Progastrin peptides increase the risk of developing colonic tumors: Impact on colonic stem cells

Current Colorectal Cancer Reports

Volumn 8, Issue 4, 2012, Pages 277-289

  Singh, Pomila ^a   Sarkar, Shubhashish ^a   Kantara, Carla ^a   Maxwell, Carrie ^a  

^a University of Texas Medical Branch School of Medicine   (United States)

Author keywords

; Catenin; Aberrant crypt foci; Adenocarcinomas; Adenomas; Akt; Cancer stem cells; Cell surface associated annexin A2; Chromosomal instability; Cluster of differentiation 133; Cluster of differentiation 44; Colon carcinogenesis; Colonic crypts; Colorectal cancer; CpG island methylator phenotype; Curcumin; Cytochrome c oxidase subunit Vb; Doublecortin Ca+2 calmodulin kinase like protein; Extracellular signalregulated kinases; Hyperplastic polyps; Janus kinase; Leucine rich repeat containing G protein coupled receptor 5; Microsatellite instability; Nuclear factor B; P38 mitogen activated protein kinase; Phosphoinositide 3 kinase; Progastrin glycineextended gastrin; Rous Sarcoma viral gene encoded kinase; Signal transducer and activator of transcription 3

Indexed keywords

BETA CATENIN; CD133 ANTIGEN; CHOLECYSTOKININ A RECEPTOR; CHOLECYSTOKININ B RECEPTOR; CURCUMIN; CYCLIN D1; CYCLOOXYGENASE 2; CYTOCHROME C OXIDASE; FATTY ACID BINDING PROTEIN; GASTRIN; GELATINASE A; GLYCOGEN SYNTHASE KINASE 3BETA; HEPARIN BINDING EPIDERMAL GROWTH FACTOR; HERMES ANTIGEN; INTERLEUKIN 8; JAGGED1; JANUS KINASE; LIPOCORTIN 2; MATRIX METALLOPROTEINASE; MITOGEN ACTIVATED PROTEIN KINASE; NOTCH RECEPTOR; ORNITHINE DECARBOXYLASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROGASTRIN; PROTIRELIN; SOMATOMEDIN; STAT3 PROTEIN; TRANSCRIPTION FACTOR RELA; VASCULOTROPIN;

ABERRANT CRYPT FOCUS; APOPTOSIS; ARTICLE; AUTOCRINE EFFECT; CANCER CELL; CANCER RISK; CARBOXY TERMINAL SEQUENCE; CELL PROLIFERATION; CELL RENEWAL; CELL STRAIN HEK293; CHROMOSOMAL INSTABILITY; CITROBACTER RODENTIUM; COLON ADENOCARCINOMA; COLON CANCER; COLON CARCINOGENESIS; DOWN REGULATION; GENE EXPRESSION; GENE SILENCING; HUMAN; HYPERGASTRINEMIA; IMMUNOPRECIPITATION; INTERNALIZATION; INTESTINE EPITHELIUM CELL; INTRACELLULAR SIGNALING; LOSS OF FUNCTION MUTATION; MESENCHYME CELL; MICROSATELLITE INSTABILITY; MOLECULAR INTERACTION; NONHUMAN; PROTEIN BINDING; STEM CELL; TRANSGENIC MOUSE; TUMOR MICROENVIRONMENT; UPREGULATION; ZOLLINGER ELLISON SYNDROME;

EID: 84869138090     PISSN: 15563790     EISSN: 15563804     Source Type: Journal    
DOI: 10.1007/s11888-012-0144-3     Document Type: Article

References (112)

1. Lund T, Olsen J, Rehfeld JF. Cloning and sequencing of the bovine gastrin gene. Mol Endocrinol. 1989;3(10):1585-8.
2. Kang SC, Agarwal KL, Yoo OJ. Molecular cloning and sequence analysis of cDNA coding for canine gastrin. Biochem Int. 1989;18(3):631-6.
