Project title: Identify and validate molecular targets for therapy in a newly developed human midgut carcinoid tumor cell line

Lee Ellis, MD MD Anderson Cancer Center

Lee Ellis, MD
  • Status: Completed
  • Year(s): 2006
  • Research Type: Basic
  • Primary Tumor Site: Small intestine
  • Area of Inquiry: Models

General Description

Utilizing a newly established cell line (there are only 2 in the world), we will determine proteins that mediate tumor growth by standard molecular biologic techniques. Once these targets are identified, we will use combinations of targeted therapies to inhibit growth in a novel model of liver metastasis in mice. We will also establish new cell lines, as we have a large clinical practice treating patients with carcinoid tumors. Identification of molecular targets will allow for the rapid development of new therapies to be tested in subsequent years in clinical trials by Dr. James Yao and colleagues.

Results

Attempted to create neuroendocrine cell lines. Funding from NETRF supported Lee Ellis’s work that provided a new cell line for study by numerous labs around the world. Initial studies identified new targets for therapy that can be tested in clinical trials. NETRF funding supported the first study reporting on cancer stem cells in carcinoid tumors. Cancer stem cells are thought to be the originating cells in cancers that mediate resistance to therapies and metastasis.

Publications

Van Buren G, Rashid A, Yang AD, Abdalla EK, Gray MJ, Liu W, Somcio R, Fan F, Camp ER, Yao JC, Ellis LM. The development and characterization of a human midgut carcinoid cell line. Clin Cancer Res. 2007 13(16): 4704-4712.

