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AAT-007/Cancer

EP4 Antagonist for Immuno-Oncology Therapy PGE2/EP4 Immuno-Oncology Publication List
1. Cancer Types
Bladder:
  1. Miyata Y, Kanda S, Nomata K, Eguchi J, Kanetake H. Expression of cyclooxygenase-2 and EP4 receptor in transitional cell carcinoma of the upper urinary tract. J Urol 2005 Jan;173(1):56-60.

    http://www.ncbi.nlm.nih.gov/pubmed/16609907?dopt=abstract
  2. Miyata Y, Ohba K, Kanda S, Nomata K, Eguchi J, Hayashi T, et al. Pathological function of prostaglandin E2 receptors in transitional cell carcinoma of the upper urinary tract. Virchows Arch 2006 Jun;448(6):822-829.

    http://www.ncbi.nlm.nih.gov/pubmed/15592025?dopt=abstract
Breast:
  1. Xin X, Majumder M, Girish GV, Mohindra V, Maruyama T, Lala PK. Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model. Lab Invest 2012 Aug;92(8):1115-1128.

    http://www.ncbi.nlm.nih.gov/pubmed/22641101?dopt=abstract
  2. Timoshenko AV, Xu G, Chakrabarti S, Lala PK, Chakraborty C. Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells. Exp Cell Res 2003 Oct 1;289(2):265-274.

    http://www.ncbi.nlm.nih.gov/pubmed/14499627?dopt=abstract
  3. Timoshenko AV, Lala PK, Chakraborty C. PGE2-mediated upregulation of iNOS in murine breast cancer cells through the activation of EP4 receptors. Int J Cancer 2004 Jan 20;108(3):384-389.

    http://www.ncbi.nlm.nih.gov/pubmed/14648704?dopt=abstract
  4. Timoshenko AV, Chakraborty C, Wagner GF, Lala PK. COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer 2006 Apr 24;94(8):1154-1163.

    http://www.ncbi.nlm.nih.gov/pubmed/16570043?dopt=abstract
  5. Subbaramaiah K, Hudis C, Chang SH, Hla T, Dannenberg AJ. EP2 and EP4 receptors regulate aromatase expression in human adipocytes and breast cancer cells. Evidence of a BRCA1 and p300 exchange. J Biol Chem 2008 Feb 8;283(6):3433-3444.

    http://www.ncbi.nlm.nih.gov/pubmed/18083712?dopt=abstract
  6. Robertson FM, Simeone AM, Mazumdar A, Shah AH, McMurray JS, Ghosh S, et al. Molecular and pharmacological blockade of the EP4 receptor selectively inhibits both proliferation and invasion of human inflammatory breast cancer cells. J Exp Ther Oncol 2008;7(4):299-312.

    http://www.ncbi.nlm.nih.gov/pubmed/19227010?dopt=abstract
  7. Robertson FM, Simeone AM, Lucci A, McMurray JS, Ghosh S, Cristofanilli M. Differential regulation of the aggressive phenotype of inflammatory breast cancer cells by prostanoid receptors EP3 and EP4. Cancer 2010 Jun 1;116(11 Suppl):2806-2814.

    http://www.ncbi.nlm.nih.gov/pubmed/20503412?dopt=abstract
  8. Reno F, Baj G, Surico N, Cannas M. Exogenous prostaglandin E2 inhibits TPA induced matrix metalloproteinase-9 production in MCF-7 cells. Prostaglandins Other Lipid Mediat 2004 Apr;73(3-4):237-247.

    http://www.ncbi.nlm.nih.gov/pubmed/21097507?dopt=abstract
  9. Qian X, Zhang J, Liu J. Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP/PKA signaling pathway. J Biol Chem 2011 Jan 21;286(3):2111-2120.

    http://www.ncbi.nlm.nih.gov/pubmed/21097507?dopt=abstract
  10. Qian X, Gu L, Ning H, Zhang Y, Hsueh EC, Fu M, et al. Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2. J Immunol 2013 Jun 1;190(11):5894-5902.

    http://www.ncbi.nlm.nih.gov/pubmed/23645882?dopt=abstract
  11. Pan MR, Hou MF, Chang HC, Hung WC. Cyclooxygenase-2 up-regulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells. J Biol Chem 2008 Apr 25;283(17):11155-11163.

    http://www.ncbi.nlm.nih.gov/pubmed/18319253?dopt=abstract
  12. Ma X, Kundu N, Rifat S, Walser T, Fulton AM. Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Cancer Res 2006 Mar 15;66(6):2923-2927.

    http://www.ncbi.nlm.nih.gov/pubmed/16540639?dopt=abstract
  13. Ma X, Kundu N, Ioffe OB, Goloubeva O, Konger R, Baquet C, et al. Prostaglandin E receptor EP1 suppresses breast cancer metastasis and is linked to survival differences and cancer disparities. Mol Cancer Res 2010 Oct;8(10):1310-1318.