3. Kovac S, Shulkes A, Baldwin GS. Peptide processing and biology in human disease. Curr Opin Endocrinol Diabetes Obes. 2009;16(1):79-85. In this review article, the authors describe in detail the steps involved in enzymatic processing of propeptide hormones including progastrins, and also review the biological activity of the propeptide and processed forms, as currently known.
4. Walsh JH. Gastrins. In: Walsh JH, Dockray GJ, editors. Gut peptides: Biochemistry and physiology. New York: Raven; 1994. p. 75-121.
5. Singh P, Dai B, Wu H, Owlia A. Role of autocrine and endocrine gastrin-like peptides in colonic carcinogenesis. Curr Opin Gastroenterol. 2000;16(1):68-77.
6. Rengifo-Cam W, Singh P. Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment. Curr Pharm Des. 2004;10(19):2345-58.
7. Lipkin M. Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res. 1988;48(2):235-45.
8. Singh P, Velasco M, Given R, Varro A, Wang TC. Progastrin expression predisposes mice to colon carcinomas and adenomas in response to a chemical carcinogen. Gastroenterology. 2000;119 (1):162-71.
9. Singh P, Velasco M, Given R, Wargovich M, Varro A, Wang TC. Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM. Am J Physiol Gastrointest Liver Physiol. 2000;278(3):G390-9.
10. Cobb S, Wood T, Ceci J, Varro A, Velasco M, Singh P. Intestinal expression of mutant and wild-type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice. Cancer. 2004;100(6):1311-23.
11. Jin G, Ramanathan V, Quante M, Baik GH, Yang X, Wang SS, Tu S, Gordon SA, Pritchard DM, Varro A, Shulkes A, Wang TC. Inactivating cholecystokinin-2 receptor inhibits progastrindependent colonic crypt fission, proliferation, and colorectal cancer in mice. J Clin Invest. 2009;119(9):2691-701. doi:10.1172/JCI38918. The article describes a possible role of CCK2R in mediating growth effects of progastrin. However, in a letter to the editor, P. Singh and S. Sarkar cited several reports in the literature which strongly disagree with this conclusion. The letter is published along with the article.
12. Ottewell PD, Varro A, Dockray GJ, Kirton CM, Watson AJ, Wang TC, Dimaline R, Pritchard DM. COOH-terminal 26-amino acid residues of progastrin are sufficient for stimulation of mitosis in murine colonic epithelium in vivo. Am J Physiol Gastrointest Liver Physiol. 2005;288(3):G541-9. E.
13. Ramanathan V, Jin G, Westphalen CB, Whelan A, Dubeykovskiy A, Takaishi S, Wang TC. P53 gene mutation increases progastrin dependent colonic proliferation and colon cancer formation in mice. Cancer Investig. 2012;30(4):275-86.
14. Watson SA, Smith AM. Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis. Cancer Res. 2001;61(2):625-31.
15. Warner AS, Glick ME, Fogt F. Multiple large hyperplastic polyps of the colon coincident with adenocarcinoma. Am J Gastroenterol. 1994;89(1):123-5.
16. Huang EH, Whelan RL, Gleason NR, Maeda JS, Terry MB, Lee SW, Neugut AI, Forde KA. Increased incidence of colorectal adenomas in follow-up evaluation of patients with newly diagnosed hyperplastic polyps. Surg Endosc. 2001;15(7):646-8.
17. Kang GH. Four molecular subtypes of colorectal cancer and their precursor lesions. Arch Pathol Lab Med. 2011;135(6):698-703. In this review the author describes the four molecular pathways believed to be associated with the development of colorectal growths/CRCs based on the literature. Some of these pathways are presented diagrammatically in Fig.1 of the current article.
18. Smith AM, Watson SA. Gastrin and gastrin receptor activation: an early event in the adenoma-carcinoma sequence. Gut. 2000;47 (6):820-4.
19. Singh P, Deng X, Rengifo-Cam W, Raju G. Relative levels of gastrin and CCK2R-RNA in fresh biopsies of hyper-proliferative and adenomatous polyps from the colon of patients. Gastroenterology. 2005;128(4). Supplement2.
