Skip to main content

Advertisement

Log in

Molecular Prognostic Factors in Adenocarcinoma of the Esophagus and Gastroesophageal Junction

Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Objective

This review describes genetic and molecular changes related to adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) with emphasis on prognostic value and possibilities for targeted therapy in clinical setting.

Summary background data

Adenocarcinoma of the esophagus or GEJ is an aggressive disease with early lymphatic and hematogenous dissemination. Molecular pathology has revealed many molecular mechanisms of disease progression, which are related to prognosis. Some of these factors can be seen as prognostic factors per se. Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options.

Methods

A review of recent English literature (1990–October 2005) concerning esophageal adenocarcinoma was performed. This review focuses on genetic and molecular changes as prognosticators of adenocarcinoma of the esophagus and GEJ.

Results

A bewildering number of biomarkers have been described. Many genes and molecules have prognostic impact (cyclin D1, EGFR, Her-2/Neu, APC, TGF-β, Endoglin, CTGF, P53, Bcl-2, NF-κB, Cox-2, E-cadherin, β-catenin, uPA, MMP-1,3,7,9, TIMP, T h 1/T h 2 balance, CRP, PTHrP).

Conclusions

Adenocarcinomas of the esophagus and GEJ show multiple genetic alterations, which indicate that progression of cancer is a multistep complex process with many different alterations. Presumably, it is not one molecular factor that can predict the biological behavior of this cancer. The combination of diverse genetic alterations may better predict prognosis. In future, gene expression analysis with microarrays may reveal important prognostic information and the discovery of new genes and molecules associated with tumor progression and dissemination will enhance prognostication and offers adjuvant therapeutic options.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

FIG. 1.
FIG. 2.

Abbreviations

APC:

Adenomatous polyposis coli

bp:

Base pair

CAM:

Cell adhesion molecules

COX-2:

Cyclooxygenase-2

CRP:

C-reactive protein

CTGF:

Connective tissue growth factor

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

GEJ:

Gastroesophageal junction

GERD:

Gastroesophageal reflux disease

HGD:

High grade dysplasia

LOH:

Loss of heterozygosity

MMPs:

Matrix metalloproteinases

NF-κB:

Nuclear factor κ B

PCNA:

Proliferating cell nuclear antigen

PTHrP:

Parathyroid hormone-related peptide

Rb:

Retinoblastoma protein

TGF-α:

Transforming growth factor α

TGF-β:

Transforming growth factor β

TIMP:

Tissue inhibitor of metalloproteinases

uPA:

Urokinase-type plasminogen activator

VEGF:

Vascular endothelial growth factor

References

  1. Bollschweiler E, Wolfgarten E, Gutschow C, et al. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer 2001; 92:549–55

    PubMed  CAS  Google Scholar 

  2. Botterweck AA, Schouten LJ, Volovics A, et al. Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries. Int J Epidemiol 2000; 29:645–54

    PubMed  CAS  Google Scholar 

  3. Devesa SS, Blot WJ, Fraumeni JF, Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998; 83:2049–53

    PubMed  CAS  Google Scholar 

  4. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005; 97:142–6

    PubMed  Google Scholar 

  5. van Blankenstein M., Looman CW, Hop WC, et al. The incidence of adenocarcinoma and squamous cell carcinoma of the esophagus: Barrett’s esophagus makes a difference. Am J Gastroenterol 2005; 100:766–74

    PubMed  Google Scholar 

  6. Siewert JR, Stein HJ, Feith M, et al. Histologic tumor type is an independent prognostic parameter in esophageal cancer: lessons from more than 1,000 consecutive resections at a single center in the Western world. Ann Surg 2001; 234:360–7

    PubMed  CAS  Google Scholar 

  7. Rudiger SJ, Feith M, Werner M, et al. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 2000; 232:353–61

    Google Scholar 

  8. de Manzoni G., Pedrazzani C, Pasini F, et al. Pattern of recurrence after surgery in adenocarcinoma of the gastro-oesophageal junction. Eur J Surg Oncol 2003; 29:506–10

    PubMed  Google Scholar 

  9. Hulscher JB, van Sandick JW, Tijssen JG, et al. The recurrence pattern of esophageal carcinoma after transhiatal resection. J Am Coll Surg 2000; 191:143–8

    PubMed  CAS  Google Scholar 

  10. Mariette C, Balon JM, Piessen G, et al. Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease. Cancer 2003; 97:1616–23

