Top

International Journal of Colorectal Disease

Published in:

01-02-2007 | Original Article

Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis

Authors: Cinzia Azzoni, Lorena Bottarelli, Nicoletta Campanini, Gabriella Di Cola, Giovanni Bader, Antonio Mazzeo, Carlo Salvemini, Silvia Morari, Davide Di Mauro, Enrico Donadei, Luigi Roncoroni, Cesare Bordi, Leopoldo Sarli

Published in: International Journal of Colorectal Disease | Issue 2/2007

Abstract

Background and aims

Colorectal cancer (CRC) ranks as the fourth most frequently diagnosed cancer worldwide. CRCs that arise proximally or distally to the splenic flexure show differences in epidemiologic incidence, morphology, and molecular alterations, suggesting the existence of two categories of CRC based on the site of origin. The aim of the present work is to investigate the histological and molecular differences between CRCs located proximally and distally to the splenic flexure, and their potential involvement in tumor prognosis and therapeutic strategies.

Methods

We evaluated 120 patients affected by sporadic CRC for clinicopathologic features, microsatellite instability (MSI), loss of heterozygosity (LOH) of chromosomes 18q, 8p, and 4p; they were also investigated for hMlh1, hMsh2, Fhit, p27, and Cox-2 immunostaining.

Results

The mucinous histotype was more frequent in the proximal than in the distal CRCs (p<0.004). The frequency of MSI phenotype was higher in proximal than in distal tumors (p<0.001); moreover, reduced or absent hMlh1, Fhit, p27 immunohistochemical expressions were more frequent in proximal than in distal tumors (p<0.001 and 0.01 for p27). In contrast, the frequency of LOH in 18q was higher in distal than in proximal tumors (p=0.002). No significant differences were observed between proximal and distal tumors in the frequency of LOH in 8p and altered expression of hMsh2 and p53 protein.

Conclusion

These different features may reflect different genetic pathways of carcinogenesis and support the hypothesis of a different mechanism of cancer development between the proximal and the distal colon, with potential implications in the therapeutic approach.

Society AC, http://www.cancer.org/docroot/NWS/content/NWS_1_1x_ACS_Updates_Colorectal_Screening_Guidelines_.asp (2003)

Berrino F, Capocaccia R, Estève J (1999) Survival of cancer patients in Europe: the EUROCARE-2 study. In: IARC Scientific Publications. International Agency for Research on Cancer, Lyon

Bufill JA (1990) Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 113:779–788PubMed

Ponz de Leon M, Sacchetti C, Sassatelli R, Zanghieri G, Roncucci L, Scalmati A (1990) Evidence for the existence of different types of large bowel tumor: suggestions from the clinical data of a population-based registry. J Surg Oncol 44:35–43PubMed

Pocard M, Salmon RJ, Muleris M, Remvikos Y, Bara J, Dutrillaux B, Poupon MF (1995) Two colons–two cancers? Proximal or distal adenocarcinoma: arguments for a different carcinogenesis. Bull Cancer 82:10–21PubMed

Distler P, Holt PR (1997) Are right- and left-sided colon neoplasms distinct tumors? Dig Dis 15:302–311PubMedCrossRef

Bonithon-Kopp C, Benhamiche AM (1999) Are there several colorectal cancers? Epidemiological data. Eur J Cancer Prev 8:S3–S12PubMedCrossRef

Lindblom A (2001) Different mechanisms in the tumorigenesis of proximal and distal colon cancers. Curr Opin Oncol 13:63–69PubMedCrossRef

Iacopetta B (2002) Are there two sides to colorectal cancer? Int J Cancer 101:403–408PubMedCrossRef

10.

Cucino C, Buchner A, Sonnenberg (2002) Continued rightward shift of colorectal cancer. Dis Colon Rectum 45:1035–1040PubMedCrossRef

11.

Gonzalez EC, Roetzheim RG, Ferrante JM, Campbell R (2001) Predictors of proximal vs. distal colorectal cancers. Dis Colon Rectum 44:251–258PubMedCrossRef

12.

