Targeting mTOR network in colorectal cancer therapy

World Journal of Gastroenterology

Volumn 20, Issue 15, 2014, Pages 4178-4188

  Wang, Xiao Wen ^a   Zhang, Yan Jie ^b  

^a RUTGERS CANCER INSTITUTE OF NEW JERSEY   (United States)

^b School of Medicine   (China)

Author keywords

Chemotherapy; Colorectal cancer; Drug resistance; Mechanistic target of rapamycin inhibitor; Mechanistic target of rapamycin pathway

Indexed keywords

ACETYLSALICYLIC ACID; CYCLIN D1; CYCLOOXYGENASE 2 INHIBITOR; EPIDERMAL GROWTH FACTOR RECEPTOR; EVEROLIMUS; FLUOROURACIL; HIGH MOBILITY GROUP B1 PROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INITIATION FACTOR 4E; IRINOTECAN; K RAS PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; METFORMIN; MITOGEN ACTIVATED PROTEIN KINASE; MONOCLONAL ANTIBODY; OXALIPLATIN; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN KINASE B; S6 KINASE; SOMATOMEDIN C RECEPTOR; TANDUTINIB; TRANSCRIPTION FACTOR; TUBERIN; ANTINEOPLASTIC AGENT; MTOR PROTEIN, HUMAN; NONSTEROID ANTIINFLAMMATORY AGENT; PROTEIN P53; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE; TP53 PROTEIN, HUMAN; WNT PROTEIN;

ABERRANT CRYPT FOCUS; ADENOCARCINOMA; ADENOMATOUS POLYP; AMINO ACID BLOOD LEVEL; APOPTOSIS; ARTICLE; AUTOPHAGY; CANCER CHEMOTHERAPY; CARCINOGENESIS; CELL CYCLE ARREST; CELL TRANSFORMATION; CELLULAR STRESS SIGNAL; CHROMOSOMAL INSTABILITY; COLON POLYPOSIS; COLORECTAL CANCER; DIABETES MELLITUS; DNA REPAIR; HUMAN; HYPERINSULINEMIA; INCIDENCE; INTESTINE POLYP; MICROSATELLITE INSTABILITY; MITOGENESIS; MOLECULAR INTERACTION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POMEGRANATE; PROGNOSIS; SENESCENCE; SURVIVAL RATE; TUBEROUS SCLEROSIS; TUMOR SUPPRESSOR GENE; WNT SIGNALING PATHWAY; ANIMAL; BIOLOGICAL MODEL; COLORECTAL NEOPLASMS; DRUG RESISTANCE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORK; GENETICS; METABOLISM; SIGNAL TRANSDUCTION;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTINEOPLASTIC AGENTS; AUTOPHAGY; COLORECTAL NEOPLASMS; DRUG RESISTANCE, NEOPLASM; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE REGULATORY NETWORKS; HUMANS; MAP KINASE SIGNALING SYSTEM; METFORMIN; MODELS, BIOLOGICAL; PROGNOSIS; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES; TUMOR SUPPRESSOR PROTEIN P53; WNT PROTEINS;

EID: 84898871677     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i15.4178     Document Type: Article

References (141)

1. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274-293 [PMID: 22500797 DOI: 10.1016/j.cell.2012.03.017]
2. Howell JJ, Ricoult SJ, Ben-Sahra I, Manning BD. A growing role for mTOR in promoting anabolic metabolism. Biochem Soc Trans 2013; 41: 906-912 [PMID: 23863154 DOI: 10.1042/ bst20130041]
3. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003; 11: 895-904 [PMID: 12718876 DOI: 10.1016/S1097-2765(03)00114-X]
4. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T, Mizushima N. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 2010; 285: 20109-20116 [PMID: 20427287 DOI: 10.1074/jbc.M110.121699]
5. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-175 [PMID: 12150925 DOI: 10.1016/S0092-8674(02)00808-5]
6. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007; 9: 316-323 [PMID: 17277771 DOI: 10.1038/ncb1547]
7. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-1302 [PMID: 15268862 DOI: 10.1016/j.cub.2004.06.054]
8. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006; 16: 1865-1870 [PMID: 16919458 DOI: 10.1016/ j.cub.2006.08.001]
9. Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J 2011; 436: 169-179 [PMID: 21413931 DOI: 10.1042/bj20102103]
10. Zheng XF, Florentino D, Chen J, Crabtree GR, Schreiber SL. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 1995; 82: 121-130 [PMID: 7606777 DOI: 10.1016/0092-8674(95)90058-6]