20. Do C, Bertrand C, Palasse J, Delisle MB, Shulkes A, Cohen-Jonathan-Moyal E, Ferrand A, Seva C. A new biomarker that predicts colonic neoplasia outcome in patients with hyperplastic colonic polyps. Cancer Prev Res (Phila). 2012;5(4):675-84. Data presented in this article from a large group of patients strongly suggest that progastrin expression by hyperplastic colonic growths can be used as a prognostic biomarker. High levels of progastrin expression may predict a worse prognosis for the patient, and require closer surveillance.
21. Chakladar A, Dubeykovskiy A, Wojtukiewicz LJ, Pratap J, Lei S, Wang TC. Synergistic activation of the murine gastrin promoter by oncogenic Ras and beta-catenin involves SMAD recruitment. Biochem Biophys Res Commun. 2005;336(1):190-6.
22. Koh TJ, Bulitta CJ, Fleming JV, Dockray GJ, Varro A, Wang TC. Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. J Clin Invest. 2000;106(4):533-9.
23. Singh P, Owlia A, Varro A, Dai B, Rajaraman S, Wood T. Gastrin gene expression is required for the proliferation and tumorigenicity of human colon cancer cells. Cancer Res. 1996;56(18):4111-5.
24. Singh P, Kumar S, Townsend CM, Thompson JC. Structural requirements for the binding of gastrin to mouse colon cancer cells. Surg Forum. 1987;38:171-3.
25. Seva C, Dickinson CJ, Yamada T. Growth-promoting effects of glycine-extended progastrin. Science. 1994;265(5170):410-2.
26. Ogunwobi OO, Beales IL. Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways. Regul Pept. 2006;134 (1):1-8.
27. Beales IL, Ogunwobi OO. Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation. J Mol Endocrinol. 2009;42(4):305-18.
28. Baldwin GS, Zhang QX. Measurement of gastrin and transforming growth factor alpha messenger RNA levels in colonic carcinoma cell lines by quantitative polymerase chain reaction. Cancer Res. 1992;52(8):2261-7.
29. Van Solinge WW, Nielsen FC, Friis-Hansen L, Falkmer UG, Rehfeld JF. Expression but incomplete maturation of progastrin in colorectal carcinomas. Gastroenterology. 1993;104(4):1099-107.
30. Singh P, Xu Z, Dai B, Rajaraman S, Rubin N, Dhruva B. Incomplete processing of progastrin expressed by human colon cancer cells: role of noncarboxyamidated gastrins. Am J Physiol. 1994;266(3 Pt 1):G459-68.
31. Ciccotosto GD, McLeish A, Hardy KJ, Shulkes A. Expression, processing, and secretion of gastrin in patients with colorectal carcinoma. Gastroenterology. 1995;109(4):1142-53.
32. Siddheshwar RK, Gray JC, Kelly SB. Plasma levels of progastrin but not amidated gastrin or glycine extended gastrin are elevated in patients with colorectal carcinoma. Gut. 2001;48(1):47-52.
33. Konturek PC, Rembiasz K, Burnat G, Konturek SJ, Tusinela M, Bielanski W, Rehfeld J, Karcz D, Hahn E. Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer. Dig Dis Sci. 2006;51(4):779-87.
34. Baldwin GS, Hollande F, Yang Z, Karelina Y, Paterson A, Strang R, Fourmy D, Neumann G, Shulkes A. Biologically active recombinant human progastrin(6-80) contains a tightly bound calcium ion. J Biol Chem. 2001;276(11):7791-6.
35. Singh P, Lu X, Cobb S, Miller BT, Tarasova N, Varro A, Owlia A. Progastrin1-80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites. Am J Physiol Gastrointest Liver Physiol. 2003;284(2):G328-39.
36. Wang TC, Koh TJ, Varro A, Cahill RJ, Dangler CA, Fox JG, Dockray GJ. Processing and proliferative effects of human progastrin in transgenic mice. J Clin Invest. 1996;98(8):1918-29.