    http://www.ncbi.nlm.nih.gov/pubmed/20858737?dopt=abstract
  14. Ma X, Kundu N, Collin PD, Goloubeva O, Fulton AM. Frondoside A inhibits breast cancer metastasis and antagonizes prostaglandin E receptors EP4 and EP2. Breast Cancer Res Treat 2012 Apr;132(3):1001-1008.

    http://www.ncbi.nlm.nih.gov/pubmed/23482441?dopt=abstract
  15. Ma X, Holt D, Kundu N, Reader J, Goloubeva O, Take Y, et al. A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE-mediated immunosuppression and inhibits breast cancer metastasis. Oncoimmunology 2013 Jan 1;2(1):e22647.

    http://www.ncbi.nlm.nih.gov/pubmed/23482441?dopt=abstract
  16. Kundu N, Ma X, Kochel T, Goloubeva O, Staats P, Thompson K, et al. Prostaglandin E receptor EP4 is a therapeutic target in breast cancer cells with stem-like properties. Breast Cancer Res Treat 2013 Nov 27.

    http://www.ncbi.nlm.nih.gov/pubmed/24281828?dopt=abstract
  17. Kundu N, Ma X, Holt D, Goloubeva O, Ostrand-Rosenberg S, Fulton AM. Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. Breast Cancer Res Treat 2009 Sep;117(2):235-242.

    http://www.ncbi.nlm.nih.gov/pubmed/18792778?dopt=abstract
  18. Karavitis J, Zhang M. COX2 regulation of breast cancer bone metastasis. Oncoimmunology 2013 Mar 1;2(3):e23129.

    http://www.ncbi.nlm.nih.gov/pubmed/23802065?dopt=abstract
  19. Karavitis J, Hix LM, Shi YH, Schultz RF, Khazaie K, Zhang M. Regulation of COX2 expression in mouse mammary tumor cells controls bone metastasis and PGE2-induction of regulatory T cell migration. PLoS One 2012;7(9):e46342.

    http://www.ncbi.nlm.nih.gov/pubmed/23029485?dopt=abstract
  20. Holt DM, Ma X, Kundu N, Collin PD, Fulton AM. Modulation of host natural killer cell functions in breast cancer via prostaglandin E2 receptors EP2 and EP4. J Immunother 2012 Feb-Mar;35(2):179-188.

    http://www.ncbi.nlm.nih.gov/pubmed/22306906?dopt=abstract
  21. Holt D, Ma X, Kundu N, Fulton A. Prostaglandin E(2) (PGE (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4. Cancer Immunol Immunother 2011 Nov;60(11):1577-1586.

    http://www.ncbi.nlm.nih.gov/pubmed/21681369?dopt=abstract
  22. Fulton AM, Ma X, Kundu N. Targeting prostaglandin E EP receptors to inhibit metastasis. Cancer Res 2006 Oct 15;66(20):9794-9797.

    http://www.ncbi.nlm.nih.gov/pubmed/17047037?dopt=abstract
  23. Chuang CW, Pan MR, Hou MF, Hung WC. Cyclooxygenase-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 in breast cancer cells. J Cell Physiol 2013 Feb;228(2):341-348.

    http://www.ncbi.nlm.nih.gov/pubmed/22718198?dopt=abstract
Cervical:
  1. Sales KJ, Katz AA, Millar RP, Jabbour HN. Seminal plasma activates cyclooxygenase-2 and prostaglandin E2 receptor expression and signalling in cervical adenocarcinoma cells. Mol Hum Reprod 2002 Dec;8(12):1065-1070.

    http://www.ncbi.nlm.nih.gov/pubmed/12468638?dopt=abstract
  2. Sales KJ, Katz AA, Davis M, Hinz S, Soeters RP, Hofmeyr MD, et al. Cyclooxygenase-2 expression and prostaglandin E(2) synthesis are up-regulated in carcinomas of the cervix: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors. J Clin Endocrinol Metab 2001 May;86(5):2243-2249.

    http://www.ncbi.nlm.nih.gov/pubmed/11344234?dopt=abstract
  3. Oh JM, Kim SH, Lee YI, Seo M, Kim SY, Song YS, et al. Human papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cells.

    http://www.ncbi.nlm.nih.gov/pubmed/16574793?dopt=abstract
  4. Muller M, Sales KJ, Katz AA, Jabbour HN. Seminal plasma promotes the expression of tumorigenic and angiogenic genes in cervical adenocarcinoma cells via the E-series prostanoid 4 receptor. Endocrinology 2006 Jul;147(7):3356-3365.

    http://www.ncbi.nlm.nih.gov/pubmed/16574793?dopt=abstract
  5. Liu H, Xiao J, Yang Y, Liu Y, Ma R, Li Y, et al. COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer. Microvasc Res 2011 Sep;82(2):131-140.