11. Thoreen CC, Sabatini DM. Rapamycin inhibits mTORC1, but not completely. Autophagy 2009; 5: 725-726 [PMID: 19395872 DOI: 10.1074/jbc.M9003012]
12. Laplante M, Sabatini DM. Mtor signaling. Cold Spring Harbor Perspectives in Biology, 2012; 3
13. Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 2010; 22: 169-176 [PMID: 19945836 DOI: 10.1016/j.ceb.2009.10.007]
14. Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, Halley DJ, Sampson JR, Wienecke R, DeClue JE. The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 2000; 19: 6306-6316 [PMID: 11175345 DOI: 10.1038/sj.onc.1204009]
15. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006; 126: 955-968 [PMID: 16959574 DOI: 10.1016/j.cell.2006.06.055]
16. Findlay GM, Yan L, Procter J, Mieulet V, Lamb RF. A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling. Biochem J 2007; 403: 13-20 [PMID: 17253963 DOI: 10.1042/BJ20061881]
17. Byfield MP, Murray JT, Backer JM. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 2005; 280: 33076-33082 [PMID: 16049009 DOI: 10.1074/jbc.M507201200]
18. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas G. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OHkinase. Proc Natl Acad Sci USA 2005; 102: 14238-14243 [PMID: 16176982 DOI: 10.1073/pnas.0506925102]
19. Efeyan A, Zoncu R, Chang S, Gumper I, Snitkin H, Wolfson RL, Kirak O, Sabatini DD, Sabatini DM. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 2013; 493: 679-683 [PMID: 23263183 DOI: 10.1038/nature11745]
20. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 2012; 150: 1196-1208 [PMID: 22980980 DOI: 10.1016/j.cell.2012.07.032]
21. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 2010; 141: 290-303 [PMID: 20381137 DOI: 10.1016/j.cell.2010.02.024]
22. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008; 320: 1496-1501 [PMID: 18497260 DOI: 10.1126/science. 1157535]
23. Globocan 2013, Cancer Fact Sheets for Colorectal Cancer. Available from: URL: http://globocan.iarc.fr/Pages/ fact_sheets_cancer.aspx
24. Siegel R, Naishadham D, Jemal A. Cancer statistics 2012. Cancer J Clin 2012: 62: 10-29 [PMID: 22237781 DOI: 10.3322/ caac.20138]
25. Howlader N, NA, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). Seer cancer statistics review 1975-2010. Bethesda, MD: National Cancer Institute, 2013: 1975-2005
26. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 2009; 361: 2449-2460 [PMID: 20018966 DOI: 10.1056/NEJMra0804588]
27. Morán A, Ortega P, de Juan C, Fernández-Marcelo T, Frías C, Sánchez-Pernaute A, Torres AJ, Díaz-Rubio E, Iniesta P, Benito M. Differential colorectal carcinogenesis: Molecular basis and clinical relevance. World J Gastrointest Oncol 2010; 2: 151-158 [PMID: 21160823 DOI: 10.4251/wjgo.v2.i3.151]
28. Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis 2008; 29: 673-680 [PMID: 17942460 DOI: 10.1093/carcin/bgm228]
29. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759-767 [PMID: 2188735 DOI: 10.1016/0092-8674(90)90186-I]
30. Slattery ML, Herrick JS, Lundgreen A, Fitzpatrick FA, Curtin K, Wolff RK. Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk: mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Akt1. Carcinogenesis 2010; 31: 1604-1611 [PMID: 20622004 DOI: 10.1093/carcin/bgq142]
31. Fearnhead NS, Wilding JL, Bodmer WF. Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull 2002; 64: 27-43 [PMID: 12421723 DOI: 10.1093/bmb/64.1.27]
32. Grady WM, Markowitz SD. Genetic and epigenetic alterations in colon cancer. Annu Rev Genomics Hum Genet 2002; 3: 101-128 [PMID: 12142355 DOI: 10.1146/annurev.genom.3.022502.103043]
33. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997; 275: 1787-1790 [PMID: 9065402 DOI: 10.1126/ science.275.5307.1787]