37. Koh TJ, Dockray GJ, Varro A, Cahill RJ, Dangler CA, Fox JG, Wang TC. Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation. J Clin Invest. 1999;103(8):1119-26.
38. Wu H, Owlia A, Singh P. Precursor peptide progastrin reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP. Am J Physiol. 2003;285(6):G1097-110.
39. Singh P. Inhibition of endogenous gastrin expression for treatment of colorectal cancer. US Patent 5, 786, 213.
40. Hollande F, Imdahl A, Mantamadiotis T, Ciccotosto GD, Shulkes A, Baldwin GS. Glycine-extended gastrin acts as an autocrine growth factor in a nontransformed colon cell line. Gastroenterology. 1997;113(5):1576-88.
41. Ferrand A, Sandrin MS, Shulkes A, Baldwin GS. Expression of gastrin precursors by CD133-positive colorectal cancer cells is crucial for tumour growth. Biochim Biophys Acta. 2009;1793 (3):477-88. The article describes expression of progastrins by CRC stem cells for the first time. The autocrine role of gastrin gene expression in dictating the tumorigenic potential of colon cancer cells was also confirmed.
42. Singh P. Immunogenic compositions comprising progastrin and uses thereof. US Patent 7,854,932 issued on 21 December 2010. This patent describes the generation of monoclonal antibodies and a specific vaccine for targeting growth/co-carcinogenic effects of progastrin peptides in vivo.
43. Williamson RC, Bauer FL, Oscarson JE, Ross JS, Malt RA. Promotion of azoxymethane-induced colonic neoplasia by resection of the proximal small bowel. Cancer Res. 1978;38 (10):3212-7.
44. Karlin DA, McBath M, Jones RD, Elwyn KE, Romsdahl MM. Hypergastrinemia and colorectal carcinogenesis in the rat. Cancer Lett. 1985;29(1):73-8.
45. Pinson DM, Havu N, Sztern MI, Mattsson H, Looney GA, Kimler BF, Hurwitz A. Drug-induced hypergastrinemia: absence of trophic effects on colonic carcinoma in rats. Gastroenterology. 1995;108(4):1068-74.
46. Bardram L. Progastrin in serum from Zollinger-Ellison patients. An indicator of malignancy? Gastroenterology. 1990;98 (6):1420-6.
47. Smith AM, Varro A, Watson SA, Hardcastle JD. Progastrin and glycine extended gastrin-17 are overexpressed in pernicious anaemia patients. Gastroenterology. 1998;114(Supplement 1):A1181.
48. Diehl D, Oesterle D, Elmlinger MW, Hoeflich A, Wolf E, Lahm H. IGF-II transgenic mice display increased aberrant colon crypt multiplicity and tumor volume after 1,2-dimethylhydrazine treatment. J Carcinog. 2006;5:24.
49. Iacopetta B. Are there two sides to colorectal cancer. Int J Cancer. 2002;101:403-8.
50. Watanabe T, Kobunai T, Toda E, Yamamoto Y, Kanazawa T, Kazama Y, Tanaka J, Tanaka T, Konishi T, Okayama Y, Sugimoto Y, Oka T, Sasaki S, Muto T, Nagawa H. Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers. Cancer Res. 2006;66(20):9804-8.
51. Glebov OK, Rodriguez LM, Nakahara K, Jenkins J, Cliatt J, Humbyrd CJ, DeNobile J, Soballe P, Simon R, Wright G, Lynch P, Patterson S, Lynch H, Gallinger S, Buchbinder A, Gordon G, Hawk E, Kirsch IR. Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomarkers Prev. 2003;12(8):755-62.
52. Wu H, Rao GN, Dai B, Singh P. Autocrine gastrins in colon cancer cells up-regulate cytochrome c oxidase Vb and downregulate efflux of cytochrome c and activation of caspase-3. J Biol Chem. 2000;275(42):32491-8.