    http://www.ncbi.nlm.nih.gov/pubmed/22641101?dopt=abstract
Colorectal:
  1. Yuan A, Steigen SE, Goll R, Vonen B, Husbekk A, Cui G, et al. Dendritic cell infiltration pattern along the colorectal adenoma-carcinoma sequence. APMIS 2008 Jun;116(6):445-456.

    http://www.ncbi.nlm.nih.gov/pubmed/18754318?dopt=abstract
  2. Yuan A, Steigen SE, Goll R, Vonen B, Husbekk A, Cui G, et al. Dendritic cell infiltration pattern along the colorectal adenoma-carcinoma sequence. APMIS 2008 Jun;116(6):445-456.

    http://www.ncbi.nlm.nih.gov/pubmed/18754318?dopt=abstract
  3. Yang L, Huang Y, Porta R, Yanagisawa K, Gonzalez A, Segi E, et al. Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res 2006 Oct 1;66(19):9665-9672.

    http://www.ncbi.nlm.nih.gov/pubmed/17018624?dopt=abstract
  4. Yang L, Huang Y, Porta R, Yanagisawa K, Gonzalez A, Segi E, et al. Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res 2006 Oct 1;66(19):9665-9672.

    http://www.ncbi.nlm.nih.gov/pubmed/17018624?dopt=abstract
  5. Wu CH, Shih YW, Chang CH, Ou TT, Huang CC, Hsu JD, et al. EP4 upregulation of Ras signaling and feedback regulation of Ras in human colon tissues and cancer cells. Arch Toxicol 2010 Sep;84(9):731-740.

    http://www.ncbi.nlm.nih.gov/pubmed/20571779?dopt=abstract
  6. Wu CH, Shih YW, Chang CH, Ou TT, Huang CC, Hsu JD, et al. EP4 upregulation of Ras signaling and feedback regulation of Ras in human colon tissues and cancer cells. Arch Toxicol 2010 Sep;84(9):731-740.

    http://www.ncbi.nlm.nih.gov/pubmed/20571779?dopt=abstract
  7. Sheng H, Shao J, Washington MK, DuBois RN. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol Chem 2001 May 25;276(21):18075-18081.

    http://www.ncbi.nlm.nih.gov/pubmed/11278548?dopt=abstract
  8. Mutoh M, Watanabe K, Kitamura T, Shoji Y, Takahashi M, Kawamori T, et al. Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res 2002 Jan 1;62(1):28-32.

    http://www.ncbi.nlm.nih.gov/pubmed/11782353?dopt=abstract
  9. Liu X, Lazenby AJ, Siegal GP. Signal transduction cross-talk during colorectal tumorigenesis. Adv Anat Pathol 2006 Sep;13(5):270-274.

    http://www.ncbi.nlm.nih.gov/pubmed/16998321?dopt=abstract
  10. Leone V, di Palma A, Ricchi P, Acquaviva F, Giannouli M, Di Prisco AM, et al. PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation. Am J Physiol Gastrointest Liver Physiol 2007 Oct;293(4):G673-81.

    http://www.ncbi.nlm.nih.gov/pubmed/17640974?dopt=abstract
  11. Kitamura T, Itoh M, Noda T, Tani K, Kobayashi M, Maruyama T, et al. Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice. Cancer Sci 2003 Jul;94(7):618-621.

    http://www.ncbi.nlm.nih.gov/pubmed/12841871?dopt=abstract
  12. Hull MA, Ko SC, Hawcroft G. Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? Mol Cancer Ther 2004 Aug;3(8):1031-1039.

    http://www.ncbi.nlm.nih.gov/pubmed/15299086?dopt=abstract
  13. Hawcroft G, Loadman PM, Belluzzi A, Hull MA. Effect of eicosapentaenoic acid on E-type prostaglandin synthesis and EP4 receptor signaling in human colorectal cancer cells. Neoplasia 2010 Aug;12(8):618-627.

    http://www.ncbi.nlm.nih.gov/pubmed/20689756?dopt=abstract
  14. Hawcroft G, Ko CW, Hull MA. Prostaglandin E2-EP4 receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells. Oncogene 2007 May 10;26(21):3006-3019.

    http://www.ncbi.nlm.nih.gov/pubmed/17130837?dopt=abstract
  15. Gustafsson A, Hansson E, Kressner U, Nordgren S, Andersson M, Wang W, et al. EP1-4 subtype, COX and PPAR gamma receptor expression in colorectal cancer in prediction of disease-specific mortality. Int J Cancer 2007 Jul 15;121(2):232-240.

    http://www.ncbi.nlm.nih.gov/pubmed/17290397?dopt=abstract
  16. Fujino H, Chen XB, Regan JW, Murayama T. Indomethacin decreases EP2 prostanoid receptor expression in colon cancer cells. Biochem Biophys Res Commun 2007 Aug 3;359(3):568-573.