  1. Gock M, Mullins CS, Harnack C, Prall F, Ramer R, Göder A, Krämer OH, Klar E, Linnebacher M. Establishment, functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line. World J Gastroenterol. 2018 Sep 7;24(33):3749-3759. doi: 10.3748/wjg.v24.i33.3749.
  2. Barazeghi E, Prabhawa S, Norlén O, Hellman P, Stålberg P, Westin G. Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors. BMC Cancer. 2018 Jul 25;18(1):764. doi: 10.1186/s12885-018-4579-z.
  3. Døssing KBV, Kjær C, Vikeså J, Binderup T, Knigge U, Culler MD, Kjær A, Federspiel B, Friis-Hansen L. Somatostatin Analogue Treatment Primarily Induce miRNA Expression Changes and Up-Regulates Growth Inhibitory miR-7 and miR-148a in Neuroendocrine Cells. Genes (Basel). 2018 Jul 4;9(7). pii: E337. doi: 10.3390/genes9070337.
  4. Kawasaki K, Fujii M, Sato T. Gastroenteropancreatic neuroendocrine neoplasms: genes, therapies and models. Dis Model Mech. 2018 Feb 26;11(2). pii: dmm029595. doi: 10.1242/dmm.029595.
  5. Hofving T, Arvidsson Y, Almobarak B, Inge L, Pfragner R, Persson M, Stenman G, Kristiansson E, Johanson V, Nilsson O. The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines. Endocr Relat Cancer. 2018 Mar;25(3):367-380. doi: 10.1530/ERC-17-0445. Erratum in: Endocr Relat Cancer. 2018 Apr;25(4):X1-X2.
  6. Cives M, Quaresmini D, Rizzo FM, Felici C, D’Oronzo S, Simone V, Silvestris F. Osteotropism of neuroendocrine tumors: role of the CXCL12/ CXCR4 pathway in promoting EMT in vitro. Oncotarget. 2017 Apr 4;8(14):22534-22549. doi: 10.18632/oncotarget.15122.
  7. Li YM, Liu XY. Molecular mechanisms underlying application of serum procalcitonin and stool miR-637 in prognosis of acute ischemic stroke. Am J Transl Res. 2016 Oct 15;8(10):4242-4249. eCollection 2016.
  8. Fotouhi O, Kjellin H, Larsson C, Hashemi J, Barriuso J, Juhlin CC, Lu M, Höög A, Pastrián LG, Lamarca A, Soto VH, Zedenius J, Mendiola M, Lehtiö J, Kjellman M. Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors. J Clin Endocrinol Metab. 2016 Oct;101(10):3616-3627. Epub 2016 Jul 26.
  9. Edfeldt K, Hellman P, Westin G, Stalberg P. A plausible role for actin gamma smooth muscle 2 (ACTG2) in small intestinal neuroendocrine tumorigenesis. BMC Endocr Disord. 2016 Apr 23;16:19. doi: 10.1186/s12902-016-0100-3.
  10. Døssing KB, Binderup T, Kaczkowski B, Jacobsen A, Rossing M, Winther O, Federspiel B, Knigge U, Kjær A, Friis-Hansen L. Down-Regulation of miR-129-5p and the let-7 Family in Neuroendocrine Tumors and Metastases Leads to Up-Regulation of Their Targets Egr1, G3bp1, Hmga2 and Bach1. Genes (Basel). 2014 Dec 24;6(1):1-21. doi: 10.3390/genes6010001.
  11. Fotouhi O, Adel Fahmideh M, Kjellman M, Sulaiman L, Höög A, Zedenius J, Hashemi J, Larsson C. Global hypomethylation and promoter methylation in small intestinal neuroendocrine tumors: an in vivo and in vitro study. Epigenetics. 2014 Jul;9(7):987-97. doi: 10.4161/epi.28936. Epub 2014 Apr 24.
  12. Krieg A, Mersch S, Boeck I, Dizdar L, Weihe E, Hilal Z, Krausch M, Möhlendick B, Topp SA, Piekorz RP, Huckenbeck W, Stoecklein NH, Anlauf M, Knoefel WT. New model for gastroenteropancreatic large-cell neuroendocrine carcinoma: establishment of two clinically relevant cell lines. PLoS One. 2014 Feb 14;9(2):e88713. doi: 10.1371/journal.pone.0088713. eCollection 2014.
  13. Randle RW, Northrup SA, Sirintrapun SJ, Lyles DS, Stewart JH 4th. Oncolytic vesicular stomatitis virus as a treatment for neuroendocrine tumors. Surgery. 2013 Dec;154(6):1323-29; discussion 1329-30. doi: 10.1016/j.surg.2013.04.050. Epub 2013 Aug 22.
  14. Li SC, Martijn C, Cui T, Essaghir A, Luque RM, Demoulin JB, Castaño JP, Öberg K, Giandomenico V. The somatostatin analogue octreotide inhibits growth of small  intestine neuroendocrine tumour cells. PLoS One. 2012;7(10):e48411. doi: 10.1371/journal.pone.0048411. Epub 2012 Oct 31.
  15. Samuel S, Gaur P, Fan F, Xia L, Gray MJ, Dallas NA, Bose D, Rodriguez-Aguayo C, Lopez-Berestein G, Plowman G, Bagri A, Sood AK, Ellis LM. Neuropilin-2mediated β-catenin signaling and survival in human gastro-intestinal cancer cell lines. PLoS One. 2011;6(10):e23208. doi: 10.1371/journal.pone.0023208. Epub 2011 Oct 20.
  16. Chen Z, Forman LW, Miller KA, English B, Takashima A, Bohacek RA, Williams RM, Faller DV. Protein kinase Cδ inactivation inhibits cellular proliferation and decreases survival in human neuroendocrine tumors. Endocr Relat Cancer. 2011 Dec  1;18(6):759-71. doi: 10.1530/ERC-10-0224. Print 2011 Dec.
  17. Yu D, Jin C, Leja J, Majdalani N, Nilsson B, Eriksson F, Essand M. Adenovirus with hexon Tat-protein transduction domain modification exhibits increased therapeutic effect in experimental neuroblastoma and neuroendocrine tumors. J Virol. 2011 Dec;85(24):13114-23. doi: 10.1128/JVI.05759-11. Epub 2011 Sep 28.
  18. Gaur P, Sceusi EL, Samuel S, Xia L, Fan F, Zhou Y, Lu J, Tozzi F, Lopez-Berestein G, Vivas-Mejia P, Rashid A, Fleming JB, Abdalla EK, Curley SA, Vauthey JN, Sood AK, Yao JC, Ellis LM. Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors. Gastroenterology. 2011 Nov;141(5):1728-37. doi: 10.1053/j.gastro.2011.07.037. Epub 2011 Jul 30.
  19. Alexander VM, Roy M, Steffens KA, Kunnimalaiyaan M, Chen H. Azacytidine induces cell cycle arrest and suppression of neuroendocrine markers in carcinoids. Int J Clin Exp Med. 2010 Mar 28;3(2):95-102.
  20. Kulke MH, Scherübl H. Accomplishments in 2008 in the management of gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res. 2009 Sep;3(5 Supplement 2):S62-6.

