorectal cancer (CRC) and highlight recent advances in our understanding of how PPARδ and COX-2-drevided PGE2 signaling coordinately promote chronic colonic inflammation and colitis-associate tumorigenesis. Elucidating the role of PPARδ in inflammation and CRC may provide a rationale for development of PPARδ antagonists as new therapeutic agents in treatment of IBD and CRC.- Published
- 2014
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39. Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth.
- Author
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Wang D, Fu L, Ning W, Guo L, Sun X, Dey SK, Chaturvedi R, Wilson KT, and DuBois RN
- Subjects
- Adenoma pathology, Animals, Cell Communication physiology, Cell Line, Tumor, Colitis chemically induced, Colitis pathology, Colorectal Neoplasms pathology, Cyclooxygenase 2 metabolism, Dextran Sulfate toxicity, Dietary Fats metabolism, Dinoprostone metabolism, Epithelial Cells cytology, Epithelial Cells metabolism, Humans, Macrophages cytology, Macrophages metabolism, Male, Mice, Mice, Knockout, Monocytes cytology, Monocytes metabolism, Receptors, Cytoplasmic and Nuclear genetics, Adenoma metabolism, Colitis metabolism, Colorectal Neoplasms metabolism, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
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 E2 (PGE2), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE2 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 PGE2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.
- Published
- 2014
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40. Myeloid-derived suppressor cells link inflammation to cancer.
- Author
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Wang D and DuBois RN
- Abstract
Our recent work has provided the first evidence that MDSCs promote chronic colonic inflammation and colitis-associated carcinogenesis. Our findings not only reveal a novel function of MDSCs in connecting inflammation to cancer, but also provide a rationale for developing effective therapeutic strategies to subvert inflammation- and tumor-induced immunosuppression.
- Published
- 2014
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41. Role of inflammation and inflammatory mediators in colorectal cancer.
- Author
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Dubois RN
- Subjects
- Adenoma genetics, Adenoma immunology, Adenoma pathology, Animals, Azoxymethane, Colitis chemically induced, Colitis genetics, Colitis immunology, Colitis pathology, Colitis prevention & control, Colon immunology, Colon pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Colorectal Neoplasms pathology, Colorectal Neoplasms prevention & control, Cyclooxygenase 2 metabolism, Dextran Sulfate, Dinoprostone metabolism, Disease Models, Animal, Genes, APC, Humans, Inflammation Mediators immunology, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Mice, Inbred BALB C, Mice, Knockout, Rats, Receptors, Interleukin-8B deficiency, Receptors, Interleukin-8B genetics, Receptors, Interleukin-8B metabolism, Adenoma metabolism, Colitis metabolism, Colon metabolism, Colorectal Neoplasms metabolism, Inflammation Mediators metabolism, Intestinal Mucosa metabolism
- Abstract
Chronic inflammation is a risk factor for several different cancers including colorectal cancer (CRC). However, the mechanisms underlying the contribution of inflammation to cancer remain elusive. Pro-inflammatory mediators such as cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) contribute to cancer progression. Here, we show that COX-2 is an immediate-early response gene induced by growth factors and pro-inflammatory cytokines and its levels are elevated in human CRCs. Furthermore, we show that COX-2-derived PGE2 promotes colonic tumor growth via silencing certain tumor suppressors and DNA repair genes by DNA methylation in colonic epithelial tumor cells. We also report that C-X-C motif chemokine receptor 2 accelerates colonic inflammation and colitis-associated tumorigenesis by mediating myeloid-derived suppressor cell recruitment to the tumor microenvironment. These findings not only support a rationale to target these pro-inflammatory pathways for cancer prevention and treatment but also provide support for developing new therapeutic approaches to subvert chronic inflammation- and tumor-induced immunosuppression.