    http://www.ncbi.nlm.nih.gov/pubmed/17555711?dopt=abstract
  17. Edwards TL, Shrubsole MJ, Cai Q, Li G, Dai Q, Rex DK, et al. A study of prostaglandin pathway genes and interactions with current nonsteroidal anti-inflammatory drug use in colorectal adenoma. Cancer Prev Res (Phila) 2012 Jun;5(6):855-863.

    http://www.ncbi.nlm.nih.gov/pubmed/22551900?dopt=abstract
  18. Doherty GA, Byrne SM, Molloy ES, Malhotra V, Austin SC, Kay EW, et al. Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer. BMC Cancer 2009 Jun 26;9:207-2407-9-207.

    http://www.ncbi.nlm.nih.gov/pubmed/19558693?dopt=abstract
  19. Cherukuri DP, Chen XB, Goulet AC, Young RN, Han Y, Heimark RL, et al. The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells. Exp Cell Res 2007 Aug 15;313(14):2969-2979.

    http://www.ncbi.nlm.nih.gov/pubmed/16540660?dopt=abstract
  20. Chell SD, Witherden IR, Dobson RR, Moorghen M, Herman AA, Qualtrough D, et al. Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence. Cancer Res 2006 Mar 15;66(6):3106-3113.

    http://www.ncbi.nlm.nih.gov/pubmed/16540660?dopt=abstract
  21. Chandramouli A, Onyeagucha BC, Mercado-Pimentel ME, Stankova L, Shahin NA, LaFleur BJ, et al. MicroRNA-101 (miR-101) post-transcriptionally regulates the expression of EP4 receptor in colon cancers. Cancer Biol Ther 2012 Feb 1;13(3):175-183.

    http://www.ncbi.nlm.nih.gov/pubmed/22353936?dopt=abstract
  22. Chandramouli A, Onyeagucha BC, Mercado-Pimentel ME, Stankova L, Shahin NA, LaFleur BJ, et al. MicroRNA-101 (miR-101) post-transcriptionally regulates the expression of EP4 receptor in colon cancers. Cancer Biol Ther 2012 Feb 1;13(3):175-183.

    http://www.ncbi.nlm.nih.gov/pubmed/22353936?dopt=abstract
  23. Chandramouli A, Mercado-Pimentel ME, Hutchinson A, Gibadulinova A, Olson ER, Dickinson S, et al. The induction of S100p expression by the Prostaglandin E(2) (PGE(2))/EP4 receptor signaling pathway in colon cancer cells. Cancer Biol Ther 2010 Nov 15;10(10):1056-1066.

    http://www.ncbi.nlm.nih.gov/pubmed/20890108?dopt=abstract
Gastric:
  1. Takehara H, Iwamoto J, Mizokami Y, Takahashi K, Ootubo T, Miura S, et al. Involvement of cyclooxygenase-2--prostaglandin E2 pathway in interleukin-8 production in gastric cancer cells. Dig Dis Sci 2006 Dec;51(12):2188-2197.

    http://www.ncbi.nlm.nih.gov/pubmed/17078003?dopt=abstract
  2. Piazuelo E, Santander S, Cebrian C, Jimenez P, Pastor C, Garcia-Gonzalez MA, et al. Characterization of the prostaglandin E2 pathway in a rat model of esophageal adenocarcinoma. Curr Cancer Drug Targets 2012 Feb;12(2):132-143.

    http://www.ncbi.nlm.nih.gov/pubmed/22165968?dopt=abstract
  3. Oshima H, Popivanova BK, Oguma K, Kong D, Ishikawa TO, Oshima M. Activation of epidermal growth factor receptor signaling by the prostaglandin E(2) receptor EP4 pathway during gastric tumorigenesis. Cancer Sci 2011 Apr;102(4):713-719.

    http://www.ncbi.nlm.nih.gov/pubmed/21205091?dopt=abstract
  4. Oshima H, Hioki K, Popivanova BK, Oguma K, Van Rooijen N, Ishikawa TO, et al. Prostaglandin E(2) signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors. Gastroenterology 2011 Feb;140(2):596-607.e7.

    http://www.ncbi.nlm.nih.gov/pubmed/21070778?dopt=abstract
  5. Okuyama T, Ishihara S, Sato H, Rumi MA, Kawashima K, Miyaoka Y, et al. Activation of prostaglandin E2-receptor EP2 and EP4 pathways induces growth inhibition in human gastric carcinoma cell lines. J Lab Clin Med 2002 Aug;140(2):92-102.