Koketsu S, Watanabe T, Tada T, Kanazawa T, Ueda E, Nagawa H (2003) Sporadic colorectal cancer in elderly people. Hepatogastroenterology 50:1749–1752PubMed

13.

Gannon CJ, Malone DL, Royal RE, Schreiber M, Bass BL, Napolitano LM (2002) Advanced proximal colon cancer. Surg Endosc 16:446–449PubMedCrossRef

14.

Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386:623–627PubMedCrossRef

15.

Martin L, Assem M, Piard F (1999) Are there several types of colorectal carcinomas? Correlations with genetic data. Eur J Cancer Prev 8:S13–S20 (Dec)PubMedCrossRef

16.

Haydon AM, J.R. J (2002) Emerging pathways in colorectal-cancer development. Lancet Oncol 3:83–88PubMedCrossRef

17.

Arribas R, Ribas M, Risques RA, Masramon L, Tortola S, Marcuello E, Aiza G, Miro R, Capella G, Peinado MA (1999) Prospective assessment of allelic losses at 4p14-16 in colorectal cancer: two mutational patterns and a locus associated with poorer survival. Clin Cancer Res 5:3454–3459PubMed

18.

Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767PubMedCrossRef

19.

Tejpar S, Van Cutsem E (2002) Molecular and genetic defects in colorectal tumorigenesis. Best Pract Res Clin Gastroenterol 16:171–185PubMedCrossRef

20.

Halling KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ, Moon-Tasson L, Mahoney MR, Sargent DJ, O’Connell MJ, Witzig TE, Farr GHJ, Goldberg RM, Thibodeau SN (1999) Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 91:1295–1303PubMedCrossRef

21.

Modrich P (1991) Mechanisms and biological effects of mismatch repair. Annu Rev Genet 25:229–253PubMedCrossRef

22.

Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K (1997) Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA 94:13771–13776PubMedCrossRef

23.

Andachi H, Yashima K, Koda M, Kawaguchi K, Kitamura A, Hosoda A, Kishimoto Y, Shiota G, Ito H, Makino M, Kaibara N, Kavasaki H, Murawaki Y (2002) Reduced FHIT expression is associated with mismatch repair deficiency in human advanced colorectal carcinoma. Br J Cancer 87:441–445PubMedCrossRef

24.

Nephew KP, Huang TH (2003) Epigenetic gene silencing in cancer initiation and progression. Cancer Lett 190:125–133PubMedCrossRef

25.

Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M (1997) Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3:231–234PubMedCrossRef

26.

Sheehan KM, Sheahan K, O’Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, Murray FE (1999) The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 282:1254–1257PubMedCrossRef

27.

Morosetti R, Kawamata N, Gombart AF, Miller CW, Hatta Y, Hirama T, Said JW, Tomonaga M, Koeffler HP (1995) Alterations of the p27KIP1 gene in non-Hodgkin’s lymphomas and adult T-cell leukemia/lymphoma. Blood 86:1924–1930PubMed

28.

Spirin KS, Simpson JF, Takeuchi S, Kawamata N, Miller CW, Koeffler HP (1996) p27/Kip1 mutation found in breast cancer. Cancer Res 56:2400–2404PubMed

29.

Tenjo T, Toyoda M, Okuda J, Watanabe I, Yamamoto T, Tanaka K, Ohtani M, Nohara T, Kawasaki H, Tanigawa N (2000) Prognostic significance of p27(kip1) protein expression and spontaneous apoptosis in patients with colorectal adenocarcinomas. Oncology 58:45–51PubMedCrossRef

30.

Zhang H, Sun XF (2001) Loss of p27 expression predicts poor prognosis in patients with Dukes’ B stage or proximal colorectal cancer. Int J Oncol 19:49–52PubMed

31.

Manne U, Jhala NC, Jones J, Weiss HL, Chatla C, Meleth S, Suarez-Cuervo C, Grizzle WE (2004) Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage. Clin Cancer Res 10:1743–1752PubMedCrossRef

32.

