Despite the large amount of data in cancer biology and many studies into the likely survival of colorectal cancer (CRC) patients, knowledge regarding the issue of CRC prognostic biomarkers remains poor. The Tumor-Node-Metastasis (TNM) staging system continues to be the most powerful and reliable predictor of the clinical outcome of CRC patients. The exponential increase of knowledge in the field of molecular genetics has lead to the identification of specific alterations involved in the malignant progression. Many of these genetic alterations were proposed as biomarkers which could be used in clinical practice to estimate CRC prognosis. Recently there has been an explosive increase in the number of putative biomarkers able to predict the response to specific adjuvant treatment. In this review we explore and summarize data concerning prognostic and predictive biomarkers and we attempt to shed light on recent research that could lead to the emergence of new biomarkers in CRC.
References
[1]
Parkin, D.M.; Bray, F.; Ferlay, J.; Pisani, P. Global cancer statistics, 2002. CA Cancer J. Clin. 2005, 55, 74–108.
[2]
O'Connell, J.B.; Maggard, M.A.; Ko, C.Y. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J. Nat. Cancer Inst. 2004, 96, 1420–1425.
Sobin, L.H.; Fleming, I.D. TNM classification of malignant tumors, fifth edition. Cancer 1997, 80, 1803–1804.
[5]
Dukes, C. The classification of cancer of the rectum. Dis. Colon Rectum. 1980, 23, 605–611.
[6]
Andre, T.; Boni, C.; Navarro, M.; Tabernero, J.; Hickish, T.; Topham, C.; Bonetti, A.; Clingan, P.; Bridgewater, J.; Rivera, F.; et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 2009, 27, 3109–3116.
[7]
Andre, T.; Quinaux, E.; Louvet, C.; Colin, P.; Gamelin, E.; Bouche, O.; Achille, E.; Piedbois, P.; Tubiana-Mathieu, N.; Boutan-Laroze, A.; et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: Final results of GERCOR C96.1. J. Clin. Oncol. 2007, 25, 3732–3738.
[8]
Le Voyer, T.E.; Sigurdson, E.R.; Hanlon, A.L.; Mayer, R.J.; Macdonald, J.S.; Catalano, P.J.; Haller, D.G. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J. Clin. Oncol. 2003, 21, 2912–2919.
[9]
Mamounas, E.; Wieand, S.; Wolmark, N.; Bear, H.D.; Atkins, J.N.; Song, K.; Jones, J.; Rockette, H. Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: Results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J. Clin. Oncol. 1999, 17, 1349–1355.
[10]
Saltz, L.B.; Niedzwiecki, D.; Hollis, D.; Goldberg, R.M.; Hantel, A.; Thomas, J.P.; Fields, A.L.; Mayer, R.J. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803. J. Clin. Oncol. 2007, 25, 3456–3461.
[11]
Van Cutsem, E.; Labianca, R.; Bodoky, G.; Barone, C.; Aranda, E.; Nordlinger, B.; Topham, C.; Tabernero, J.; Andre, T.; Sobrero, A.F.; et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J. Clin. Oncol. 2009, 27, 3117–3125.
[12]
Locker, G.Y.; Hamilton, S.; Harris, J.; Jessup, J.M.; Kemeny, N.; Macdonald, J.S.; Somerfield, M.R.; Hayes, D.F.; Bast, R.C., Jr. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J. Clin. Oncol. 2006, 24, 5313–5327.
[13]
van't Veer, L.J.; Dai, H.; van de Vijver, M.J.; He, Y.D.; Hart, A.A.; Mao, M.; Peterse, H.L.; van der Kooy, K.; Marton, M.J.; Witteveen, A.T.; et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415, 530–536.
[14]
van de Vijver, M.J.; He, Y.D.; van't Veer, L.J.; Dai, H.; Hart, A.A.; Voskuil, D.W.; Schreiber, G.J.; Peterse, J.L.; Roberts, C.; Marton, M.J.; et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 2002, 347, 1999–2009.
Vogelstein, B.; Fearon, E.R.; Hamilton, S.R.; Kern, S.E.; Preisinger, A.C.; Leppert, M.; Nakamura, Y.; White, R.; Smits, A.M.; Bos, J.L. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 1988, 319, 525–532.
[17]
Lengauer, C.; Kinzler, K.W.; Vogelstein, B. Genetic instabilities in human cancers. Nature 1998, 396, 643–649.
[18]
Lothe, R.A.; Peltomaki, P.; Meling, G.I.; Aaltonen, L.A.; Nystrom-Lahti, M.; Pylkkanen, L.; Heimdal, K.; Andersen, T.I.; Moller, P.; Rognum, T.O.; et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 1993, 53, 5849–5852.
Grady, W.M. Genomic instability and colon cancer. Cancer Metast. Rev. 2004, 23, 11–27.
[21]
Aaltonen, L.A.; Peltomaki, P.; Leach, F.S.; Sistonen, P.; Pylkkanen, L.; Mecklin, J.P.; Jarvinen, H.; Powell, S.M.; Jen, J.; Hamilton, S.R.; et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993, 260, 812–816.
[22]
Ionov, Y.; Peinado, M.A.; Malkhosyan, S.; Shibata, D.; Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993, 363, 558–561.
[23]
Jass, J.R.; Young, J.; Leggett, B.A. Evolution of colorectal cancer: Change of pace and change of direction. J. Gastroenterol. Hepatol. 2002, 17, 17–26.
[24]
Peltomaki, P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J. Clin. Oncol. 2003, 21, 1174–1179.
[25]
Laghi, L.; Bianchi, P.; Malesci, A. Differences and evolution of the methods for the assessment of microsatellite instability. Oncogene 2008, 27, 6313–6321.