53. Capaldi RA, Marusich MF, Taanman JW. Mammalian cytochrome-c oxidase: characterization of enzyme and immunological detection of subunits in tissue extracts and whole cells. Methods Enzymol. 1995;260:117-32.
54. Yang WL, Iacono L, Tang WM, Chin KV. Novel function of the regulatory subunit of protein kinase A: regulation of cytochrome c oxidase activity and cytochrome c release. Biochemistry. 1998;37(40):14175-80.
55. Narayan S, Rajakumar G, Prouix H, Singh P. Estradiol is trophic for colon cancer: Effect on ornithine decarboxylase and c-myc mRNA. Gastroenterology. 1992;103:1823-32.
56. Wang JY, McCormack SA, Viar MJ, Johnson LR. Secretin inhibits induction of ornithine decarboxylase activity by gastrin in duodenal mucosa and IEC-6 cells. Am J Physiol. 1994;267(2 Pt 1):G276-84.
57. Clarke PA, Dickson JH, Harris JC, Grabowska A, Watson SA. Gastrin enhances the angiogenic potential of endothelial cells via modulation of heparin-binding epidermal-like growth factor. Cancer Res. 2006;66(7):3504-12.
58. Bertrand C, Kowalski-Chauvel A, Do C, Résa C, Najib S, Daulhac L, Wang TC, Ferrand A, Seva C. A gastrin precursor, gastrin-gly, upregulates VEGF expression in colonic epithelial cells through an HIF-1-independent mechanism. Int J Cancer. 2010;126(12):2847-57.
59. Brown D, Yallampalli U, Owlia A, Singh P. pp60c-Src Kinase mediates growth effects of the full-length precursor progastrin1-80 peptide on rat intestinal epithelial cells, in vitro. Endocrinology. 2003;144(1):201-11.
60. Grabowska AM, Watson SA. Role of gastrin peptides in carcinogenesis. Cancer Lett. 2007;257(1):1-15.
61. Ferrand A, Wang TC. Gastrin and cancer: a review. Cancer Lett. 2006;238(1):15-29.
62. Rengifo-Cam W, Umar S, Sarkar S, Singh P. Antiapoptotic effects of progastrin on pancreatic cancer cells are mediated by sustained activation of nuclear factor-{kappa}B. Cancer Res. 2007;67(15):7266-74.
63. Umar S, Sarkar S, Cowey S, Singh P. Activation of NF-kappaB is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo. Oncogene. 2008;27(42):5599-611. A critical role of p65 NF&B for mediating antiapoptotic and growth effects of progastrins on proximal colonic crypts of mice is described in relation to colocalization of ANXA2 with progastrin in colonic crypt cells. Related literature regarding the importance of NFκB signaling pathways in cancer cells is discussed.
64. Pannequin J, Bonnans C, Delaunay N, Ryan J, Bourgaux JF, Joubert D, Hollande F. The wnt target jagged-1 mediates the activation of notch signaling by progastrin in human colorectal cancer cells. Cancer Res. 2009;69(15):6065-73. The cross talk between the Wnt and Notch signaling pathways in mediating the growth effects of progastrins on human CRCs is discussed.
65. Pannequin J, Delaunay N, Buchert M, Surrel F, Bourgaux JF, Ryan J, Boireau S, Coelho J, Pélegrin A, Singh P, Shulkes A, Yim M, Baldwin GS, Pignodel C, Lambeau G, Jay P, Joubert D, Hollande F. Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Gastroenterology. 2007;133(5):1554-68.
66. Umar S, Sarkar S, Wang Y, Singh P. Functional cross-talk between beta-catenin and NFkappaB signaling pathways in colonic crypts of mice in response to progastrin. J Biol Chem. 2009;284(33):22274-84. The cross talk between NFκB and β-catenin signaling pathways in mediating growth effects of progastrins on colonic crypts in mice is discussed. A novel mechanism by which β-catenin is activated downstream of NFκB activation in colonic crypts of transgenic mice overexpressing progastrins is reported.
67. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011;140(6):1807-16. This review discusses the literature which demonstrates a strong association between inflammatory bowel disease and inflammation and CR.C.
68. Hayakawa Y, Hirata Y, Nakagawa H, Sakamoto K, Hikiba Y, Otsuka M, Ijichi H, Ikenoue T, Tateishi K, Akanuma M, Ogura K, Yoshida H, Ichijo H, Omata M, Maeda S. Apoptosis signalregulating kinase 1 regulates colitis and colitis-associated tumorigenesis by the innate immune responses. Gastroenterology. 2010;138(3):1055-67.e1-4. In this article the authors report the risk of developing colonic tumors in mouse models of colitis. Infection with Citrobacter rodentium was used as one of the models for inducing colitis-like symptoms.
69. Na SY, Myung SJ. Obesity and colorectal cancer. Korean J Gastroenterol. 2012;59(1):16-26. The risk of developing CRCs in obese patients is reviewed in this article.
70. Umar S, Singh P. Synergistic effects of progastrin (PG) and Citrobacter rodentium (CR) on the growth of proximal and distal colonic epithelial cells in FVB/N mice: associated changes in the levels of β-catenin, NF-κB and ERK1/2. Gastroenterology. 2008;134(4): Supplement 1, Page A-295.
71. Kovac S, Anderson GJ, Baldwin GS. Gastrins, iron homeostasis and colorectal cancer. Biochim Biophys Acta. 2011;1813(5):889-95.
72. Singh P, Owlia A, Espeijo R, Dai B. Novel gastrin receptors mediate mitogenic effects of gastrin and processing intermediates of gastrin on Swiss 3 T3 fibroblasts. Absence of detectable cholecystokinin (CCK)-A and CCK-B receptors. J Biol Chem. 1995;270(15):8429-38.
73. Bold RJ, Ishizuka J, Townsend Jr. CM, Thompson JC. Gastrin stimulates growth of human colon cancer cells via a receptor other than CCK-A or CCK-B. Biochem Biophys Res Commun. 1994;202(3):1222-6.
74. Singh P, Wu H, Clark C, Owlia A. Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells. Oncogene. 2007;26(3):425-40.
75. Przemeck SM, Varro A, Berry D, Steele I,Wang TC, Dockray GJ, Pritchard DM. Hypergastrinemia increases gastric epithelial susceptibility to apoptosis. Regul Pept. 2008;146(1-3):147-56.
76. Sebens Müerköster S, Rausch AV, Isberner A, Minkenberg J, Blaszczuk E, Witt M, Fölsch UR, Schmitz F, Schäfer H, Arlt A. The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition. Oncogene. 2008;27(8):1122-34.
77. Reubi JC, Schaer JC, Waser B. Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res. 1997;57(7):1377-86.
78. Dubeykovskiy A, Nguyen T, Dubeykovskaya Z, Lei S,Wang TC. Flow cytometric detection of progastrin interaction with gastrointestinal cells. Regul Pept. 2008;151(1-3):106-14.
79. Chicone L, Narayan S, Townsend Jr. CM, Singh P. The presence of a 33-40 KDa gastrin binding protein on human and mouse colon cancer. Biochem Biophys Res Commun. 1989;164(1):512-9.
80. Speir GR, Takeuchi K, Peitsch W, Johnson LR. Mucosal gastrin receptor VII up-and downregulation. Am J Physiol. 1982;242(3): G243-9.
81. Singh P. Role Annexin-II in GI cancers: interaction with gastrins/progastrins. Cancer Lett. 2007;252(1):19-35.
82. Ortiz-Zapater E, Peiró S, Roda O, Corominas JM, Aguilar S, Ampurdanés C, Real FX, Navarro P. Tissue plasminogen activator induces pancreatic cancer cell proliferation by a non-catalytic mechanism that requires extracellular signal-regulated kinase 1/2 activation through epidermal growth factor receptor and annexin A2. Am J Pathol. 2007;170(5):1573-84.