    http://www.ncbi.nlm.nih.gov/pubmed/12228765?dopt=abstract
  6. Iwamoto J, Mizokami Y, Takahashi K, Matsuoka T, Matsuzaki Y. The effects of cyclooxygenase2-prostaglandinE2 pathway on Helicobacter pylori-induced urokinase-type plasminogen activator system in the gastric cancer cells. Helicobacter 2008 Jun;13(3):174-182.

    http://www.ncbi.nlm.nih.gov/pubmed/18466392?dopt=abstract
Lung:
  1. Zheng Y, Ritzenthaler JD, Sun X, Roman J, Han S. Prostaglandin E2 stimulates human lung carcinoma cell growth through induction of integrin-linked kinase: the involvement of EP4 and Sp1. Cancer Res 2009 Feb 1;69(3):896-904.

    http://www.ncbi.nlm.nih.gov/pubmed/17018624?dopt=abstract
  2. Yang L, Huang Y, Porta R, Yanagisawa K, Gonzalez A, Segi E, et al. Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res 2006 Oct 1;66(19):9665-9672.

    http://www.ncbi.nlm.nih.gov/pubmed/17018624?dopt=abstract
  3. Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, et al. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 2005 Jun 15;65(12):5211-5220.

    http://www.ncbi.nlm.nih.gov/pubmed/15958566?dopt=abstract
  4. Ritzenthaler JD, Roman J, Han S. PPARbeta/delta agonist increases the expression of PGE2 receptor subtype EP4 in human lung carcinoma cells. Methods Mol Biol 2009;512:309-323.

    http://www.ncbi.nlm.nih.gov/pubmed/19347285?dopt=abstract
  5. Liu H, Yang Y, Xiao J, Lv Y, Liu Y, Yang H, et al. COX-2-mediated regulation of VEGF-C in association with lymphangiogenesis and lymph node metastasis in lung cancer. Anat Rec (Hoboken) 2010 Nov;293(11):1838-1846.

    http://www.ncbi.nlm.nih.gov/pubmed/20830783?dopt=abstract
  6. Kim JI, Lakshmikanthan V, Frilot N, Daaka Y. Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. Mol Cancer Res 2010 Apr;8(4):569-577.

    http://www.ncbi.nlm.nih.gov/pubmed/20353998?dopt=abstract
  7. Katoh H, Hosono K, Ito Y, Suzuki T, Ogawa Y, Kubo H, et al. COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems. Am J Pathol 2010 Mar;176(3):1469-1483.

    http://www.ncbi.nlm.nih.gov/pubmed/20110411?dopt=abstract
  8. Ho MY, Liang SM, Hung SW, Liang CM. MIG-7 controls COX-2/PGE2-mediated lung cancer metastasis. Cancer Res 2013 Jan 1;73(1):439-449.

    http://www.ncbi.nlm.nih.gov/pubmed/23149922?dopt=abstract
Ovarian:
  1. Spinella F, Rosano L, Di Castro V, Natali PG, Bagnato A. Endothelin-1-induced prostaglandin E2-EP2, EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion. J Biol Chem 2004 Nov 5;279(45):46700-46705.

    http://www.ncbi.nlm.nih.gov/pubmed/15347673?dopt=abstract
  2. Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res 2011 Dec 15;71(24):7463-7470.

    http://www.ncbi.nlm.nih.gov/pubmed/22025564?dopt=abstract
  3. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 2011 Nov 17;118(20):5498-5505.

    http://www.ncbi.nlm.nih.gov/pubmed/21972293?dopt=abstract
Prostate:
  1. Zhang Y, Daaka Y. PGE2 promotes angiogenesis through EP4 and PKA Cgamma pathway. Blood 2011 Nov 10;118(19):5355-5364.

    http://www.ncbi.nlm.nih.gov/pubmed/21926356?dopt=abstract
  2. Wang X, Klein RD. Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor-mediated cAMP pathway. Mol Carcinog 2007 Nov;46(11):912-923.

    http://www.ncbi.nlm.nih.gov/pubmed/17427962?dopt=abstract
  3. Vo BT, Morton D,Jr, Komaragiri S, Millena AC, Leath C, Khan SA. TGF-beta effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. Endocrinology 2013 May;154(5):1768-1779.

    http://www.ncbi.nlm.nih.gov/pubmed/23515290?dopt=abstract
  4. Terada N, Shimizu Y, Kamba T, Inoue T, Maeno A, Kobayashi T, et al. Identification of EP4 as a potential target for the treatment of castration-resistant prostate cancer using a novel xenograft model. Cancer Res 2010 Feb 15;70(4):1606-1615.

    http://www.ncbi.nlm.nih.gov/pubmed/20145136?dopt=abstract
  5. Misra UK, Pizzo SV. Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways. PLoS One 2013 Apr 30;8(4):e63150.

    http://www.ncbi.nlm.nih.gov/pubmed/23646189?dopt=abstract
  6. Liu XH, Kirschenbaum A, Weinstein BM, Zaidi M, Yao S, Levine AC. Prostaglandin E2 modulates components of the Wnt signaling system in bone and prostate cancer cells. Biochem Biophys Res Commun 2010 Apr 9;394(3):715-720.