[26]
Cunningham, J.M.; Christensen, E.R.; Tester, D.J.; Kim, C.Y.; Roche, P.C.; Burgart, L.J.; Thibodeau, S.N. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998, 58, 3455–3460.
[27]
Kane, M.F.; Loda, M.; Gaida, G.M.; Lipman, J.; Mishra, R.; Goldman, H.; Jessup, J.M.; Kolodner, R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997, 57, 808–811.
[28]
Kinzler, K.W.; Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 1996, 87, 159–170.
Kolodner, R.D.; Hall, N.R.; Lipford, J.; Kane, M.F.; Rao, M.R.; Morrison, P.; Wirth, L.; Finan, P.J.; Burn, J.; Chapman, P.; et al. Human mismatch repair genes and their association with hereditary non-polyposis colon cancer. Cold Spring Harb. Symp. Quant. Biol. 1994, 59, 331–338.
[31]
Aaltonen, L.A.; Peltomaki, P. Genes involved in hereditary nonpolyposis colorectal carcinoma. Anticancer Res. 1994, 14, 1657–1660.
[32]
de la Chapelle, A.; Peltomaki, P. Genetics of hereditary colon cancer. Annu. Rev. Genet. 1995, 29, 329–348.
[33]
Hendriks, Y.M.; de Jong, A.E.; Morreau, H.; Tops, C.M.; Vasen, H.F.; Wijnen, J.T.; Breuning, M.H.; Brocker-Vriends, A.H. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): A guide for clinicians. CA Cancer J. Clin. 2006, 56, 213–225.
[34]
Alexander, J.; Watanabe, T.; Wu, T.T.; Rashid, A.; Li, S.; Hamilton, S.R. Histopathological identification of colon cancer with microsatellite instability. Am. J. Pathol. 2001, 158, 527–535.
[35]
Gafa, R.; Maestri, I.; Matteuzzi, M.; Santini, A.; Ferretti, S.; Cavazzini, L.; Lanza, G. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer 2000, 89, 2025–2037.
[36]
Greenson, J.K.; Bonner, J.D.; Ben-Yzhak, O.; Cohen, H.I.; Miselevich, I.; Resnick, M.B.; Trougouboff, P.; Tomsho, L.D.; Kim, E.; Low, M.; et al. Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am. J. Surg. Pathol. 2003, 27, 563–570.
[37]
Jass, J.R.; Do, K.A.; Simms, L.A.; Iino, H.; Wynter, C.; Pillay, S.P.; Searle, J.; Radford-Smith, G.; Young, J.; Leggett, B. Morphology of sporadic colorectal cancer with DNA replication errors. Gut. 1998, 42, 673–679.
[38]
Kim, H.; Jen, J.; Vogelstein, B.; Hamilton, S.R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol. 1994, 145, 148–156.
[39]
Malesci, A.; Laghi, L.; Bianchi, P.; Delconte, G.; Randolph, A.; Torri, V.; Carnaghi, C.; Doci, R.; Rosati, R.; Montorsi, M.; et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin. Cancer Res. 2007, 13, 3831–3839.
[40]
Smyrk, T.C.; Watson, P.; Kaul, K.; Lynch, H.T. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 2001, 91, 2417–2422.
[41]
Ward, R.; Meagher, A.; Tomlinson, I.; O'Connor, T.; Norrie, M.; Wu, R.; Hawkins, N. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001, 48, 821–829.
[42]
Popat, S.; Hubner, R.; Houlston, R.S. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 2005, 23, 609–618.
[43]
Walther, A.; Houlston, R.; Tomlinson, I. Association between chromosomal instability and prognosis in colorectal cancer: A meta-analysis. Gut. 2008, 57, 941–950.
[44]
Koopman, M.; Kortman, G.A.; Mekenkamp, L.; Ligtenberg, M.J.; Hoogerbrugge, N.; Antonini, N.F.; Punt, C.J.; van Krieken, J.H. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br. J. Cancer 2009, 100, 266–273.
[45]
Elsaleh, H.; Iacopetta, B. Microsatellite instability is a predictive marker for survival benefit from adjuvant chemotherapy in a population-based series of stage III colorectal carcinoma. Clin. Colorectal. Cancer 2001, 1, 104–109.
[46]
Benatti, P.; Gafa, R.; Barana, D.; Marino, M.; Scarselli, A.; Pedroni, M.; Maestri, I.; Guerzoni, L.; Roncucci, L.; Menigatti, M.; et al. Microsatellite instability and colorectal cancer prognosis. Clin. Cancer Res. 2005, 11, 8332–8340.
[47]
Jover, R.; Zapater, P.; Castells, A.; Llor, X.; Andreu, M.; Cubiella, J.; Balaguer, F.; Sempere, L.; Xicola, R.M.; Bujanda, L.; et al. The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status. Eur. J. Cancer 2009, 45, 365–373.
[48]
Ribic, C.M.; Sargent, D.J.; Moore, M.J.; Thibodeau, S.N.; French, A.J.; Goldberg, R.M.; Hamilton, S.R.; Laurent-Puig, P.; Gryfe, R.; Shepherd, L.E.; et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N. Engl. J. Med. 2003, 349, 247–257.
[49]
Sargent, D.J.; Marsoni, S.; Thibodeau, S.N.; Labianca, R.; Hamilton, S.R.; Torri, V.; Monges, G.; Ribic, C.; Grothey, A.; Gallinger, S. Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials. J. Clin. Oncol. 2008, 26 Suppl. 15. Abstract 4008.
[50]
Sinicrope, F.A.; Sargent, D.J. Clinical implications of microsatellite instability in sporadic colon cancers. Curr. Opin. Oncol. 2009, 21, 369–373.