83. Sarkar S, Kantara C, Singh P. Clathrin mediates endocytosis of progastrin and activates MAPKs: role of cell surface annexin A2. Am J Physiol Gastrointest Liver Physiol. 2012;302(7):G712-22. The important role of endocytosis in measuring biological effects of progastrins on intestinal cells is described. The article describes the methods used to confirm the association of progastrins with CS-ANXA2. The role of CS-ANXA2 in the tumorigenic/metastatic potential of cancer cells is reviewed. The critical role of CME in biological effects of ligand-membrane receptors is also discussed.
84. Sarkar S, Swiercz R, Kantara C, Hajjar KA, Singh P. Annexin A2 mediates up-regulation of NF-κB, β-catenin, and stem cell in response to progastrin in mice and HEK-293 cells. Gastroenterology. 2011;140(2):583-595.e4. Data demonstrating a critical role of CS-ANXA2 in upregulating NFκB/β-catenin/stem cell markers in response to progastrins in vitro and in vivo using ANXA2 knockout mice are presented. A novel finding was that activation of both NFκB and β-catenin was required to measure maximum growth effects in response to progastrins.
85. Sarkar S, Kantara C, Ortiz I, Swiercz R, Kuo J, Davey R, Escobar K, Ullrich R, Singh P. Progastrin overexpression imparts tumorigenic/metastatic potential to embryonic epithelial cells: Phenotypic differences between transformed and nontransformed stem cells. Int J Cancer. 2012;131(7):E1088-99. Several novel concepts are presented in this article. Transformation of embryonic cells by constitutive expression of the gastrin gene in the cell is described for the first time. Significant differences in the phenotype of transformed versus nontransformed stem cells were identified, and could be used as a biomarker for assessing the tumorigenic potential of cells in the future. The article also describes a specific ligand for diagnosing CRCs.
86. Kesavan K, Ratliff J, Johnson EW, Dahlberg W, Asara JM, Misra P, Frangioni JV, Jacoby DB. Annexin A2 is a molecular target for TM601, a peptide with tumor-targeting and antiangiogenic effects. J Biol Chem. 2010;285(7):4366-74. The authors report an important role of CS-ANXA2 in mediating the metastatic potential of cancer cells, and the development of a peptide ligand (TM601) for blocking the effects.
87. Shiozawa Y, Havens AM, Jung Y, Ziegler AM, Pedersen EA, Wang J, Wang J, Lu G, Roodman GD, Loberg RD, Pienta KJ, Taichman RS. Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem. 2008;105(2):370-80.
88. Valapala M, Vishwanatha JK. Lipid raft endocytosis and exosomal transport facilitate extracellular trafficking of annexin A2. J Biol Chem. 2011;286(35):30911-25. The authors describe the mechanisms by which ANXA2 is trafficked extracellularly within exosomes from cancer cells, and endocytotic mechanisms by which exosomes are reinternalized. These findings provide possible mechanisms by which activated oncogenic molecules in transformed cells can be exported via exosomes and potentially "infect" other cells.
89. Wielenga V, Smits R, Korinek V, Smit L, Kielman M, Fodde R, Clevers R, Pals S. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol. 1999;154(2):515-23.
90. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449(7165):1003-7.
91. Takebe N, Ivy SP. Controversies in cancer stem cells: targeting embryonic signaling pathways. Clin Cancer Res. 2010;16 (12):3106-12.
92. Godley JM, Brand SJ. Regulation of the gastrin promoter by epidermal growth factor and neuropeptides. Proc Natl Acad Sci U S A. 1989;86(9):3036-40.
93. Brand SJ,Wang TC. Gastrin gene expression and regulation in rat islet cell lines. J Biol Chem. 1988;263(32):16597-603.
94. Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269(2):199-225. The authors review a vast amount of literature in this field which describes the chemopreventive effects of curcumin on growth and metastasis of cancer cells in relation to signaling pathways targeted by curcumin.
95. Mahmoud NN, Carothers AM, Grunberger D, Bilinski RT, Churchill MR, Martucci C, Newmark HL, Bertagnolli MM. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis. 2000;21(5):921-7.