- Published
- 2014
42. HIG2 promotes colorectal cancer progression via hypoxia-dependent and independent pathways.
- Author
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Kim SH, Wang D, Park YY, Katoh H, Margalit O, Sheffer M, Wu H, Holla VR, Lee JS, and DuBois RN
- Subjects
- Animals, Blotting, Western, Cell Hypoxia, Cell Line, Tumor, Cell Survival genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Disease Progression, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, Heterografts pathology, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mice, Mice, Nude, Neoplasm Proteins metabolism, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Tumor Burden genetics, Colorectal Neoplasms genetics, Hypoxia, Neoplasm Proteins genetics, Signal Transduction genetics
- Abstract
HIG2 (hypoxia-inducible gene 2) is a biomarker of hypoxia and elevated in several cancers. Here, we show that HIG2 also upregulated HIF-1α expression under hypoxic conditions and enhanced AP-1 expression under normoxic conditions, which affects colorectal cancer cell survival. Importantly, over-expression of HIG2 promoted tumor growth by suppressing apoptosis in a mouse orthotopic model. These results are likely relevant to human disease since we found that the expression of HIG2 is gradually elevated as tumors progress. Collectively, these findings suggest that HIG2 plays an important role in promoting colorectal cancer growth in hypoxia-dependent and independent manners., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
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43. CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis.
- Author
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Katoh H, Wang D, Daikoku T, Sun H, Dey SK, and Dubois RN
- Subjects
- Adoptive Transfer, Animals, Azoxymethane, CD8-Positive T-Lymphocytes immunology, Carcinogenesis chemically induced, Carcinogenesis immunology, Cells, Cultured, Chemokine CXCL1 physiology, Chemotaxis, Colitis chemically induced, Colitis immunology, Colorectal Neoplasms chemically induced, Colorectal Neoplasms immunology, Cytotoxicity, Immunologic, Dextran Sulfate, Dinoprostone physiology, Humans, Inflammation Mediators metabolism, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Mice, Mice, Inbred BALB C, Mice, Knockout, Myeloid Cells transplantation, Tumor Microenvironment, Carcinogenesis metabolism, Colitis metabolism, Colorectal Neoplasms metabolism, Myeloid Cells metabolism, Receptors, Interleukin-8B metabolism
- Abstract
A large body of evidence indicates that chronic inflammation is one of several key risk factors for cancer initiation, progression, and metastasis. However, the underlying mechanisms responsible for the contribution of inflammation and inflammatory mediators to cancer remain elusive. Here, we present genetic evidence that loss of CXCR2 dramatically suppresses chronic colonic inflammation and colitis-associated tumorigenesis through inhibiting infiltration of myeloid-derived suppressor cells (MDSCs) into colonic mucosa and tumors in a mouse model of colitis-associated cancer. CXCR2 ligands were elevated in inflamed colonic mucosa and tumors and induced MDSC chemotaxis. Adoptive transfer of wild-type MDSCs into Cxcr2(-/-) mice restored AOM/DSS-induced tumor progression. MDSCs accelerated tumor growth by inhibiting CD8(+) T cell cytotoxic activity., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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44. An inflammatory mediator, prostaglandin E2, in colorectal cancer.
- Author
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Wang D and DuBois RN
- Subjects
- Animals, Colorectal Neoplasms pathology, Humans, Risk Factors, Tumor Escape immunology, Tumor Microenvironment immunology, Colorectal Neoplasms immunology, Dinoprostone immunology
- Abstract
It is widely accepted that intake of dietary fats and chronic inflammation are risk factors for developing colorectal cancer. Arachidonic acid is a major component of animal fats, and the bioactive lipids produced from this substrate play critical roles in a variety of biologic processes, including cancer. Cyclooxygenase-derived prostaglandin E2 is a known proinflammatory lipid mediator that promotes tumor progression. Metabolism of arachidonic acid by the cyclooxygenase pathway provides one mechanism for the contribution of dietary fats and chronic inflammation to carcinogenesis. In this review, we highlight recent advances in our understanding of how a proinflammatory mediator prostaglandin E2 promotes colorectal cancer immune evasion. These findings may provide a rationale for the development of new therapeutic approaches to subvert tumor-induced immunosuppression.
- Published
- 2013
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45. Urinary PGE-M: a promising cancer biomarker.