34. Easwaran V, Lee SH, Inge L, Guo L, Goldbeck C, Garrett E, Wiesmann M, Garcia PD, Fuller JH, Chan V, Randazzo F, Gundel R, Warren RS, Escobedo J, Aukerman SL, Taylor RN, Fantl WJ. beta-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res 2003; 63: 3145-3153 [PMID: 12810642]
35. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422-426 [PMID: 10201372 DOI: 10.1038/18884]
36. Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, Knuechel R, Kirchner T. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 2001; 98: 10356-10361 [PMID: 11526241 DOI: 10.1073/ pnas.171610498]
37. Schneikert J, Behrens J. The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut 2007; 56: 417-425 [PMID: 16840506 DOI: 10.1136/gut.2006.093310]
38. Goss KH, Groden J. Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol 2000; 18: 1967-1979 [PMID: 10784639]
39. Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM. Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc Natl Acad Sci USA 2008; 105: 13544-13549 [PMID: 18768809 DOI: 10.1073/pnas.0800041105]
40. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501 [PMID: 12094235 DOI: 10.1038/nrc839]
41. Scheid MP, Marignani PA, Woodgett JR. Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 2002; 22: 6247-6260 [PMID: 12167717 DOI: 10.1128/MCB.22.17.6247-6260.2002]
42. Phillips WA, St Clair F, Munday AD, Thomas RJ, Mitchell CA. Increased levels of phosphatidylinositol 3-kinase activity in colorectal tumors. Cancer 1998; 83: 41-47 [PMID: 9655291]
43. Roymans D, Slegers H. Phosphatidylinositol 3-kinases in tumor progression. Eur J Biochem 2001; 268: 487-498 [PMID: 11168386 DOI: 10.1046/j.1432-1327.2001.01936.x]
44. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098-1101 [PMID: 15718470 DOI: 10.1126/science.1106148]
45. Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, Silliman N, Ptak J, Szabo S, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Lengauer C, Velculescu VE. Colorectal cancer: mutations in a signalling pathway. Nature 2005; 436: 792 [PMID: 16094359 DOI: 10.1038/436792a]
46. Johnson SM, Gulhati P, Rampy BA, Han Y, Rychahou PG, Doan HQ, Weiss HL, Evers BM. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg 2010; 210: 767-776, 776-778 [PMID: 20421047 DOI: 10.1016/j.jamcollsurg.2009.12.008]
47. Ekstrand AI, Jönsson M, Lindblom A, Borg A, Nilbert M. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer. Fam Cancer 2010; 9: 125-129 [PMID: 19731079 DOI: 10.1007/s10689-009-9293-1]
48. Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, Bertario L, Leo E, Pierotti MA, Pilotti S. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 2009; 20: 84-90 [PMID: 18669866 DOI: 10.1093/annonc/mdn541]
49. Pandurangan AK. Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways. Asian Pac J Cancer Prev 2013; 14: 2201-2205 [PMID: 23725112]
50. De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 2011; 12: 594-603 [PMID: 21163703 DOI: 10.1016/S1470-2045(10)70209-6]
51. Shuch B, Ricketts CJ, Vocke CD, Komiya T, Middelton LA, Kauffman EC, Merino MJ, Metwalli AR, Dennis P, Linehan WM. Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer. J Urol 2013; 190: 1990-1998 [PMID: 23764071 DOI: 10.1016/ j.juro.2013.06.012]
52. Pritchard CC, Smith C, Marushchak T, Koehler K, Holmes H, Raskind W, Walsh T, Bennett RL. A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med 2013; 15: 1004-1007 [PMID: 23619277 DOI: 10.1038/gim.2013.51]
53. Thiem S, Pierce TP, Palmieri M, Putoczki TL, Buchert M, Preaudet A, Farid RO, Love C, Catimel B, Lei Z, Rozen S, Gopalakrishnan V, Schaper F, Hallek M, Boussioutas A, Tan P, Jarnicki A, Ernst M. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J Clin Invest 2013; 123: 767-781 [PMID: 23321674 DOI: 10.1172/ JCI65086]
54. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500-1508 [PMID: 16452206 DOI: 10.1158/0008-5472.can-05-2925]
55. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov 2011; 1: 248-259 [PMID: 22140653 DOI: 10.1158/2159-8290. cd-11-0085]
56. Levine AJ, Finlay CA, Hinds PW. P53 is a tumor suppressor gene. Cell 2004; 116: S67-S69, 1 p following S69 [PMID: 15055586]
57. Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, Hamilton S, Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 1990; 50: 7717-7722 [PMID: 2253215]
58. Feng Z. p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol 2010; 2: a001057 [PMID: 20182617 DOI: 10.1101/cshperspect. a001057]
59. Feng Z, Levine AJ. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 2010; 20: 427-434 [PMID: 20399660 DOI: 10.1016/ j.tcb.2010.03.004]
60. Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 1995; 377: 646-649 [PMID: 7566179 DOI: 10.1038/377646a0]
61. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW. Regulation of PTEN transcription by p53. Mol Cell 2001; 8: 317-325 [PMID: 11545734 DOI: 10.1016/ S1097-2765(01)00323-9]
62. Budanov AV, Karin M. P53 target genes sestrin1 and sestrin2 connect genotoxic stress and mtor signaling. Cell 2008: 134: 451-460 [PMID: 18692468 DOI: 10.1016/j.cell.2008.06.028]
63. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 2005; 102: 8204-8209 [PMID: 15928081 DOI: 10.1073/ pnas.0502857102]
64. Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKTmTOR pathways. Cancer Res 2007; 67: 3043-3053 [PMID: 17409411 DOI: 10.1158/0008-5472.can-06-4149]
65. Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell 2002; 10: 995-1005 [PMID: 12453409 DOI: 10.1016/ S1097-2765(02)00706-2]
66. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18: 2893-2904 [PMID: 15545625 DOI: 10.1101/gad.1256804]
67. Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta 2007; 1773: 1177-1195 [PMID: 17428555 DOI: 10.1016/ j.bbamcr.2007.01.012]
68. Rajalingam K, Schreck R, Rapp UR, and Albert Š, Ras oncogenes and their downstream targets. BBA 2007: 1773: 1177-1195
69. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006; 441: 424-430 [PMID: 16724053 DOI: 10.1038/nature04869]
70. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121: 179-193 [PMID: 15851026 DOI: 10.1016/ j.cell.2005.02.031]
71. Ballif BA, Roux PP, Gerber SA, MacKeigan JP, Blenis J, Gygi SP. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc Natl Acad Sci USA 2005; 102: 667-672 [PMID: 15647351 DOI: 10.1073/ pnas.0409143102]
72. Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J. RAS/ERK signaling promotes sitespecific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 2007; 282: 14056-14064 [PMID: 17360704 DOI: 10.1074/jbc.M700906200]
73. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G. S6K1(-/-)/ S6K2(-/-) mice exhibit perinatal lethality and rapamycinsensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 2004; 24: 3112-3124 [PMID: 15060135 DOI: 10.1128/mcb.24.8.3112-3124.2004]
74. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 2004; 101: 13489-13494 [PMID: 15342917 DOI: 10.1073/pnas.0405659101]
75. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132-141 [PMID: 21258367 DOI: 10.1038/ ncb2152]
76. García-Mauriño S, Alcaide A, Domínguez C. Pharmacological control of autophagy: therapeutic perspectives in inflammatory bowel disease and colorectal cancer. Curr Pharm Des 2012; 18: 3853-3873 [PMID: 22632751 DOI: 10.2174/13816121 2802083653]
77. Francipane MG, Lagasse E. Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor Torin-1. Oncotarget 2013; 4: 1948-1962 [PMID: 24185040]
78. Raina K, Agarwal C, Wadhwa R, Serkova NJ, Agarwal R. Energy deprivation by silibinin in colorectal cancer cells: a double-edged sword targeting both apoptotic and autophagic machineries. Autophagy 2013; 9: 697-713 [PMID: 23445752 DOI: 10.4161/auto.23960]