Gaur P, Sceusi EL, Samuel S, Xia L, Fan F, Zhou Y, Lu J, Tozzi F, Lopez-Berestein G, Vivas-Mejia P, Rashid A, Fleming JB, Abdalla EK, Curley SA, Vauthey J-N, Sood AK, Yao JC, Ellis LM.  Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors. Gastroenterology. 2011;141(5):1728-37.

1: Waldum HL, Öberg K, Sørdal ØF, Sandvik AK, Gustafsson BI, Mjønes P, Fossmark R. Not only stem cells, but also mature cells, particularly neuroendocrine cells, may develop into tumours: time for a paradigm shift. Therap Adv Gastroenterol. 2018 May 27;11:1756284818775054. doi: 10.1177/1756284818775054. eCollection 2018. Review. PubMed PMID: 29872453; PubMed Central PMCID: PMC5974566.

2: Kawasaki K, Fujii M, Sato T. Gastroenteropancreatic neuroendocrine neoplasms: genes, therapies and models. Dis Model Mech. 2018 Feb 26;11(2). pii: dmm029595. doi: 10.1242/dmm.029595. Review. PubMed PMID: 29590641; PubMed Central PMCID: PMC5894937.

3: Fan F, Wang R, Boulbes DR, Zhang H, Watowich SS, Xia L, Ye X, Bhattacharya R, Ellis LM. Macrophage conditioned medium promotes colorectal cancer stem cell phenotype via the hedgehog signaling pathway. PLoS One. 2018 Jan 2;13(1):e0190070. doi: 10.1371/journal.pone.0190070. eCollection 2018. PubMed PMID: 29293549; PubMed Central PMCID: PMC5749743.

4: Aristizabal Prada ET, Auernhammer CJ. Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. Endocr Connect. 2018 Jan;7(1):R1-R25. doi: 10.1530/EC-17-0286. Epub 2017 Nov 16. Review. PubMed PMID: 29146887; PubMed Central PMCID: PMC5754510.

5: Tanabe E, Kitayoshi M, Fujii K, Ohmori H, Luo Y, Kadochi Y, Mori S, Fujiwara R, Nishiguchi Y, Sasaki T, Kuniyasu H. Fatty acids inhibit anticancer effects of 5-fluorouracil in mouse cancer cell lines. Oncol Lett. 2017 Jul;14(1):681-686. doi: 10.3892/ol.2017.6190. Epub 2017 May 17. PubMed PMID: 28693221; PubMed Central PMCID: PMC5494753.

6: Liu Y, Tu L, Wang L, Long J, Wang J, Wang Y, Luo F, Cao D. The accumulation of macrophages attenuates the effect of recombinant human endostatin on lung cancer. Onco Targets Ther. 2016 Oct 25;9:6581-6595. eCollection 2016. PubMed PMID: 27822063; PubMed Central PMCID: PMC5087788.

7: Wang XF, Zhang XW, Hua RX, Du YQ, Huang MZ, Liu Y, Cheng YF, Guo WJ. Mel-18 negatively regulates stem cell-like properties through downregulation of miR-21 in gastric cancer. Oncotarget. 2016 Sep 27;7(39):63352-63361. doi: 10.18632/oncotarget.11221. PubMed PMID: 27542229; PubMed Central PMCID: PMC5325369.

8: Gaur P, Hunt CR, Pandita TK. Emerging therapeutic targets in esophageal adenocarcinoma. Oncotarget. 2016 Jul 26;7(30):48644-48655. doi: 10.18632/oncotarget.8777. Review. PubMed PMID: 27102294; PubMed Central PMCID: PMC5217045.

9: Krampitz GW, George BM, Willingham SB, Volkmer JP, Weiskopf K, Jahchan N, Newman AM, Sahoo D, Zemek AJ, Yanovsky RL, Nguyen JK, Schnorr PJ, Mazur PK, Sage J, Longacre TA, Visser BC, Poultsides GA, Norton JA, Weissman IL. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4464-9. doi: 10.1073/pnas.1600007113. Epub 2016 Mar 31. Erratum in: Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5538. PubMed PMID: 27035983; PubMed Central PMCID: PMC4843455.