- Author
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Wang D and DuBois RN
- Subjects
- Female, Humans, Biomarkers, Tumor urine, Breast Neoplasms diagnosis, Obesity complications, Postmenopause drug effects
- Abstract
Cancer prevention, early diagnosis, and targeted therapies are the keys to success in better cancer control and treatment. A big challenge remains to identify biomarkers for predicting who may have higher cancer risk and are able to respond to certain chemopreventive agents as well as for assessing a patient's response during treatment. Although a large body of evidence indicates that chronic inflammation is a risk factor for cancer, it is unclear whether inflammatory biomarkers can be used to predict cancer risk, progression, and death. Considering the importance of the proinflammatory COX-2-derived prostaglandin E2 (PGE2) in inflammation and cancer, Morris and colleagues found that urinary PGE-M is positively associated with obesity, smoking, and lung metastases in patients with breast cancer (4). Along the same lines, Kim and colleagues showed a potential association between urinary PGE-M and breast cancer risk in postmenopausal women (beginning on page 511). In agreement with previous reports, their findings indicate that urinary PGE-M may serve as a promising biomarker for prognosticating cancer risk and disease progression.
- Published
- 2013
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46. Changes in cancer cell metabolism revealed by direct sample analysis with MALDI mass spectrometry.
- Author
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Pirman DA, Efuet E, Ding XP, Pan Y, Tan L, Fischer SM, DuBois RN, and Yang P
- Subjects
- Alprostadil metabolism, Animals, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cyclooxygenase 2 genetics, Humans, Lipid Metabolism drug effects, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, Mice, Transgenic, Organ Specificity, Phospholipases A2 genetics, Phospholipases A2 metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Alprostadil analogs & derivatives, Carcinoma, Non-Small-Cell Lung metabolism, Cyclooxygenase 2 metabolism, Eicosapentaenoic Acid pharmacology, Gene Expression Regulation, Neoplastic drug effects, Lung Neoplasms metabolism, Metabolomics
- Abstract
Biomarker discovery using mass spectrometry (MS) has recently seen a significant increase in applications, mainly driven by the rapidly advancing field of metabolomics. Instrumental and data handling advancements have allowed for untargeted metabolite analyses which simultaneously interrogate multiple biochemical pathways to elucidate disease phenotypes and therapeutic mechanisms. Although most MS-based metabolomic approaches are coupled with liquid chromatography, a few recently published studies used matrix-assisted laser desorption (MALDI), allowing for rapid and direct sample analysis with minimal sample preparation. We and others have reported that prostaglandin E3 (PGE3), derived from COX-2 metabolism of the omega-3 fatty acid eicosapentaenoic acid (EPA), inhibited the proliferation of human lung, colon and pancreatic cancer cells. However, how PGE3 metabolism is regulated in cancer cells, particularly human non-small cell lung cancer (NSCLC) cells, is not fully understood. Here, we successfully used MALDI to identify differences in lipid metabolism between two human non-small-cell lung cancer (NSCLC) cell lines, A549 and H596, which could contribute to their differential response to EPA treatment. Analysis by MALDI-MS showed that the level of EPA incorporated into phospholipids in H596 cells was 4-fold higher than A549 cells. Intriguingly, H596 cells produced much less PGE3 than A549 cells even though the expression of COX-2 was similar in these two cell lines. This appears to be due to the relatively lower expression of cytosolic phospholipase A2 (cPLA2) in H596 cells than that of A549 cells. Additionally, the MALDI-MS approach was successfully used on tumor tissue extracts from a K-ras transgenic mouse model of lung cancer to enhance our understanding of the mechanism of action of EPA in the in vivo model. These results highlight the utility of combining a metabolomics workflow with MALDI-MS to identify the biomarkers that may regulate the metabolism of omega-3 fatty acids and ultimately affect their therapeutic potentials.
- Published
- 2013
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47. Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor.