79. Luo Y, Yoneda J, Ohmori H, Sasaki T, Shimbo K, Eto S, Kato Y, Miyano H, Kobayashi T, Sasahira T, Chihara Y, Kuniyasu H. Cancer usurps skeletal muscle as an energy repository. Cancer Res 2014; 74: 330-340 [PMID: 24197136 DOI: 10.1158/0008-5472.can-13-1052]
80. Alqurashi N, Gopalan V, Smith RA, Lam AK. Clinical impacts of mammalian target of rapamycin expression in human colorectal cancers. Hum Pathol 2013; 44: 2089-2096 [PMID: 23773481 DOI: 10.1016/j.humpath.2013.03.014]
81. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, Lee EY, Weiss HL, O'Connor KL, Gao T, Evers BM. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011; 71: 3246-3256 [PMID: 21430067 DOI: 10.1158/0008-5472.can-10-4058]
82. Aoki K, Tamai Y, Horiike S, Oshima M, Taketo MM. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/-compound mutant mice. Nat Genet 2003; 35: 323-330 [PMID: 14625550 DOI: 10.1038/ng1265]
83. Menon S, Yecies JL, Zhang HH, Howell JJ, Nicholatos J, Harputlugil E, Bronson RT, Kwiatkowski DJ, Manning BD. Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice. Sci Signal 2012; 5: ra24 [PMID: 22457330 DOI: 10.1126/scisignal.2002739]
84. Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007; 12: 112-124 [PMID: 17275731 DOI: 10.1016/j.drudis.2006.12.008]
85. Sun SY. mTOR kinase inhibitors as potential cancer therapeutic drugs. Cancer Lett 2013; 340: 1-8 [PMID: 23792225 DOI: 10.1016/j.canlet.2013.06.017]
86. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009; 27: 2278-2287 [PMID: 19332717 DOI: 10.1200/ jco.2008.20.0766]
87. Zhang YJ, Dai Q, Sun DF, Xiong H, Tian XQ, Gao FH, Xu MH, Chen GQ, Han ZG, Fang JY. mTOR signaling pathway is a target for the treatment of colorectal cancer. Ann Surg Oncol 2009; 16: 2617-2628 [PMID: 19517193 DOI: 10.1245/ s10434-009-0555-9]
88. Zhang YJ, Duan Y, Zheng XF. Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 2011; 16: 325-331 [PMID: 21333749 DOI: 10.1016/j.drudis.2011.02.008]
89. Kim DD, Eng C. The promise of mTOR inhibitors in the treatment of colorectal cancer. Expert Opin Investig Drugs 2012; 21: 1775-1788 [PMID: 22978346 DOI: 10.1517/13543784. 2012.721353]
90. Altomare I, Hurwitz H. Everolimus in colorectal cancer. Expert Opin Pharmacother 2013; 14: 505-513 [PMID: 23406528 DOI: 10.1517/14656566.2013.770473]
91. Price TJ, Segelov E, Burge M, Haller DG, Ackland SP, Tebbutt NC, Karapetis CS, Pavlakis N, Sobrero AF, Cunningham D, Shapiro JD. Current opinion on optimal treatment for colorectal cancer. Expert Rev Anticancer Ther 2013; 13: 597-611 [PMID: 23617351 DOI: 10.1586/era.13.37]
92. Wong A, Ma BB. Personalizing therapy for colorectal cancer. Clin Gastroenterol Hepatol 2014; 12: 139-144 [PMID: 24025538 DOI: 10.1016/j.cgh.2013.08.040]
93. Gulhati P, Cai Q, Li J, Liu J, Rychahou PG, Qiu S, Lee EY, Silva SR, Bowen KA, Gao T, Evers BM. Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res 2009; 15: 7207-7216 [PMID: 19934294 DOI: 10.1158/1078-0432.ccr-09-1249]
94. Ng K, Tabernero J, Hwang J, Bajetta E, Sharma S, Del Prete SA, Arrowsmith ER, Ryan DP, Sedova M, Jin J, Malek K, Fuchs CS. Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Clin Cancer Res 2013; 19: 3987-3995 [PMID: 23743569 DOI: 10.1158/1078-0432.ccr-13-0027]
95. Spindler KL, Sorensen MM, Pallisgaard N, Andersen RF, Havelund BM, Ploen J, Lassen U, Jakobsen AK. Phase II trial of temsirolimus alone and in combination with irinotecan for KRAS mutant metastatic colorectal cancer: outcome and results of KRAS mutational analysis in plasma. Acta Oncol 2013; 52: 963-970 [PMID: 23514584 DOI: 10.3109/0284186X.2013.776175]
96. Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, Geuna M, Frattini M, Baselga J, Gallicchio M, Biffo S, Bardelli A. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010; 120: 2858-2866 [PMID: 20664172 DOI: 10.1172/JCI37539]