[51]
French, A.J.; Sargent, D.J.; Burgart, L.J.; Foster, N.R.; Kabat, B.F.; Goldberg, R.; Shepherd, L.; Windschitl, H.E.; Thibodeau, S.N. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin. Cancer Res. 2008, 14, 3408–3415.
[52]
Weisenberger, D.J.; Siegmund, K.D.; Campan, M.; Young, J.; Long, T.I.; Faasse, M.A.; Kang, G.H.; Widschwendter, M.; Weener, D.; Buchanan, D.; et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 2006, 38, 787–793.
[53]
Ogino, S.; Nosho, K.; Kirkner, G.J.; Kawasaki, T.; Meyerhardt, J.A.; Loda, M.; Giovannucci, E.L.; Fuchs, C.S. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009, 58, 90–96.
[54]
Barault, L.; Charon-Barra, C.; Jooste, V.; de la Vega, M.F.; Martin, L.; Roignot, P.; Rat, P.; Bouvier, A.M.; Laurent-Puig, P.; Faivre, J.; et al. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res. 2008, 68, 8541–8546.
[55]
Shen, L.; Toyota, M.; Kondo, Y.; Lin, E.; Zhang, L.; Guo, Y.; Hernandez, N.S.; Chen, X.; Ahmed, S.; Konishi, K.; et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 18654–18659.
[56]
Ogino, S.; Goel, A. Molecular classification and correlates in colorectal cancer. J. Mol. Diagn. 2008, 10, 13–27.
[57]
Nagasaka, T.; Sasamoto, H.; Notohara, K.; Cullings, H.M.; Takeda, M.; Kimura, K.; Kambara, T.; MacPhee, D.G.; Young, J.; Leggett, B.A.; et al. Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J. Clin. Oncol. 2004, 22, 4584–4594.
[58]
Samowitz, W.S.; Sweeney, C.; Herrick, J.; Albertsen, H.; Levin, T.R.; Murtaugh, M.A.; Wolff, R.K.; Slattery, M.L. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005, 65, 6063–6069.
[59]
Ward, R.L.; Cheong, K.; Ku, S.L.; Meagher, A.; O'Connor, T.; Hawkins, N.J. Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J. Clin. Oncol. 2003, 21, 3729–3736.
[60]
Yamada, Y.; Jackson-Grusby, L.; Linhart, H.; Meissner, A.; Eden, A.; Lin, H.; Jaenisch, R. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc. Natl. Acad. Sci. USA 2005, 102, 13580–13585.
[61]
Matsuzaki, K.; Deng, G.; Tanaka, H.; Kakar, S.; Miura, S.; Kim, Y.S. The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer. Clin. Cancer Res. 2005, 11, 8564–8569.
[62]
Rodriguez, J.; Frigola, J.; Vendrell, E.; Risques, R.A.; Fraga, M.F.; Morales, C.; Moreno, V.; Esteller, M.; Capella, G.; Ribas, M.; et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 2006, 66, 8462–9468.
[63]
Fearon, E.R.; Cho, K.R.; Nigro, J.M.; Kern, S.E.; Simons, J.W.; Ruppert, J.M.; Hamilton, S.R.; Preisinger, A.C.; Thomas, G.; Kinzler, K.W.; et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 1990, 247, 49–56.
[64]
Jen, J.; Kim, H.; Piantadosi, S.; Liu, Z.F.; Levitt, R.C.; Sistonen, P.; Kinzler, K.W.; Vogelstein, B.; Hamilton, S.R. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N. Engl. J. Med. 1994, 331, 213–221.
[65]
Martinez-Lopez, E.; Abad, A.; Font, A.; Monzo, M.; Ojanguren, I.; Pifarre, A.; Sanchez, J.J.; Martin, C.; Rosell, R. Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer. Gastroenterology 1998, 114, 1180–1187.
[66]
Ogunbiyi, O.A.; Goodfellow, P.J.; Herfarth, K.; Gagliardi, G.; Swanson, P.E.; Birnbaum, E.H.; Read, T.E.; Fleshman, J.W.; Kodner, I.J.; Moley, J.F. Confirmation that chromosome 18q allelic loss in colon cancer is a prognostic indicator. J. Clin. Oncol. 1998, 16, 427–433.
[67]
Popat, S.; Houlston, R.S. A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur. J. Cancer 2005, 41, 2060–2070.
[68]
Halling, K.C.; French, A.J.; McDonnell, S.K.; Burgart, L.J.; Schaid, D.J.; Peterson, B.J.; Moon-Tasson, L.; Mahoney, M.R.; Sargent, D.J.; O'Connell, M.J.; et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J. Nat. Cancer Inst. 1999, 91, 1295–1303.
[69]
Popat, S.; Zhao, D.; Chen, Z.; Pan, H.; Shao, Y.; Chandler, I.; Houlston, R.S. Relationship between chromosome 18q status and colorectal cancer prognosis: A prospective, blinded analysis of 280 patients. Anticancer Res. 2007, 27, 627–633.
[70]
Carethers, J.M.; Hawn, M.T.; Greenson, J.K.; Hitchcock, C.L.; Boland, C.R. Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer. Gastroenterology 1998, 114, 1188–1195.
[71]
Watanabe, T.; Wu, T.T.; Catalano, P.J.; Ueki, T.; Satriano, R.; Haller, D.G.; Benson, A.B., 3rd; Hamilton, S.R. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N. Engl. J. Med. 2001, 344, 1196–1206.
[72]
Eppert, K.; Scherer, S.W.; Ozcelik, H.; Pirone, R.; Hoodless, P.; Kim, H.; Tsui, L.C.; Bapat, B.; Gallinger, S.; Andrulis, I.L.; et al. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 1996, 86, 543–552.