96. Sarkar FH, Li Y,Wang Z, Padhye S. Lesson learned from nature for the development of novel anti-cancer agents: implication of isoflavone, curcumin, and their synthetic analogs. Curr Pharm Des. 2010;16(16):1801-12. The authors review the literature which describes the inhibitory effects of curcumin and isoflavones, and their usefulness in treating cancers.
97. Rao CV, Rivenson A, Simi B, Reddy BS. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res. 1995;55(2):259-66.
98. Kawamori T, Lubet R, Steele VE, Kelloff GJ, Kaskey RB, Rao CV, Reddy BS. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res. 1999;59(3):597-601.
99. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431-6.
100. Singh P, Sarkar S, Umar S, Rengifo-Cam W, Singh AP, Wood TG. Insulin-like growth factors are more effective than progastrin in reversing proapoptotic effects of curcumin: critical role of p38MAPK. Am J Physiol Gastrointest Liver Physiol. 2010;298 (4):G551-62. Methods used to investigate apoptotic effects of curcumin in relation to several signaling pathways in the presence or absence of autocrine growth factors relevant to colon cancers are described.
101. Marín YE, Wall BA, Wang S, Namkoong J, Martino JJ, Suh J, Lee HJ, Rabson AB, Yang CS, Chen S, Ryu JH. Curcumin downregulates the constitutive activity of NF-kappaB and induces apoptosis in novel mouse melanoma cells. Melanoma Res. 2007;17(5):274-83.
102. Kunnumakkara AB, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal BB, Krishnan S. Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res. 2008;14(7):2128-36.
103. Kantara C, Ortiz, I, Sarkar S, Ullrich R, Singh P. Targeting cancer stem cells (CSCs) with curcumin±RNAi against stem-cell markers, in vitro and in vivo: effect on oncogenic pathways. Gastroenterology.2012: 142(5), Supplement 1, Page S-331.
104. Rashmi R, Kumar S, Karunagaran D. Ectopic expression of Hsp70 confers resistance and silencing its expression sensitizes human colon cancer cells to curcumin-induced apoptosis. Carcinogenesis. 2004;25(2):179-87.
105. Rashmi R, Kumar S, Karunagaran D. Ectopic expression of Bcl-XL or Ku70 protects human colon cancer cells (SW480) against curcumin-induced apoptosis while their down-regulation potentiates it. Carcinogenesis. 2004;25(10):1867-77.
106. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci. 2008;65(11):1631-52.
107. Patel BB, Sengupta R, Qazi S, Vachhani H, Yu Y, Rishi AK, Majumdar AP. Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF-1R. Int J Cancer. 2008;122(2):267-73.
108. Barry J, Fritz M, Brender JR, Smith PE, Lee DK, Ramamoorthy A. Determining the effects of lipophilic drugs on membrane structure by solid-state NMR spectroscopy: the case of the antioxidant curcumin. J Am Chem Soc. 2009;131(12):4490-8.
109. Ajani JA, Hecht JR, Ho L, Baker J, Oortgiesen M, Eduljee A, Michaeli D. An open-label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5-fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer: the GC4 study. Cancer. 2006;106(9):1908-16.
110. Singh P, Singh G. Development of progastrin (PG) specific monoclonal antibodies (Mabs) and PG specific vaccine for attenuating growth factor effects of autocrine and endocrine PG-like peptides on colon cancer cells and colon carcinogenesis, respectively. Gastroenterology. 2007;132(Supplement 2, A-400):69-70.
111. Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 2010;122(3):777-85. Methods used to investigate inhibitory effects of curcumin on breast cancer stem cells are described.
112. Yu Y, Kanwar SS, Patel BB, Nautiyal J, Sarkar FH, Majumdar AP. Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Transl Oncol. 2009;2(4):321-8. Methods used to examine inhibitory effects of curcumin in the presence or absence of chemotherapeutic agents on colon cancer stem cells are described.