    http://www.ncbi.nlm.nih.gov/pubmed/20227393?dopt=abstract
  7. Li Z, Zhang Y, Kim WJ, Daaka Y. PGE2 promotes renal carcinoma cell invasion through activated RalA. Oncogene 2013 Mar 14;32(11):1408-1415.

    http://www.ncbi.nlm.nih.gov/pubmed/22580611?dopt=abstract
  8. Kim HN, Narayanan NK, Lasano S, Narayanan B. Modulation of PGE2-induced EP4 expression on snail signaling and the impact on epithelial-mesenchymal transition: significance of EP4 antagonism. Anticancer Res 2011 Dec;31(12):4347-4357.

    http://www.ncbi.nlm.nih.gov/pubmed/22199300?dopt=abstract
  9. Jain S, Chakraborty G, Raja R, Kale S, Kundu GC. Prostaglandin E2 regulates tumor angiogenesis in prostate cancer. Cancer Res 2008 Oct 1;68(19):7750-7759.

    http://www.ncbi.nlm.nih.gov/pubmed/18829529?dopt=abstract
  10. Huang HF, Shu P, Murphy TF, Aisner S, Fitzhugh VA, Jordan ML. Significance of divergent expression of prostaglandin EP4 and EP3 receptors in human prostate cancer. Mol Cancer Res 2013 Apr;11(4):427-439.

    http://www.ncbi.nlm.nih.gov/pubmed/23364535?dopt=abstract
EP4 Antagonist for Immuno-Oncology Therapy PGE2/EP4 Immuno-Oncology Publication List
2. Immune System
EP4 Review:
  1. Norel X. Prostanoid receptors in the human vascular wall. ScientificWorldJournal 2007 Sep 1;7:1359-1374.

    http://www.ncbi.nlm.nih.gov/pubmed/17767355?dopt=abstract
  2. Konya V, Marsche G, Schuligoi R, Heinemann A. E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther 2013 Jun;138(3):485-502.

    http://www.ncbi.nlm.nih.gov/pubmed/23523686?dopt=abstract
Immuno Oncology Review:
  1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008 Jul 24;454(7203):436-444.

    http://www.ncbi.nlm.nih.gov/pubmed/18650914?dopt=abstract
  2. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 2013 Sep 19;501(7467):346-354.

    http://www.ncbi.nlm.nih.gov/pubmed/24048067?dopt=abstract
  3. Jinushi M. The role of innate immune signals in antitumor immunity. Oncoimmunology 2012 Mar 1;1(2):189-194.

    http://www.ncbi.nlm.nih.gov/pubmed/22720240?dopt=abstract
  4. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012 Mar 15;12(4):298-306.

    http://www.ncbi.nlm.nih.gov/pubmed/22419253?dopt=abstract
  5. Devaud C, John LB, Westwood JA, Darcy PK, Kershaw MH. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. Oncoimmunology 2013 Aug 1;2(8):e25961.

    http://www.ncbi.nlm.nih.gov/pubmed/24083084?dopt=abstract
  6. Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 2012 Feb;22(1):33-40.

    http://www.ncbi.nlm.nih.gov/pubmed/22210179?dopt=abstract
PGE2 / Immuno Oncology Review:
  1. Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer 2010 Mar;10(3):181-193.

    http://www.ncbi.nlm.nih.gov/pubmed/20168319?dopt=abstract
  2. Sha W, Brune B, Weigert A. The multi-faceted roles of prostaglandin E2 in cancer-infiltrating mononuclear phagocyte biology. Immunobiology 2012 Dec;217(12):1225-1232.

    http://www.ncbi.nlm.nih.gov/pubmed/22727331?dopt=abstract
  3. Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol 2012 Jan 1;188(1):21-28.

    http://www.ncbi.nlm.nih.gov/pubmed/22187483?dopt=abstract
  4. Chen EP, Smyth EM. COX-2 and PGE2-dependent immunomodulation in breast cancer. Prostaglandins Other Lipid Mediat 2011 Nov;96(1-4):14-20.

    http://www.ncbi.nlm.nih.gov/pubmed/21907301?dopt=abstract
STAT3 / Immune / Cancer:
  1. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007 Jan;7(1):41-51.

    http://www.ncbi.nlm.nih.gov/pubmed/17186030?dopt=abstract
  2. Rebe C, Vegran F, Berger H, Ghiringhelli F. STAT3 activation: A key factor in tumor immunoescape. JAKSTAT 2013 Jan 1;2(1):e23010.