[73]
Hahn, S.A.; Schutte, M.; Hoque, A.T.; Moskaluk, C.A.; da Costa, L.T.; Rozenblum, E.; Weinstein, C.L.; Fischer, A.; Yeo, C.J.; Hruban, R.H.; et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996, 271, 350–353.
[74]
McLeod, H.L.; Murray, G.I. Tumour markers of prognosis in colorectal cancer. Br. J. Cancer 1999, 79, 191–203.
[75]
Klump, B.; Nehls, O.; Okech, T.; Hsieh, C.J.; Gaco, V.; Gittinger, F.S.; Sarbia, M.; Borchard, F.; Greschniok, A.; Gruenagel, H.H.; et al. Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature. Int. J. Colorectal. Dis. 2004, 19, 23–42.
[76]
Anwar, S.; Frayling, I.M.; Scott, N.A.; Carlson, G.L. Systematic review of genetic influences on the prognosis of colorectal cancer. Br. J. Surg. 2004, 91, 1275–1291.
[77]
Bosari, S.; Viale, G. The clinical significance of p53 aberrations in human tumours. Virchows Arch. 1995, 427, 229–241.
[78]
Manne, U.; Myers, R.B.; Moron, C.; Poczatek, R.B.; Dillard, S.; Weiss, H.; Brown, D.; Srivastava, S.; Grizzle, W.E. Prognostic significance of Bcl-2 expression and p53 nuclear accumulation in colorectal adenocarcinoma. Int. J. Cancer 1997, 74, 346–358.
[79]
Munro, A.J.; Lain, S.; Lane, D.P. P53 abnormalities and outcomes in colorectal cancer: A systematic review. Br. J. Cancer 2005, 92, 434–444.
[80]
Iacopetta, B.; Russo, A.; Bazan, V.; Dardanoni, G.; Gebbia, N.; Soussi, T.; Kerr, D.; Elsaleh, H.; Soong, R.; Kandioler, D.; et al. Functional categories of TP53 mutation in colorectal cancer: Results of an international collaborative study. Ann. Oncol. 2006, 17, 842–847.
[81]
Takayama, T.; Katsuki, S.; Takahashi, Y.; Ohi, M.; Nojiri, S.; Sakamaki, S.; Kato, J.; Kogawa, K.; Miyake, H.; Niitsu, Y. Aberrant crypt foci of the colon as precursors of adenoma and cancer. N. Engl. J. Med. 1998, 339, 1277–1284.
[82]
Gnanasampanthan, G.; Elsaleh, H.; McCaul, K.; Iacopetta, B. Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer. J. Pathol. 2001, 195, 543–548.
[83]
Andreyev, H.J.; Norman, A.R.; Cunningham, D.; Oates, J.R.; Clarke, P.A. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J. Nat. Cancer Inst. 1998, 90, 675–684.
[84]
Andreyev, H.J.; Norman, A.R.; Cunningham, D.; Oates, J.; Dix, B.R.; Iacopetta, B.J.; Young, J.; Walsh, T.; Ward, R.; Hawkins, N.; et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br. J. Cancer 2001, 85, 692–696.
[85]
Belly, R.T.; Rosenblatt, J.D.; Steinmann, M.; Toner, J.; Sun, J.; Shehadi, J.; Peacock, J.L.; Raubertas, R.F.; Jani, N.; Ryan, C.K. Detection of mutated K12-ras in histologically negative lymph nodes as an indicator of poor prognosis in stage II colorectal cancer. Clin. Colorectal. Cancer 2001, 1, 110–116.
[86]
Ahnen, D.J.; Feigl, P.; Quan, G.; Fenoglio-Preiser, C.; Lovato, L.C.; Bunn, P.A., Jr.; Stemmerman, G.; Wells, J.D.; Macdonald, J.S.; Meyskens, F.L., Jr. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: A Southwest Oncology Group study. Cancer Res. 1998, 58, 1149–1158.
[87]
Ogino, S.; Meyerhardt, J.A.; Irahara, N.; Niedzwiecki, D.; Hollis, D.; Saltz, L.B.; Mayer, R.J.; Schaefer, P.; Whittom, R.; Hantel, A.; et al. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin. Cancer Res. 2009, 15, 7322–7329.
[88]
Roth, A.D.; Tejpar, S.; Delorenzi, M.; Yan, P.; Fiocca, R.; Klingbiel, D.; Dietrich, D.; Biesmans, B.; Bodoky, G.; Barone, C.; et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J. Clin. Oncol. 2010, 28, 466–474.
[89]
Karapetis, C.S.; Khambata-Ford, S.; Jonker, D.J.; O'Callaghan, C.J.; Tu, D.; Tebbutt, N.C.; Simes, R.J.; Chalchal, H.; Shapiro, J.D.; Robitaille, S.; et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 2008, 359, 1757–1765.
[90]
Bouzourene, H.; Gervaz, P.; Cerottini, J.P.; Benhattar, J.; Chaubert, P.; Saraga, E.; Pampallona, S.; Bosman, F.T.; Givel, J.C. p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer. Eur. J. Cancer 2000, 36, 1008–1015.
[91]
Tortola, S.; Marcuello, E.; Gonzalez, I.; Reyes, G.; Arribas, R.; Aiza, G.; Sancho, F.J.; Peinado, M.A.; Capella, G. p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer. J. Clin. Oncol. 1999, 17, 1375–1381.
[92]
Westra, J.L.; Schaapveld, M.; Hollema, H.; de Boer, J.P.; Kraak, M.M.; de Jong, D.; ter Elst, A.; Mulder, N.H.; Buys, C.H.; Hofstra, R.M.; et al. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J. Clin. Oncol. 2005, 23, 5635–5643.