- Author
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Charo C, Holla V, Arumugam T, Hwang R, Yang P, Dubois RN, Menter DG, Logsdon CD, and Ramachandran V
- Subjects
- Cell Movement drug effects, Cell Proliferation drug effects, Cells, Cultured, Collagen Type I genetics, Collagen Type I metabolism, Collagen Type I, alpha 1 Chain, Cyclooxygenase 2 metabolism, Dinoprostone metabolism, Gene Expression drug effects, Humans, Immunohistochemistry, Matrix Metalloproteinase 2 genetics, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Naphthalenes pharmacology, Pancreatic Stellate Cells metabolism, Phenylbutyrates pharmacology, RNA Interference, Receptors, Prostaglandin E, EP4 Subtype antagonists & inhibitors, Receptors, Prostaglandin E, EP4 Subtype metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Cyclooxygenase 2 genetics, Dinoprostone pharmacology, Pancreatic Stellate Cells drug effects, Receptors, Prostaglandin E, EP4 Subtype genetics
- Abstract
Objectives: Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis and pancreatic adenocarcinoma. We observed correlation between levels of cyclooxygenase 2 (COX-2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. The aims of this study were to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSCs) and to identify the receptor involved., Methods: Immunohistochemistry, reverse transcription-polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction were used to assess COX-2, extracellular matrix, and matrix metalloproteinase gene expression. Eicosanoid profile was determined by liquid chromatography-tandem mass spectrometry. Human pancreatic stellate cell proliferation was assessed by MTS assay, migration by Boyden chamber assay, and invasion using an invasion chamber. Transient silencing was obtained by small interfering RNA., Results: Human pancreatic stellate cells express COX-2 and synthesize PGE2. Prostaglandin E2 stimulated HPSC proliferation, migration, and invasion and stimulated expression of both extracellular matrix and matrix metalloproteinase genes. Human pancreatic stellate cells expressed all 4 EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE2-mediated HPSC activation. Specificity of EP4 for the effects of PGE2 on stellate cells was confirmed using specific antagonists., Conclusions: Our data indicate that PGE2 regulates pancreatic stellate cell profibrotic activities via EP4 receptor, thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia.
- Published
- 2013
- Full Text
- View/download PDF
48. Metronomic topotecan for colorectal cancer: a promising new option.
- Author
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Wang D, Margalit O, and DuBois RN
- Subjects
- Animals, Female, Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colonic Neoplasms drug therapy, Liver Neoplasms prevention & control
- Published
- 2013
- Full Text
- View/download PDF
49. The role of anti-inflammatory drugs in colorectal cancer.
- Author
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Wang D and DuBois RN
- Subjects
- Colorectal Neoplasms epidemiology, Global Health, Humans, Morbidity trends, Prognosis, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Colorectal Neoplasms prevention & control
- Abstract
A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet, and lifestyle are key risk factors for colorectal cancer (CRC). Prevention of CRC has long been considered a plausible approach for the population and individuals at high risk for developing this disease. A significant effort has been made in the development of novel drugs for both prevention and treatment over the past two decades. This review highlights recent advances in our understanding of the role of nonsteroidal anti-inflammatory drugs in CRC prevention and adjuvant treatment. Moreover, we focus on the molecular mechanisms underlying the antitumor effects of these drugs in CRC. The knowledge of how anti-inflammatory agents inhibit cancer formation and progression may provide a rationale for the development of more effective chemopreventive and chemotherapeutic agents with less toxicity.
- Published
- 2013
- Full Text
- View/download PDF
50. AACR Cancer Progress Report 2012.
- Author
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Cantley LC, Dalton WS, DuBois RN, Finn OJ, Futreal PA, Golub TR, Hait WN, Lozano G, Maris JM, Nelson WG, Sawyers CL, Schreiber SL, Spitz MR, and Steeg PS
- Subjects
- Biomedical Research economics, Biomedical Research trends, Female, Financing, Government statistics & numerical data, Humans, Male, Neoplasms diagnosis, Research Support as Topic statistics & numerical data, Societies, Scientific, United States, Biomedical Research methods, Neoplasms prevention & control, Neoplasms therapy, Research Report
- Published
- 2012
- Full Text
- View/download PDF
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