    http://www.ncbi.nlm.nih.gov/pubmed/24058791?dopt=abstract
  3. Han C, Demetris AJ, Stolz DB, Xu L, Lim K, Wu T. Modulation of Stat3 activation by the cytosolic phospholipase A2alpha and cyclooxygenase-2-controlled prostaglandin E2 signaling pathway. J Biol Chem 2006 Aug 25;281(34):24831-24846.

    http://www.ncbi.nlm.nih.gov/pubmed/16790433?dopt=abstract
  4. Frias MA, Rebsamen MC, Gerber-Wicht C, Lang U. Prostaglandin E2 activates Stat3 in neonatal rat ventricular cardiomyocytes: A role in cardiac hypertrophy. Cardiovasc Res 2007 Jan 1;73(1):57-65.

    http://www.ncbi.nlm.nih.gov/pubmed/17067562?dopt=abstract
  5. Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V, et al. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res 2013 Apr 15;73(8):2480-2492.

    http://www.ncbi.nlm.nih.gov/pubmed/23436796?dopt=abstract
  6. Cheon H, Rho YH, Choi SJ, Lee YH, Song GG, Sohn J, et al. Prostaglandin E2 augments IL-10 signaling and function. J Immunol 2006 Jul 15;177(2):1092-1100.

    http://www.ncbi.nlm.nih.gov/pubmed/16818766?dopt=abstract
T cells:
  1. Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E2 and T cells: friends or foes? Immunol Cell Biol 2012 Jul;90(6):579-586.

    http://www.ncbi.nlm.nih.gov/pubmed/21946663?dopt=abstract
  2. Okano M, Sugata Y, Fujiwara T, Matsumoto R, Nishibori M, Shimizu K, et al. E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2. Immunology 2006 Jul;118(3):343-352.

    http://www.ncbi.nlm.nih.gov/pubmed/16827895?dopt=abstract
Th17 cells:
  1. Qian X, Gu L, Ning H, Zhang Y, Hsueh EC, Fu M, et al. Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2. J Immunol 2013 Jun 1;190(11):5894-5902.

    http://www.ncbi.nlm.nih.gov/pubmed/23645882?dopt=abstract
  2. Napolitani G, Acosta-Rodriguez EV, Lanzavecchia A, Sallusto F. Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+ T cells. Eur J Immunol 2009 May;39(5):1301-1312.

    http://www.ncbi.nlm.nih.gov/pubmed/19384872?dopt=abstract
  3. Murugaiyan G, Saha B. Protumor vs antitumor functions of IL-17. J Immunol 2009 Oct 1;183(7):4169-4175.

    http://www.ncbi.nlm.nih.gov/pubmed/23083809?dopt=abstract
  4. Hemdan NY, Birkenmeier G, Wichmann G. Key molecules in the differentiation and commitment program of T helper 17 (Th17) cells up-to-date. Immunol Lett 2012 Dec 17;148(2):97-109.

    http://www.ncbi.nlm.nih.gov/pubmed/23159638?dopt=abstract
  5. Duffy MM, Pindjakova J, Hanley SA, McCarthy C, Weidhofer GA, Sweeney EM, et al. Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor. Eur J Immunol 2011 Oct;41(10):2840-2851.

    http://www.ncbi.nlm.nih.gov/pubmed/21710489?dopt=abstract
  6. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, et al. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med 2009 Mar 16;206(3):535-548.

    http://www.ncbi.nlm.nih.gov/pubmed/19273625?dopt=abstract
  7. Adamik J, Henkel M, Ray A, Auron PE, Duerr R, Barrie A. The IL17A and IL17F loci have divergent histone modifications and are differentially regulated by prostaglandin E2 in Th17 cells. Cytokine 2013 Oct;64(1):404-412.

    http://www.ncbi.nlm.nih.gov/pubmed/23800789?dopt=abstract
Treg:
  1. Soontrapa K, Honda T, Sakata D, Yao C, Hirata T, Hori S, et al. Prostaglandin E2-prostaglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression. Proc Natl Acad Sci U S A 2011 Apr 19;108(16):6668-6673.

    http://www.ncbi.nlm.nih.gov/pubmed/21460251?dopt=abstract
  2. Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, et al. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 2005 Jun 15;65(12):5211-5220.

    http://www.ncbi.nlm.nih.gov/pubmed/15958566?dopt=abstract
  3. Karavitis J, Zhang M. COX2 regulation of breast cancer bone metastasis. Oncoimmunology 2013 Mar 1;2(3):e23129.

    http://www.ncbi.nlm.nih.gov/pubmed/23802065?dopt=abstract
  4. Karavitis J, Hix LM, Shi YH, Schultz RF, Khazaie K, Zhang M. Regulation of COX2 expression in mouse mammary tumor cells controls bone metastasis and PGE2-induction of regulatory T cell migration. PLoS One 2012;7(9):e46342.

    http://www.ncbi.nlm.nih.gov/pubmed/23029485?dopt=abstract
  5. Brudvik KW, Tasken K. Modulation of T cell immune functions by the prostaglandin E(2) - cAMP pathway in chronic inflammatory states. Br J Pharmacol 2012 May;166(2):411-419.