97. Altomare I, Bendell JC, Bullock KE, Uronis HE, Morse MA, Hsu SD, Zafar SY, Blobe GC, Pang H, Honeycutt W, Sutton L, Hurwitz HI. A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer. Oncologist 2011; 16: 1131-1137 [PMID: 21795432 DOI: 10.1634/ theoncologist.2011-0078]
98. Bullock KE, Hurwitz HI, Uronis HE, Morse MA, Blobe GC, Hsu SD, Zafar SY, Nixon AB, Howard LA, and Bendell JC. Bevacizumab (b) plus everolimus (e) in refractory metastatic colorectal cancer (mcrc). J Clin Oncol 2009; 27: 4080
99. Wolpin BM, Ng K, Zhu AX, Abrams T, Enzinger PC, Mc-Cleary NJ, Schrag D, Kwak EL, Allen JN, Bhargava P, Chan JA, Goessling W, Blaszkowsky LS, Supko JG, Elliot M, Sato K, Regan E, Meyerhardt JA, Fuchs CS. Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer. Oncologist 2013; 18: 377-378 [PMID: 23580238 DOI: 10.1634/theoncologist. 2012-0378]
100. Moroney J, Fu S, Moulder S, Falchook G, Helgason T, Levenback C, Hong D, Naing A, Wheler J, Kurzrock R. Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity. Clin Cancer Res 2012; 18: 5796-5805 [PMID: 22927482 DOI: 10.1158/1078-0432.CCR-12-1158]
101. Chu C, Noël-Hudson MS, Boige V, Goéré D, Marion S, Polrot M, Bigot L, Gonin P, Farinotti R, Bonhomme-Faivre L. Therapeutic efficiency of everolimus and lapatinib in xenograft model of human colorectal carcinoma with KRAS mutation. Fundam Clin Pharmacol 2013; 27: 434-442 [PMID: 22458846 DOI: 10.1111/j.1472-8206.2012.01035.x]
102. Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 2009; 27: 5931-5937 [PMID: 19884549 DOI: 10.1200/ jco.2009.22.4295]
103. Sharma S, Reid T, Hoosen S, Garrett C, Beck J, Davidson S, MacKenzie M, Brandt U, and Hecht J. Phase i study of rad001 (everolimus), cetuximab, and irinotecan as second-line therapy in metastatic colorectal cancer (mcrc). J Clin Oncol 2009; 27: 15115
104. Gulhati P, Zaytseva YY, Valentino JD, Stevens PD, Kim JT, Sasazuki T, Shirasawa S, Lee EY, Weiss HL, Dong J, Gao T, Evers BM. Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers harboring oncogenic KRAS and PIK3CA. Carcinogenesis 2012; 33: 1782-1790 [PMID: 22696593 DOI: 10.1093/carcin/bgs203]
105. Anthony L, Bajetta E, Kocha W, Panneerselvam A, Saletan S, and O'Dorisio T, Efficacy and safety of everolimus plus octreotide lar in patients with colorectal neuroendocrine tumors (net): Subgroup analysis of the phase iii radiant-2 trial. Am J Gastroenterol 2011: 106: S154-S155 [DOI: 10.1038/ajg.2011.336_6]
106. Bradshaw-Pierce EL, Pitts TM, Kulikowski G, Selby H, Merz AL, Gustafson DL, Serkova NJ, Eckhardt SG, Weekes CD. Utilization of quantitative in vivo pharmacology approaches to assess combination effects of everolimus and irinotecan in mouse xenograft models of colorectal cancer. PLoS One 2013; 8: e58089 [PMID: 23520486 DOI: 10.1371/journal.pone.0058089]
107. Fang DD, Zhang CC, Gu Y, Jani JP, Cao J, Tsaparikos K, Yuan J, Thiel M, Jackson-Fisher A, Zong Q, Lappin PB, Hayashi T, Schwab RB, Wong A, John-Baptiste A, Bagrodia S, Los G, Bender S, Christensen J, Vanarsdale T. Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation. PLoS One 2013; 8: e67258 [PMID: 23826249 DOI: 10.1371/journal.pone.0067258]
108. Mueller A, Bachmann E, Linnig M, Khillimberger K, Schimanski CC, Galle PR, Moehler M. Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines. Cancer Chemother Pharmacol 2012; 69: 1601-1615 [PMID: 22543857 DOI: 10.1007/s00280-012-1869-z]
109. Roper J, Richardson MP, Wang WV, Richard LG, Chen W, Coffee EM, Sinnamon MJ, Lee L, Chen PC, Bronson RT, Martin ES, Hung KE. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS One 2011; 6: e25132 [PMID: 21966435 DOI: 10.1371/journal.pone.0025132]
110. Deming DA, Leystra AA, Farhoud M, Nettekoven L, Clipson L, Albrecht D, Washington MK, Sullivan R, Weichert JP, and Halberg RB, Mtor inhibition elicits a dramatic response in pi3k-dependent colon cancers. PLoS One 2013: 8: 1-9 [DOI: 10.1371/journal.pone.0060709]