[93]
Zauber, N.P.; Wang, C.; Lee, P.S.; Redondo, T.C.; Bishop, D.T.; Goel, A. Ki-ras gene mutations, LOH of the APC and DCC genes, and microsatellite instability in primary colorectal carcinoma are not associated with micrometastases in pericolonic lymph nodes or with patients' survival. J. Clin. Pathol. 2004, 57, 938–942.
[94]
Lievre, A.; Bachet, J.B.; Le Corre, D.; Boige, V.; Landi, B.; Emile, J.F.; Cote, J.F.; Tomasic, G.; Penna, C.; Ducreux, M.; et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66, 3992–3995.
[95]
De Roock, W.; Piessevaux, H.; De Schutter, J.; Janssens, M.; De Hertogh, G.; Personeni, N.; Biesmans, B.; Van Laethem, J.L.; Peeters, M.; Humblet, Y.; et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol. 2008, 19, 508–515.
[96]
Khambata-Ford, S.; Garrett, C.R.; Meropol, N.J.; Basik, M.; Harbison, C.T.; Wu, S.; Wong, T.W.; Huang, X.; Takimoto, C.H.; Godwin, A.K.; et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 2007, 25, 3230–3237.
[97]
Bokemeyer, C.; Bondarenko, I.; Makhson, A.; Hartmann, J.T.; Aparicio, J.; de Braud, F.; Donea, S.; Ludwig, H.; Schuch, G.; Stroh, C.; et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 2009, 27, 663–671.
[98]
Van Cutsem, E.; Kohne, C.H.; Hitre, E.; Zaluski, J.; Chang Chien, C.R.; Makhson, A.; D'Haens, G.; Pinter, T.; Lim, R.; Bodoky, G.; et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 2009, 360, 1408–1417.
[99]
Amado, R.G.; Wolf, M.; Peeters, M.; Van Cutsem, E.; Siena, S.; Freeman, D.J.; Juan, T.; Sikorski, R.; Suggs, S.; Radinsky, R.; et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 2008, 26, 1626–1634.
[100]
Fransen, K.; Klintenas, M.; Osterstrom, A.; Dimberg, J.; Monstein, H.J.; Soderkvist, P. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis 2004, 25, 527–533.
[101]
Siena, S.; Sartore-Bianchi, A.; Di Nicolantonio, F.; Balfour, J.; Bardelli, A. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J. Nat. Cancer Inst. 2009, 101, 1308–1324.
[102]
Tol, J.; Nagtegaal, I.D.; Punt, C.J. BRAF mutation in metastatic colorectal cancer. N. Engl. J. Med. 2009, 361, 98–99.
[103]
Galon, J.; Fridman, W.H.; Pages, F. The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res. 2007, 67, 1883–1886.
[104]
Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867.
[105]
Dunn, G.P.; Old, L.J.; Schreiber, R.D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 2004, 22, 329–360.
[106]
Jass, J.R.; Love, S.B.; Northover, J.M. A new prognostic classification of rectal cancer. Lancet 1987, 1, 1303–1306.
[107]
Naito, Y.; Saito, K.; Shiiba, K.; Ohuchi, A.; Saigenji, K.; Nagura, H.; Ohtani, H. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998, 58, 3491–3494.
[108]
Baeten, C.I.; Castermans, K.; Hillen, H.F.; Griffioen, A.W. Proliferating endothelial cells and leukocyte infiltration as prognostic markers in colorectal cancer. Clin. Gastroenterol. Hepatol. 2006, 4, 1351–1357.
[109]
Chiba, T.; Ohtani, H.; Mizoi, T.; Naito, Y.; Sato, E.; Nagura, H.; Ohuchi, A.; Ohuchi, K.; Shiiba, K.; Kurokawa, Y.; et al. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: Possible association with suppression of micrometastasis. Br. J. Cancer 2004, 91, 1711–1717.
[110]
Correale, P.; Rotundo, M.S.; Del Vecchio, M.T.; Remondo, C.; Migali, C.; Ginanneschi, C.; Tsang, K.Y.; Licchetta, A.; Mannucci, S.; Loiacono, L.; et al. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J. Immunother 2010, 33, 435–441.
[111]
Deschoolmeester, V.; Baay, M.; Van Marck, E.; Weyler, J.; Vermeulen, P.; Lardon, F.; Vermorken, J.B. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol. 2010, 11, 19.
[112]
Diederichsen, A.C.; Hjelmborg, J.B.; Christensen, P.B.; Zeuthen, J.; Fenger, C. Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol. Immunother 2003, 52, 423–428.
[113]
Frey, D.M.; Droeser, R.A.; Viehl, C.T.; Zlobec, I.; Lugli, A.; Zingg, U.; Oertli, D.; Kettelhack, C.; Terracciano, L.; Tornillo, L. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int. J. Cancer 2010, 126, 2635–2643.
[114]
Funada, Y.; Noguchi, T.; Kikuchi, R.; Takeno, S.; Uchida, Y.; Gabbert, H.E. Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol. Rep. 2003, 10, 309–313.
[115]
Galon, J.; Costes, A.; Sanchez-Cabo, F.; Kirilovsky, A.; Mlecnik, B.; Lagorce-Pages, C.; Tosolini, M.; Camus, M.; Berger, A.; Wind, P.; et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006, 313, 1960–1964.
[116]
Guidoboni, M.; Gafa, R.; Viel, A.; Doglioni, C.; Russo, A.; Santini, A.; Del Tin, L.; Macri, E.; Lanza, G.; Boiocchi, M.; et al. Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am. J. Pathol. 2001, 159, 297–304.