    http://www.ncbi.nlm.nih.gov/pubmed/22141738?dopt=abstract
Cancer Stem Cells:
  1. Tsujii M. Cyclooxygenase, cancer stem cells and DNA methylation play important roles in colorectal carcinogenesis. Digestion 2013;87(1):12-16.

    http://www.ncbi.nlm.nih.gov/pubmed/23343963?dopt=abstract
Checkpoint:
  1. Markosyan N, Chen EP, Evans RA, Ndong V, Vonderheide RH, Smyth EM. Mammary carcinoma cell derived cyclooxygenase 2 suppresses tumor immune surveillance by enhancing intratumoral immune checkpoint activity. Breast Cancer Res 2013 Sep 3;15(5):R75.

    http://www.ncbi.nlm.nih.gov/pubmed/24004819?dopt=abstract
Dendritic Cells:
  1. Poloso NJ, Urquhart P, Nicolaou A, Wang J, Woodward DF. PGE2 differentially regulates
    monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4). Mol
    Immunol 2013 Jul;54(3-4):284-295.

    http://www.ncbi.nlm.nih.gov/pubmed/23337716?dopt=abstract
Macrophage:
  1. Ylostalo JH, Bartosh TJ, Coble K, Prockop DJ. Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an anti-inflammatory phenotype. Stem Cells 2012 Oct;30(10):2283-2296.

    http://www.ncbi.nlm.nih.gov/pubmed/22865689?dopt=abstract
  2. Tang X, Mo C, Wang Y, Wei D, Xiao H. Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology 2013 Feb;138(2):93-104.

    http://www.ncbi.nlm.nih.gov/pubmed/23113570?dopt=abstract
  3. Steenport M, Khan KM, Du B, Barnhard SE, Dannenberg AJ, Falcone DJ. Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2. J Immunol 2009 Dec 15;183(12):8119-8127.

    http://www.ncbi.nlm.nih.gov/pubmed/19923455?dopt=abstract
  4. Qian X, Zhang J, Liu J. Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP/PKA signaling pathway. J Biol Chem 2011 Jan 21;286(3):2111-2120.

    http://www.ncbi.nlm.nih.gov/pubmed/21097507?dopt=abstract
  5. Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V, et al. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res 2013 Apr 15;73(8):2480-2492.

    http://www.ncbi.nlm.nih.gov/pubmed/23436796?dopt=abstract
MDSC:
  1. Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res 2011 Dec 15;71(24):7463-7470.

    http://www.ncbi.nlm.nih.gov/pubmed/22025564?dopt=abstract
  2. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 2011 Nov 17;118(20):5498-5505.

    http://www.ncbi.nlm.nih.gov/pubmed/21972293?dopt=abstract
  3. Obermajer N, Kalinski P. Generation of myeloid-derived suppressor cells using prostaglandin E2. Transplant Res 2012 Sep 28;1(1):15-1440-1-15.

    http://www.ncbi.nlm.nih.gov/pubmed/23369567?dopt=abstract
  4. Obermajer N, Kalinski P. Key role of the positive feedback between PGE(2) and COX2 in the biology of myeloid-derived suppressor cells. Oncoimmunology 2012 Aug 1;1(5):762-764.

    http://www.ncbi.nlm.nih.gov/pubmed/22934275?dopt=abstract
  5. Mao Y, Poschke I, Wennerberg E, Pico de Coana Y, Egyhazi Brage S, Schultz I, et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res 2013 Jul 1;73(13):3877-3887.

    http://www.ncbi.nlm.nih.gov/pubmed/23633486?dopt=abstract
  6. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012 Mar 22;12(4):253-268.

    http://www.ncbi.nlm.nih.gov/pubmed/22437938?dopt=abstract
NK cells:
  1. Ma X, Holt D, Kundu N, Reader J, Goloubeva O, Take Y, et al. A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE-mediated immunosuppression and inhibits breast cancer metastasis. Oncoimmunology 2013 Jan 1;2(1):e22647.

    http://www.ncbi.nlm.nih.gov/pubmed/23482441?dopt=abstract
  2. Holt DM, Ma X, Kundu N, Collin PD, Fulton AM. Modulation of host natural killer cell functions in breast cancer via prostaglandin E2 receptors EP2 and EP4. J Immunother 2012 Feb-Mar;35(2):179-188.

    http:///www.ncbi.nlm.nih.gov/pubmed/22306906?dopt=abstract
  3. Holt D, Ma X, Kundu N, Fulton A. Prostaglandin E(2) (PGE (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4. Cancer Immunol Immunother 2011 Nov;60(11):1577-1586.

    http://www.ncbi.nlm.nih.gov/pubmed/21681369?dopt=abstract

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