111. Atreya CE, Ducker GS, Feldman ME, Bergsland EK, Warren RS, Shokat KM. Combination of ATP-competitive mammalian target of rapamycin inhibitors with standard chemotherapy for colorectal cancer. Invest New Drugs 2012; 30: 2219-2225 [PMID: 22270257 DOI: 10.1007/s10637-012-9793-y]
112. Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS, Naing A, Falchook GS, Moroney JW, Piha-Paul SA, Wheler JJ, Moulder SL, Fu S, Kurzrock R. PIK3CA mutations in patients with advanced cancers treated with PI3K/ AKT/mTOR axis inhibitors. Mol Cancer Ther 2011; 10: 558-565 [PMID: 21216929 DOI: 10.1158/1535-7163.mct-10-0994]
113. Kim A, Lee JE, Lee SS, Kim C, Lee SJ, Jang WS, Park S. Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP-BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer. Int J Cancer 2013; 133: 984-996 [PMID: 23475782 DOI: 10.1002/ijc.28073]
114. She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T, Solit DB, Rosen N. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 2010; 18: 39-51 [PMID: 20609351 DOI: 10.1016/j.ccr.2010.05.023]
115. Zhang Y, Zheng XF. mTOR-independent 4E-BP1 phosphorylation is associated with cancer resistance to mTOR kinase inhibitors. Cell Cycle 2012; 11: 594-603 [PMID: 22262166 DOI: 10.4161/cc.11.3.19096]
116. Martinelli E, Troiani T, D'Aiuto E, Morgillo F, Vitagliano D, Capasso A, Costantino S, Ciuffreda LP, Merolla F, Vecchione L, De Vriendt V, Tejpar S, Nappi A, Sforza V, Martini G, Berrino L, De Palma R, Ciardiello F. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer 2013; 133: 2089-2101 [PMID: 23629727 DOI: 10.1002/ijc.28236]
117. Wang H, Daouti S, Li WH, Wen Y, Rizzo C, Higgins B, Packman K, Rosen N, Boylan JF, Heimbrook D, Niu H. Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Res 2011; 71: 5535-5545 [PMID: 21705440 DOI: 10.1158/0008-5472. can-10-4351]
118. Coffee EM, Faber AC, Roper J, Sinnamon MJ, Goel G, Keung L, Wang WV, Vecchione L, de Vriendt V, Weinstein BJ, Bronson RT, Tejpar S, Xavier RJ, Engelman JA, Martin ES, Hung KE. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res 2013; 19: 2688-2698 [PMID: 23549875 DOI: 10.1158/1078-0432.CCR-12-2556]
119. Das D, Arber N, Jankowski JA. Chemoprevention of colorectal cancer. Digestion 2007; 76: 51-67 [PMID: 17947819 DOI: 10.1159/000108394]
120. Chia WK, Ali R, Toh HC. Aspirin as adjuvant therapy for colorectal cancer--reinterpreting paradigms. Nat Rev Clin Oncol 2012; 9: 561-570 [PMID: 22910681 DOI: 10.1038/nrclinonc.2012.137]
121. Lai SW, Liao KF. Aspirin use after diagnosis improves survival in older adults with colon cancer. J Am Geriatr Soc 2013; 61: 843-844 [PMID: 23672562 DOI: 10.1111/jgs.12236]
122. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA, Giovannucci E, Fuchs CS, Chan AT, Ogino S. Aspirin use, tumor PIK3CA mutation, and colorectalcancer survival. N Engl J Med 2012; 367: 1596-1606 [PMID: 23094721]
123. Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142: 1504-1515. e3 [PMID: 22406476 DOI: 10.1053/j.gastro.2012.02.050]
124. Zhang YJ, Bao YJ, Dai Q, Yang WY, Cheng P, Zhu LM, Wang BJ, Jiang FH. mTOR signaling is involved in indomethacin and nimesulide suppression of colorectal cancer cell growth via a COX-2 independent pathway. Ann Surg Oncol 2011; 18: 580-588 [PMID: 20803081 DOI: 10.1245/s10434-010-1268-9]
125. Ho VW, Leung K, Hsu A, Luk B, Lai J, Shen SY, Minchinton AI, Waterhouse D, Bally MB, Lin W, Nelson BH, Sly LM, Krystal G. A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Cancer Res 2011; 71: 4484-4493 [PMID: 21673053 DOI: 10.1158/0008-5472.can-10-3973]
126. Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 2005; 97: 1679-1687 [PMID: 16288121 DOI: 10.1093/jnci/dji375]
127. Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, Kip KE. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care 2011; 34: 2323-2328 [PMID: 21949223 DOI: 10.2337/ dc11-0512]