Sano H, Kawahito Y, Wilder RL, Hashiramoto A, Mukai S, Asai K, Kimura S, Kato H, Kondo M, Hla T (1995) Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55:3785–3789PubMed

33.

Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimaki A (1998) Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 58:4997–5001PubMed

34.

Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT (2000) COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89:2637–2645PubMedCrossRef

35.

Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hla T (2001) Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563–18569PubMedCrossRef

36.

Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716PubMedCrossRef

37.

Tsujii M, Kawano S, DuBois RN (1997) Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 94:3336–3340PubMedCrossRef

38.

Tsujii M, DuBois RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83:493–501PubMedCrossRef

39.

Jass JR, Sobin LH (1989). Springer, Berlin Heidelberg New York

40.

Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP (2000) American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 88:1739–1757PubMedCrossRef

41.

Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH et al (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352–358PubMedCrossRef

42.

Pahlman L (1998) Preoperative treatment of rectal cancer. In: Bleiberg H, Rougier P, Wilke H-J (eds) Management of colorectal cancer. Martin Dunitz, London, pp 156–166

43.

Dent OF, Chapuis PH, Bokey EL, Newland RC (2001) Methodology and reporting in studies of local recurrence after curative excision of the rectum for cancer. Br J Surg 88:1476–1480PubMedCrossRef

44.

Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, Kinzler KW, Vogelstein B, Hamilton SR (1994) Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331:213–221PubMedCrossRef

45.

Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819PubMedCrossRef

46.

Sarli L, Bottarelli L, Bader G, Iusco D, Pizzi S, Costi R, D’Adda T, Bertolani M, Roncoroni L, Bordi C (2004) Association between recurrence of sporadic colorectal cancer, high level of microsatellite instability, and loss of heterozygosity at chromosome 18q. Dis Colon Rectum 47:1467–1482PubMed

47.

Beckmann MW, Picard F, An HX, van Roeyen CR, Dominik SI, Mosny DS, Schnurch HG, Bender HG, Niederacher D (1996) Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br J Cancer 73:1220–1226PubMed

48.

Mueller JD, Haegle N, Keller G, Mueller E, Saretzky G, Bethke B, Stolte M, Hofler H (1998) Loss of heterozygosity and microsatellite instability in de novo versus ex-adenoma carcinomas of the colorectum. Am J Pathol 153:1977–1984PubMed

49.

Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, McDonnell SK, Schaid DJ, Vockley CW, Michels VV, Farr GHJ, O’Connell MJ (1998) Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 58:1713–1718PubMed

50.

Ward R, Meagher A, Tomlinson I, O’Connor T, Norrie M, Wu R, Hawkins N (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:821–829PubMedCrossRef

51.

Peiro´ G, Diebold J, Lohse P, Ruebsamen H, Lohse P, Baretton GB, Lohrs U (2002) Microsatellite Instability, Loss of Heterozygosity, and Loss of hMLH1 and hMSH2 Protein Expression in Endometrial Carcinoma. Hum Pathol 33:347–354PubMedCrossRef

52.

Sarli L, Bottarelli L, Azzoni C, Campanini N, Di Cola G, Bader G, Iusco D, Salvemini C, Caruso G, Donadei E, Pizzi S, D’Adda T, Renato C, Roncoroni L, Bordi C (2004) Abnormal Fhit protein expression and high frequency of microsatellite instability in sporadic colorectal cancer. Eur J Cancer 40:1581–1588PubMedCrossRef

53.

Tsihlias J, Kapusta L, Slingerland J (1999) The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med 50:401–423PubMedCrossRef

54.

Boland GP, Butt IS, Prasad R, Knox WF, Bundred NJ (2004) COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ. Br J Cancer 90:423–429PubMedCrossRef

55.