    PubMed  Google Scholar 

  11. Dresner SM, Griffin SM. Pattern of recurrence following radical oesophagectomy with two-field lymphadenectomy. Br J Surg 2000; 87:1426–33

    PubMed  CAS  Google Scholar 

  12. Wayman J, Bennett MK, Raimes SA, et al. The pattern of recurrence of adenocarcinoma of the oesophago-gastric junction. Br J Cancer 2002; 86:1223–9

    PubMed  CAS  Google Scholar 

  13. Wu PC, Posner MC. The role of surgery in the management of oesophageal cancer. Lancet Oncol 2003; 4:481–8

    PubMed  Google Scholar 

  14. Stein HJ, Siewert JR. Improved prognosis of resected esophageal cancer. World J Surg 2004; 28:520–5

    PubMed  Google Scholar 

  15. Hulscher JB, Tijssen JG, Obertop H, et al. Transthoracic versus transhiatal resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg 2001; 72:306–13

    PubMed  CAS  Google Scholar 

  16. Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002; 347:1662–9

    PubMed  Google Scholar 

  17. TNM: Classification of malignant tumours. New-York: Wiley-Liss, 2002

    Google Scholar 

  18. American joint Committee on Cancer. AJCC cancer staging handbook. Philadelphia: Lippincott-Raven, 2002

    Google Scholar 

  19. de Manzoni G., Pedrazzani C, Verlato G, et al. Comparison of old and new TNM systems for nodal staging in adenocarcinoma of the gastro-oesophageal junction. Br J Surg 2004; 91:296–303

    PubMed  Google Scholar 

  20. Eloubeidi MA, Desmond R, Arguedas MR, et al. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 2002; 95:1434–43

    PubMed  Google Scholar 

  21. Lerut T, Coosemans W, Decker G, et al. Extracapsular lymph node involvement is a negative prognostic factor in T3 adenocarcinoma of the distal esophagus and gastroesophageal junction. J Thorac Cardiovasc Surg 2003; 126:1121–8

    PubMed  CAS  Google Scholar 

  22. Nigro JJ, Demeester SR, Hagen JA, et al. Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy. J Thorac Cardiovasc Surg 1999; 117:960–8

    PubMed  CAS  Google Scholar 

  23. Lagarde SM, ten Kate FJ, de Boer DJ, et al. Extracapsular lymph node involvement in node-positive patients with adenocarcinoma of the distal esophagus or gastroesophageal junction. Am J Surg Pathol 2006; 30:171–6

    PubMed  Google Scholar 

  24. Yasui W, Oue N, Aung PP, et al. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer 2005; 8:86–94

    PubMed  CAS  Google Scholar 

  25. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene 2005; 24:7443–54

    PubMed  CAS  Google Scholar 

  26. Haber DA, Fearon ER. The promise of cancer genetics. Lancet 1998; 351(Suppl 2):SII1–8

    PubMed  Google Scholar 

  27. Kountouras J, Boura P, Lygidakis NJ. New concepts of molecular biology for colon carcinogenesis. Hepatogastroenterology 2000; 47:1291–7

    PubMed  CAS  Google Scholar 

  28. Renan MJ. How many mutations are required for tumorigenesis? Implications from human cancer data. Mol Carcinog 1993; 7:139–46

    PubMed  CAS  Google Scholar 

  29. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57–70

    PubMed  CAS  Google Scholar 

  30. Bergers G, Hanahan D, Coussens LM. Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. Int J Dev Biol 1998; 42:995–1002

    PubMed  CAS  Google Scholar 

  31. Hahn WC, Counter CM, Lundberg AS, et al. Creation of human tumour cells with defined genetic elements. Nature 1999; 400:464–8

    PubMed  CAS  Google Scholar 

  32. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87:159–70

    PubMed  CAS  Google Scholar 

  33. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993; 104:510–3

    PubMed  CAS  Google Scholar 

  34. Cameron AJ, Lomboy CT, Pera M, et al. Adenocarcinoma of the esophagogastric junction and Barrett’s esophagus. Gastroenterology 1995; 109:1541–6

    PubMed  CAS  Google Scholar 

  35. Barrett NR. Chronic peptic ulcer of the oesophagus and ‘oesophagitis’. Br J Surg 1950; 38:175–82

    PubMed  CAS  Google Scholar 

  36. Morales CP, Souza RF, Spechler SJ. Hallmarks of cancer progression in Barrett’s oesophagus. Lancet 2002; 360:1587–9

    PubMed  Google Scholar 

  37. Flejou JF. Barrett’s oesophagus: from metaplasia to dysplasia and cancer. Gut 2005; 54 (Suppl 1):i6–12

    PubMed  Google Scholar 

  38. Kyrgidis A, Kountouras J, Zavos C, et al. New molecular concepts of Barrett’s esophagus: clinical implications and biomarkers. J Surg Res 2005; 125:189–212