[117]
Laghi, L.; Bianchi, P.; Miranda, E.; Balladore, E.; Pacetti, V.; Grizzi, F.; Allavena, P.; Torri, V.; Repici, A.; Santoro, A.; et al. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol. 2009, 10, 877–884.
[118]
Lee, W.S.; Park, S.; Lee, W.Y.; Yun, S.H.; Chun, H.K. Clinical impact of tumor-infiltrating lymphocytes for survival in stage II colon cancer. Cancer 2010, 116, 5188–5199.
[119]
Menon, A.G.; Janssen-van Rhijn, C.M.; Morreau, H.; Putter, H.; Tollenaar, R.A.; van de Velde, C.J.; Fleuren, G.J.; Kuppen, P.J. Immune system and prognosis in colorectal cancer: A detailed immunohistochemical analysis. Lab. Invest. 2004, 84, 493–501.
[120]
Oberg, A.; Samii, S.; Stenling, R.; Lindmark, G. Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors. Int. J. Colorectal. Dis. 2002, 17, 25–29.
[121]
Pages, F.; Berger, A.; Camus, M.; Sanchez-Cabo, F.; Costes, A.; Molidor, R.; Mlecnik, B.; Kirilovsky, A.; Nilsson, M.; Damotte, D.; et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 2005, 353, 2654–2666.
[122]
Pages, F.; Kirilovsky, A.; Mlecnik, B.; Asslaber, M.; Tosolini, M.; Bindea, G.; Lagorce, C.; Wind, P.; Marliot, F.; Bruneval, P.; et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J. Clin. Oncol. 2009, 27, 5944–5951.
[123]
Petty, J.K.; He, K.; Corless, C.L.; Vetto, J.T.; Weinberg, A.D. Survival in human colorectal cancer correlates with expression of the T-cell costimulatory molecule OX-40 (CD134). Am. J. Surg. 2002, 183, 512–518.
[124]
Prall, F.; Duhrkop, T.; Weirich, V.; Ostwald, C.; Lenz, P.; Nizze, H.; Barten, M. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum. Pathol. 2004, 35, 808–816.
[125]
Salama, P.; Phillips, M.; Grieu, F.; Morris, M.; Zeps, N.; Joseph, D.; Platell, C.; Iacopetta, B. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J. Clin. Oncol. 2009, 27, 186–192.
[126]
Sinicrope, F.A.; Rego, R.L.; Ansell, S.M.; Knutson, K.L.; Foster, N.R.; Sargent, D.J. Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 2009, 137, 1270–1279.
[127]
Suzuki, H.; Chikazawa, N.; Tasaka, T.; Wada, J.; Yamasaki, A.; Kitaura, Y.; Sozaki, M.; Tanaka, M.; Onishi, H.; Morisaki, T.; et al. Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol. Immunother 2010, 59, 653–661.
[128]
Zlobec, I.; Baker, K.; Terracciano, L.; Peter, S.; Degen, L.; Beglinger, C.; Lugli, A. Two-marker protein profile predicts poor prognosis in patients with early rectal cancer. Br. J. Cancer 2008, 99, 1712–1717.
[129]
Zlobec, I.; Minoo, P.; Baumhoer, D.; Baker, K.; Terracciano, L.; Jass, J.R.; Lugli, A. Multimarker phenotype predicts adverse survival in patients with lymph node-negative colorectal cancer. Cancer 2008, 112, 495–502.
[130]
Mlecnik, B.; Tosolini, M.; Kirilovsky, A.; Berger, A.; Bindea, G.; Meatchi, T.; Bruneval, P.; Trajanoski, Z.; Fridman, W.H.; Pages, F.; et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J. Clin. Oncol. 2011, 29, 610–618.
[131]
Ogino, S.; Kawasaki, T.; Nosho, K.; Ohnishi, M.; Suemoto, Y.; Kirkner, G.J.; Fuchs, C.S. LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int. J. Cancer 2008, 122, 2767–2773.
[132]
Ogino, S.; Nosho, K.; Kirkner, G.J.; Kawasaki, T.; Chan, A.T.; Schernhammer, E.S.; Giovannucci, E.L.; Fuchs, C.S. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J. Nat. Cancer Inst. 2008, 100, 1734–1738.
[133]
Tougeron, D.; Fauquembergue, E.; Rouquette, A.; Le Pessot, F.; Sesboue, R.; Laurent, M.; Berthet, P.; Mauillon, J.; Di Fiore, F.; Sabourin, J.C.; et al. Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod. Pathol. 2009, 22, 1186–1195.
[134]
Michel, S.; Benner, A.; Tariverdian, M.; Wentzensen, N.; Hoefler, P.; Pommerencke, T.; Grabe, N.; von Knebel Doeberitz, M.; Kloor, M. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br. J. Cancer 2008, 99, 1867–1873.
[135]
Schwitalle, Y.; Kloor, M.; Eiermann, S.; Linnebacher, M.; Kienle, P.; Knaebel, H.P.; Tariverdian, M.; Benner, A.; von Knebel Doeberitz, M. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 2008, 134, 988–997.
[136]
Nosho, K.; Baba, Y.; Tanaka, N.; Shima, K.; Hayashi, M.; Meyerhardt, J.A.; Giovannucci, E.; Dranoff, G.; Fuchs, C.S.; Ogino, S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J. Pathol. 2010, 222, 350–366.
[137]
Weigelt, B.; Peterse, J.L.; van't Veer, L.J. Breast cancer metastasis: Markers and models. Nat. Rev. Cancer 2005, 5, 591–602.
[138]
Chambers, A.F.; Groom, A.C.; MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2002, 2, 563–572.