128. Higurashi T, Takahashi H, Endo H, Hosono K, Yamada E, Ohkubo H, Sakai E, Uchiyama T, Hata Y, Fujisawa N, Uchiyama S, Ezuka A, Nagase H, Kessoku T, Matsuhashi N, Yamanaka S, Inayama Y, Morita S, Nakajima A. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. BMC Cancer 2012; 12: 118 [PMID: 22443173 DOI: 10.1186/1471-2407-12-118]
129. Kalaany NY, Sabatini DM. Tumours with PI3K activation are resistant to dietary restriction. Nature 2009; 458: 725-731 [PMID: 19279572 DOI: 10.1038/nature07782]
130. Cufí S, Corominas-Faja B, Lopez-Bonet E, Bonavia R, Pernas S, López IÁ, Dorca J, Martínez S, López NB, Fernández SD, Cuyàs E, Visa J, Rodríguez-Gallego E, Quirantes-Piné R, Segura-Carretero A, Joven J, Martin-Castillo B, Menendez JA. Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin. Oncotarget 2013; 4: 1484-1495 [PMID: 23986086]
131. Hosono K, Endo H, Takahashi H, Sugiyama M, Uchiyama T, Suzuki K, Nozaki Y, Yoneda K, Fujita K, Yoneda M, Inamori M, Tomatsu A, Chihara T, Shimpo K, Nakagama H, Nakajima A. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog 2010; 49: 662-671 [PMID: 20564343 DOI: 10.1002/ mc.20637]
132. Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, Takahashi H, Nakajima N, Nagashima Y, Wada K, Nakagama H, Nakajima A. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci 2008; 99: 2136-2141 [PMID: 18803638 DOI: 10.1111/j.1349-7006.2008.00933.x]
133. Ponnurangam S, Standing D, Rangarajan P, Subramaniam D. Tandutinib inhibits the Akt/mTOR signaling pathway to inhibit colon cancer growth. Mol Cancer Ther 2013; 12: 598-609 [PMID: 23427297 DOI: 10.1158/1535-7163.MCT-12-0907]
134. Shishodia S. Molecular mechanisms of curcumin action: gene expression. Biofactors 2013; 39: 37-55 [PMID: 22996381 DOI: 10.1002/biof.1041]
135. Johnson SM, Gulhati P, Arrieta I, Wang X, Uchida T, Gao T, Evers BM. Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res 2009; 29: 3185-3190 [PMID: 19661333]
136. Banerjee N, Kim H, Talcott S, Mertens-Talcott S. Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR. Carcinogenesis 2013; 34: 2814-2822 [PMID: 23996930 DOI: 10.1093/carcin/ bgt295]
137. Weijenberg MP, Hughes LA, Bours MJ, Simons CC, van Engeland M, van den Brandt PA. The mTOR Pathway and the Role of Energy Balance Throughout Life in Colorectal Cancer Etiology and Prognosis: Unravelling Mechanisms Through a Multidimensional Molecular Epidemiologic Approach. Curr Nutr Rep 2013; 2: 19-26 [PMID: 23396869 DOI: 10.1007/s13668-012-0038-7]
138. Hughes LA, Simons CC, van den Brandt PA, Goldbohm RA, van Engeland M, Weijenberg MP. Body size and colorectal cancer risk after 16.3 years of follow-up: an analysis from the Netherlands Cohort Study. Am J Epidemiol 2011; 174: 1127-1139 [PMID: 21984660 DOI: 10.1093/aje/kwr247]
139. Pischon T, Lahmann PH, Boeing H, Friedenreich C, Norat T, Tjønneland A, Halkjaer J, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Guernec G, Bergmann MM, Linseisen J, Becker N, Trichopoulou A, Trichopoulos D, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, Bueno-de-Mesquita HB, Boshuizen HC, Van Guelpen B, Palmqvist R, Berglund G, Gonzalez CA, Dorronsoro M, Barricarte A, Navarro C, Martinez C, Quirós JR, Roddam A, Allen N, Bingham S, Khaw KT, Ferrari P, Kaaks R, Slimani N, Riboli E. Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2006; 98: 920-931 [PMID: 16818856 DOI: 10.1093/jnci/djj246]
140. Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc 2001; 60: 91-106 [PMID: 11310428 DOI: 10.1079/PNS200070]
141. Slattery ML, Fitzpatrick FA. Convergence of hormones, inflammation, and energy-related factors: a novel pathway of cancer etiology. Cancer Prev Res (Phila) 2009; 2: 922-930 [PMID: 19892662 DOI: 10.1158/1940-6207.capr-08-0191]