10: Ortiz-Sánchez E, Santiago-López L, Cruz-Domínguez VB, Toledo-Guzmán ME, Hernández-Cueto D, Muñiz-Hernández S, Garrido E, Cantú De León D, García-Carrancá A. Characterization of cervical cancer stem cell-like cells: phenotyping, stemness, and human papilloma virus co-receptor expression. Oncotarget. 2016 May 31;7(22):31943-54. doi: 10.18632/oncotarget.8218. PubMed PMID: 27008711; PubMed Central PMCID: PMC5077987.

11: Yang C, Zhang Y, Zhang Y, Zhang Z, Peng J, Li Z, Han L, You Q, Chen X, Rao X, Zhu Y, Liao Z. Downregulation of cancer stem cell properties via mTOR signaling pathway inhibition by rapamycin in nasopharyngeal carcinoma. Int J Oncol. 2015 Sep;47(3):909-17. doi: 10.3892/ijo.2015.3100. Epub 2015 Jul 21. PubMed PMID: 26202311; PubMed Central PMCID: PMC4532219.

12: Fan F, Bellister S, Lu J, Ye X, Boulbes DR, Tozzi F, Sceusi E, Kopetz S, Tian F, Xia L, Zhou Y, Bhattacharya R, Ellis LM. The requirement for freshly isolated human colorectal cancer (CRC) cells in isolating CRC stem cells. Br J Cancer. 2015 Feb 3;112(3):539-46. doi: 10.1038/bjc.2014.620. Epub 2014 Dec 23. PubMed PMID: 25535733; PubMed Central PMCID: PMC4453647.

13: Tomao F, Papa A, Strudel M, Rossi L, Lo Russo G, Benedetti Panici P, Ciabatta FR, Tomao S. Investigating molecular profiles of ovarian cancer: an update on cancer stem cells. J Cancer. 2014 Mar 16;5(5):301-10. doi: 10.7150/jca.8610. eCollection 2014. Review. PubMed PMID: 24723972; PubMed Central PMCID: PMC3982176.

14: Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, Zhang L, Thorland EC, Minn KT, Tentu R, Eckloff BW, Wieben ED, Wu Y, Cunningham JM, Nagorney DM, Gilbert JA, Ames MM, Beutler AS. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest. 2013 Jun;123(6):2502-8. doi: 10.1172/JCI67963. Epub 2013 May 15. PubMed PMID: 23676460; PubMed Central PMCID: PMC3668835.

15: Mitra A, Mishra L, Li S. Technologies for deriving primary tumor cells for use in personalized cancer therapy. Trends Biotechnol. 2013 Jun;31(6):347-54. doi: 10.1016/j.tibtech.2013.03.006. Epub 2013 Apr 16. Review. PubMed PMID: 23597659; PubMed Central PMCID: PMC3665643.

16: Capurso G, Fendrich V, Rinzivillo M, Panzuto F, Bartsch DK, Delle Fave G. Novel molecular targets for the treatment of gastroenteropancreatic endocrine tumors: answers and unsolved problems. Int J Mol Sci. 2012 Dec 20;14(1):30-45. doi: 10.3390/ijms14010030. Review. PubMed PMID: 23344019; PubMed Central PMCID: PMC3565249.

17: Lin SP, Lee YT, Wang JY, Miller SA, Chiou SH, Hung MC, Hung SC. Survival of cancer stem cells under hypoxia and serum depletion via decrease in PP2A activity and activation of p38-MAPKAPK2-Hsp27. PLoS One. 2012;7(11):e49605. doi: 10.1371/journal.pone.0049605. Epub 2012 Nov 20. PubMed PMID: 23185379; PubMed Central PMCID: PMC3502468.

18: Eads JR, Meropol NJ. A new era for the systemic therapy of neuroendocrine tumors. Oncologist. 2012;17(3):326-38. doi: 10.1634/theoncologist.2011-0356. Epub 2012 Feb 21. Review. PubMed PMID: 22357730; PubMed Central PMCID: PMC3316918.

Additional Details

  • Grant Duration: 2 years
  • Awards: No information
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