[139]
Woodhouse, E.C.; Chuaqui, R.F.; Liotta, L.A. General mechanisms of metastasis. Cancer 1997, 80 Suppl.8, 1529–1537.
[140]
Mehes, G.; Witt, A.; Kubista, E.; Ambros, P.F. Circulating breast cancer cells are frequently apoptotic. Am. J. Pathol. 2001, 159, 17–20.
[141]
Polyak, K.; Weinberg, R.A. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat. Rev. Cancer 2009, 9, 265–273.
[142]
Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2, 442–454.
[143]
Raymond, W.A.; Leong, A.S. Vimentin—A new prognostic parameter in breast carcinoma? J. Pathol. 1989, 158, 107–114.
[144]
Ngan, C.Y.; Yamamoto, H.; Seshimo, I.; Tsujino, T.; Man-i, M.; Ikeda, J.I.; Konishi, K.; Takemasa, I.; Ikeda, M.; Sekimoto, M.; et al. Quantitative evaluation of vimentin expression in tumour stroma of colorectal cancer. Br. J. Cancer 2007, 96, 986–992.
[145]
Dorudi, S.; Sheffield, J.P.; Poulsom, R.; Northover, J.M.; Hart, I.R. E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. Am. J. Pathol. 1993, 142, 981–986.
[146]
Kowalski, P.J.; Rubin, M.A.; Kleer, C.G. E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res. 2003, 5, R217–R222.
[147]
Peinado, H.; Olmeda, D.; Cano, A. Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat. Rev. Cancer 2007, 7, 415–428.
[148]
Chan, A.O.; Chu, K.M.; Lam, S.K.; Wong, B.C.; Kwok, K.F.; Law, S.; Ko, S.; Hui, W.M.; Yueng, Y.H.; Wong, J. Soluble E-cadherin is an independent pretherapeutic factor for long-term survival in gastric cancer. J. Clin. Oncol. 2003, 21, 2288–2293.
[149]
Gould Rothberg, B.E.; Bracken, M.B. E-cadherin immunohistochemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: A systematic review and meta-analysis. Breast Cancer Res. Treat. 2006, 100, 139–148.
[150]
Becker, K.F.; Atkinson, M.J.; Reich, U.; Becker, I.; Nekarda, H.; Siewert, J.R.; Hofler, H. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res. 1994, 54, 3845–3852.
[151]
Berx, G.; Cleton-Jansen, A.M.; Nollet, F.; de Leeuw, W.J.; van de Vijver, M.; Cornelisse, C.; van Roy, F. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J. 1995, 14, 6107–6115.
[152]
Graff, J.R.; Herman, J.G.; Lapidus, R.G.; Chopra, H.; Xu, R.; Jarrard, D.F.; Isaacs, W.B.; Pitha, P.M.; Davidson, N.E.; Baylin, S.B. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 1995, 55, 5195–5199.
[153]
Yoshiura, K.; Kanai, Y.; Ochiai, A.; Shimoyama, Y.; Sugimura, T.; Hirohashi, S. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc. Natl. Acad. Sci. USA 1995, 92, 7416–7419.
[154]
Miettinen, P.J.; Ebner, R.; Lopez, A.R.; Derynck, R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: Involvement of type I receptors. J. Cell. Biol. 1994, 127, 2021–2036.
[155]
Bierie, B.; Moses, H.L. Tumour microenvironment: TGFbeta: The molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 2006, 6, 506–520.
[156]
Blobe, G.C.; Schiemann, W.P.; Lodish, H.F. Role of transforming growth factor beta in human disease. N. Engl. J. Med. 2000, 342, 1350–1358.
[157]
Miyaki, M.; Iijima, T.; Konishi, M.; Sakai, K.; Ishii, A.; Yasuno, M.; Hishima, T.; Koike, M.; Shitara, N.; Iwama, T.; et al. Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene 1999, 18, 3098–3103.
[158]
Pino, M.S.; Kikuchi, H.; Zeng, M.; Herraiz, M.T.; Sperduti, I.; Berger, D.; Park, D.Y.; Iafrate, A.J.; Zukerberg, L.R.; Chung, D.C. Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 2010, 138, 1406–1417.
[159]
Moustakas, A.; Heldin, C.H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007, 98, 1512–1520.
[160]
Brabletz, T.; Jung, A.; Reu, S.; Porzner, M.; Hlubek, F.; Kunz-Schughart, L.A.; 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.
[161]
Batlle, E.; Sancho, E.; Franci, C.; Dominguez, D.; Monfar, M.; Baulida, J.; Garcia De Herreros, A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat. Cell. Biol. 2000, 2, 84–89.
[162]
Comijn, J.; Berx, G.; Vermassen, P.; Verschueren, K.; van Grunsven, L.; Bruyneel, E.; Mareel, M.; Huylebroeck, D.; van Roy, F. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 2001, 7, 1267–1278.
[163]
Eger, A.; Aigner, K.; Sonderegger, S.; Dampier, B.; Oehler, S.; Schreiber, M.; Berx, G.; Cano, A.; Beug, H.; Foisner, R. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 2005, 24, 2375–2385.
[164]
Hajra, K.M.; Chen, D.Y.; Fearon, E.R. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002, 62, 1613–1618.
[165]
Yang, J.; Mani, S.A.; Donaher, J.L.; Ramaswamy, S.; Itzykson, R.A.; Come, C.; Savagner, P.; Gitelman, I.; Richardson, A.; Weinberg, R.A. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117, 927–939.
[166]
Chen, Z.F.; Behringer, R.R. Twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 1995, 9, 686–699.
[167]
Hebrok, M.; Wertz, K.; Fuchtbauer, E.M. M-twist is an inhibitor of muscle differentiation. Dev. Biol. 1994, 165, 537–544.