Du W, Mah JT, Lee J, Sankila R, Sankaranarayanan R, Chia KS (2004) Incidence and survival of mucinous adenocarcinoma of the colorectum: a population-based study from an Asian country. Dis Colon Rectum 47:78–85PubMedCrossRef

56.

Green JB, Timmcke AE, Mitchell WT, Hicks TC, Gathright JBJ, Ray JE (1993) Mucinous carcinoma–just another colon cancer? Dis Colon Rectum 36:49–54PubMedCrossRef

57.

Wu CS, Tung SY, Chen PC, Kuo YC (1996) Clinicopathological study of colorectal mucinous carcinoma in Taiwan: a multivariate analysis. J Gastroenterol Hepatol 11:77–81PubMed

58.

Lanza GJ, Gafa R, Dubini A, Maestri I, Cavazzini L (1995) Clinico-pathological features and biological characterization of mucoid colorectal carcinoma. Pathologica 87:631–639

59.

Symonds DA, Vickery AL (1976) Mucinous carcinoma of the colon and rectum. Cancer 37:1891–1900PubMedCrossRef

60.

Secco GB, Fardelli R, Campora E, Lapertosa G, Gentile R, Zoli S, Prior C (1994) Primary mucinous adenocarcinomas and signet-ring cell carcinomas of colon and rectum. Oncology 51:30–34PubMedCrossRef

61.

Fleshner P, Slater G, Aufses AHJ (1989) Age and sex distribution of patients with colorectal cancer. Dis Colon Rectum 32:107–111PubMed

62.

Lanza G, Matteuzzi M, Gafa R, Orvieto E, Maestri I, Santini A, del Senno L (1998) Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79:390–395PubMedCrossRef

63.

Mensink PB, Kolkman JJ, Van Baarlen J, Kleibeuker JH (2002) Change in anatomic distribution and incidence of colorectal carcinoma over a period of 15 years: clinical considerations. Dis Colon Rectum 45:1393–1396PubMedCrossRef

64.

Gomez D, Dalal Z, Raw E, Roberts C, Lyndon PJ (2004) Anatomical distribution of colorectal cancer over a 10 year period in a district general hospital: is there a true “rightward shift”? Postgrad Med J 80:667–669PubMedCrossRef

65.

Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561PubMedCrossRef

66.

Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nystrom-Lahti M, Pylkkanen L, Heimdal K, Andersen TI, Moller P, Rognum TO, et al (1993) Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 53:5849–5852PubMed

67.

Gafà R, Maestri I, Matteuzzi M, Santini A, Ferretti S, Cavazzini L, Lanza G (2000) Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer 89:2025–2037PubMedCrossRef

68.

Liu B, Nicolaides NC, Markowitz S, Willson JK, Parsons RE, Jen J, Papadopolous N, Peltomaki P, de la Chapelle A, Hamilton SR, et al (1995) Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9:48–55PubMedCrossRef

69.

Raut CP, Pawlik TM, Rodriguez-Bigas MA (2004) Clinicopathologic features in colorectal cancer patients with microsatellite instability. Mutat Res 568:275–282PubMed

70.

Mori S, Ogata Y, Shirouzu K (2004) Biological features of sporadic colorectal carcinoma with high-frequency microsatellite instability: special reference to tumor proliferation and apoptosis. Int J Clin Oncol 9:322–329PubMedCrossRef

71.

Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, Scheithauer BW (1999) p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154:313–323PubMed

72.

Nasir A, Kaiser HE, Boulware D, Hakam A, Zhao H, Yeatman T, Barthel J, Coppola D (2004) Cyclooxygenase-2 expression in right- and left-sided colon cancer: a rationale for optimization of cyclooxygenase-2 inhibitor therapy. Clin Colorectal Cancer 3:243–247PubMedCrossRef

73.

Catalano T, Curia MC, Aceto G, Verginelli F, Cascinu S, Cama A, Mariani-Costantini R, Teti D, Battista P (2005) Mutations in the p53 and Ki-ras genes, microsatellite instability and site of tumor origin in colorectal cancer. Oncol Rep 14:625–631PubMed

74.

Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N (2005) The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol 23:7518–7528PubMedCrossRef

75.

Lukish JR, Muro K, DeNobile J, Katz R, Williams J, Cruess DF, Drucker W, Kirsch I, Hamilton SR (1998) Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg 227:51–56PubMedCrossRef

76.

Martinez-Lopez E, Abad A, Font A, Monzo M, Ojanguren I, Pifarre A, Sanchez JJ, Martin C, Rosell R (1998) Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer. Gastroenterology 114:1180–1187PubMedCrossRef

77.

Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, Benson ABr, Hamilton SR (2001) Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344:1196–1206PubMedCrossRef

78.

McLeod HL, Murray GI (1999) Tumour markers of prognosis in colorectal cancer. Br J Cancer 79:191–203PubMed

79.

Kato M, Ito Y, Kobayashi S, Isono K (1996) Detection of DCC and Ki-ras gene alterations in colorectal carcinoma tissue as prognostic markers for liver metastatic recurrence. Cancer 77:1729–1735PubMed

80.

Jernvall P, Makinen MJ, Karttunen TJ, Makela J, Vihko P (1999) Loss of heterozygosity at 18q21 is indicative of recurrence and therefore poor prognosis in a subset of colorectal cancers. Br J Cancer 79:903–908PubMedCrossRef

81.

Laurie JA, Moertel CG, Fleming TR, Wieand HS, Leigh JE, Rubin J, McCormack GW, Gerstner JB, Krook JE, Malliard J, et al (1989) Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 7:1156–1447

82.

Diep CB, Thorstensen L, Meling GI, Skovlund E, Rognum TO, Lothe RA (2003) Genetic tumor markers with prognostic impact in Dukes’ stages B and C colorectal cancer patients. J Clin Oncol 21:820–829PubMedCrossRef

83.

Ikeda Y, Mori M, Koyanagi N, Minagawa S, Kondo N, Fujimaru R, Kojima Y, Kondo A, Sugimachi K (1998) Possibility of different cancer development between the proximal and distal colon: comparison of the distribution between adenomatous polyps and cancer. Hepatogastroenterology 45:1583–1586PubMed

84.

Barratt PL, Seymour MT, Stenning SP, Georgiades I, Walker C, Birbeck K, Quirke P, Study UAtcAX-raFI (2002) DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 360:1381–1391PubMedCrossRef

85.

Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B (2000) Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355:1745–1750PubMedCrossRef

86.

Wright CM, Dent OF, Barker M, Newland RC, Chapuis PH, Bokey EL, Young JP, Leggett BA, Jass JR, Macdonald GA (2000) Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg 87:1197–1202PubMedCrossRef

87.

Ahnen DJ, Feigl P, Quan G, Fenoglio-Preiser C, Lovato LC, Bunn PAJ, Stemmerman G, Wells JD, Macdonald JS, Meyskens FLJ (1998) Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res 58:1149–1158PubMed

Title: Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis
Authors: Cinzia Azzoni
Lorena Bottarelli
Nicoletta Campanini
Gabriella Di Cola
Giovanni Bader
Antonio Mazzeo
Carlo Salvemini
Silvia Morari
Davide Di Mauro
Enrico Donadei
Luigi Roncoroni
Cesare Bordi
Leopoldo Sarli
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: International Journal of Colorectal Disease / Issue 2/2007
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI: https://doi.org/10.1007/s00384-006-0093-x

At a glance: The STEP trials

Springer Medicine

Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis

Abstract

Background and aims

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background and aims

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2007

Effect of Flt3 ligand gene transfer in experimental pancreatic cancer

Colorectal cancer in a population with endemic Schistosoma mansoni: is this an at-risk population?

Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer

Diagnostic and surgical approaches in hilar cholangiocarcinoma

Contrast-enhanced ultrasonography to detect liver metastases

Prospective randomised trial comparing ileocaecal interposition and colon-J-pouch as rectal replacement after total mesorectal excision