[168]
Maestro, R.; Dei Tos, A.P.; Hamamori, Y.; Krasnokutsky, S.; Sartorelli, V.; Kedes, L.; Doglioni, C.; Beach, D.H.; Hannon, G.J. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999, 13, 2207–2217.
[169]
Rosivatz, E.; Becker, I.; Specht, K.; Fricke, E.; Luber, B.; Busch, R.; Hofler, H.; Becker, K.F. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am. J. Pathol. 2002, 161, 1881–1891.
[170]
Valsesia-Wittmann, S.; Magdeleine, M.; Dupasquier, S.; Garin, E.; Jallas, A.C.; Combaret, V.; Krause, A.; Leissner, P.; Puisieux, A. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 2004, 6, 625–630.
[171]
Elias, M.C.; Tozer, K.R.; Silber, J.R.; Mikheeva, S.; Deng, M.; Morrison, R.S.; Manning, T.C.; Silbergeld, D.L.; Glackin, C.A.; Reh, T.A.; et al. TWIST is expressed in human gliomas and promotes invasion. Neoplasia 2005, 7, 824–837.
[172]
Yuen, H.F.; Chan, Y.P.; Wong, M.L.; Kwok, W.K.; Chan, K.K.; Lee, P.Y.; Srivastava, G.; Law, S.Y.; Wong, Y.C.; Wang, X.; et al. Upregulation of Twist in oesophageal squamous cell carcinoma is associated with neoplastic transformation and distant metastasis. J. Clin. Pathol. 2007, 60, 510–514.
[173]
Ohuchida, K.; Mizumoto, K.; Ohhashi, S.; Yamaguchi, H.; Konomi, H.; Nagai, E.; Yamaguchi, K.; Tsuneyoshi, M.; Tanaka, M. Twist, a novel oncogene, is upregulated in pancreatic cancer: clinical implication of Twist expression in pancreatic juice. Int. J. Cancer 2007, 120, 1634–1640.
[174]
Hoek, K.; Rimm, D.L.; Williams, K.R.; Zhao, H.; Ariyan, S.; Lin, A.; Kluger, H.M.; Berger, A.J.; Cheng, E.; Trombetta, E.S.; et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res. 2004, 64, 5270–5282.
[175]
Hosono, S.; Kajiyama, H.; Terauchi, M.; Shibata, K.; Ino, K.; Nawa, A.; Kikkawa, F. Expression of Twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients. Br. J. Cancer 2007, 96, 314–320.
[176]
Kyo, S.; Sakaguchi, J.; Ohno, S.; Mizumoto, Y.; Maida, Y.; Hashimoto, M.; Nakamura, M.; Takakura, M.; Nakajima, M.; Masutomi, K.; et al. High Twist expression is involved in infiltrative endometrial cancer and affects patient survival. Hum. Pathol. 2006, 37, 431–438.
[177]
Lee, T.K.; Poon, R.T.; Yuen, A.P.; Ling, M.T.; Kwok, W.K.; Wang, X.H.; Wong, Y.C.; Guan, X.Y.; Man, K.; Chau, K.L.; et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin. Cancer Res. 2006, 12, 5369–5376.
[178]
Shibata, K.; Kajiyama, H.; Ino, K.; Terauchi, M.; Yamamoto, E.; Nawa, A.; Nomura, S.; Kikkawa, F. Twist expression in patients with cervical cancer is associated with poor disease outcome. Ann. Oncol. 2008, 19, 81–85.
[179]
Watanabe, O.; Imamura, H.; Shimizu, T.; Kinoshita, J.; Okabe, T.; Hirano, A.; Yoshimatsu, K.; Konno, S.; Aiba, M.; Ogawa, K. Expression of twist and wnt in human breast cancer. Anticancer Res. 2004, 24, 3851–3856.
[180]
Zhang, Y.Q.; Guo, X.Y.; Han, S.; Chen, Y.; Ge, F.L.; Bai, F.H.; Ren, S.S.; Wei, X.F.; Ding, J.; Fan, D.M. Expression and significance of TWIST basic helix-loop-helix protein over-expression in gastric cancer. Pathology 2007, 39, 470–475.
[181]
Valdes-Mora, F.; Gomez del Pulgar, T.; Bandres, E.; Cejas, P.; Ramirez de Molina, A.; Perez-Palacios, R.; Gallego-Ortega, D.; Garcia-Cabezas, M.A.; Casado, E.; Larrauri, J.; et al. TWIST1 overexpression is associated with nodal invasion and male sex in primary colorectal cancer. Ann. Surg. Oncol. 2009, 16, 78–87.
[182]
Garber, K. Epithelial-to-mesenchymal transition is important to metastasis, but questions remain. J. Nat. Cancer Inst. 2008, 100, 232–239.
[183]
Voulgari, A.; Pintzas, A. Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim. Biophys. Acta. 2009, 1796, 75–90.
[184]
Brabletz, T.; Jung, A.; Spaderna, S.; Hlubek, F.; Kirchner, T. Opinion: Migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat. Rev. Cancer 2005, 5, 744–749.
[185]
Rees, J.R.; Onwuegbusi, B.A.; Save, V.E.; Alderson, D.; Fitzgerald, R.C. In vivo and in vitro evidence for transforming growth factor-beta1-mediated epithelial to mesenchymal transition in esophageal adenocarcinoma. Cancer Res. 2006, 66, 9583–9590.
[186]
Yang, M.H.; Wu, M.Z.; Chiou, S.H.; Chen, P.M.; Chang, S.Y.; Liu, C.J.; Teng, S.C.; Wu, K.J. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat. Cell. Biol. 2008, 10, 295–305.