    PubMed  CAS  Google Scholar 

  39. Nair KS, Naidoo R, Chetty R. Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value. J Clin Pathol 2005; 58:343–51

    PubMed  CAS  Google Scholar 

  40. Casson AG, Zheng Z, Evans SC, et al. Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma. Cancer 2005; 104:730–739

    PubMed  CAS  Google Scholar 

  41. Miller CT, Moy JR, Lin L, et al. Gene amplification in esophageal adenocarcinomas and Barrett’s with high-grade dysplasia. Clin Cancer Res 2003; 9:4819–4825

    PubMed  CAS  Google Scholar 

  42. Bani-Hani K, Martin IG, Hardie LJ, et al. Prospective study of cyclin D1 overexpression in Barrett’s esophagus: association with increased risk of adenocarcinoma. J Natl Cancer Inst 2000; 92:1316–1321

    PubMed  CAS  Google Scholar 

  43. Lin L, Prescott MS, Zhu Z, et al. Identification and characterization of a 19q12 amplicon in esophageal adenocarcinomas reveals cyclin E as the best candidate gene for this amplicon. Cancer Res 2000; 60:7021–7

    PubMed  CAS  Google Scholar 

  44. Sarbia M, Bektas N, Muller W, et al. Expression of cyclin E in dysplasia, carcinoma, and nonmalignant lesions of Barrett esophagus. Cancer 1999; 86:2597–601

    PubMed  CAS  Google Scholar 

  45. Tenderenda M. A study on the prognostic value of cyclins D1 and E expression levels in resectable gastric cancer and on some correlations between cyclins expression, histoclinical parameters and selected protein products of cell-cycle regulatory genes. J Exp Clin Cancer Res 2005; 24:405–14

    PubMed  CAS  Google Scholar 

  46. Schwartz GK. Development of cell cycle active drugs for the treatment of gastrointestinal cancers: a new approach to cancer therapy. J Clin Oncol 2005; 23:4499–508

    PubMed  CAS  Google Scholar 

  47. Bible KC, Lensing JL, Nelson SA, et al. Phase 1 trial of flavopiridol combined with cisplatin or carboplatin in patients with advanced malignancies with the assessment of pharmacokinetic and pharmacodynamic end points. Clin Cancer Res 2005; 11:5935–41

    PubMed  CAS  Google Scholar 

  48. D’errico A, Barozzi C, Fiorentino M, et al. Role and new perspectives of transforming growth factor-alpha (TGF-alpha) in adenocarcinoma of the gastro-oesophageal junction. Br J Cancer 2000; 82:865–70

    PubMed  CAS  Google Scholar 

  49. Yacoub L, Goldman H, Odze RD. Transforming growth factor-alpha, epidermal growth factor receptor, and MiB-1 expression in Barrett’s-associated neoplasia: correlation with prognosis. Mod Pathol 1997; 10:105–12

    PubMed  CAS  Google Scholar 

  50. Al-Kasspooles M, Moore JH, Orringer MB, et al. Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas. Int J Cancer 1993; 54:213–9

    PubMed  CAS  Google Scholar 

  51. Wilkinson NW, Black JD, Roukhadze E, et al. Epidermal growth factor receptor expression correlates with histologic grade in resected esophageal adenocarcinoma. J Gastrointest Surg 2004; 8:448–53

    PubMed  Google Scholar 

  52. Ross JS, McKenna BJ. The HER-2/neu oncogene in tumors of the gastrointestinal tract. Cancer Invest 2001; 19:554–68

    PubMed  CAS  Google Scholar 

  53. Wang SC, Hung MC. HER2 overexpression and cancer targeting. Semin Oncol 2001; 28:115–24

    PubMed  CAS  Google Scholar 

  54. Polkowski W, van Sandick JW, Offerhaus GJ, et al. Prognostic value of Lauren classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol 1999; 6:290–7

    PubMed  CAS  Google Scholar 

  55. Brien TP, Odze RD, Sheehan CE, et al. HER-2/neu gene amplification by FISH predicts poor survival in Barrett’s esophagus-associated adenocarcinoma. Hum Pathol 2000; 31:35–9

    PubMed  CAS  Google Scholar 

  56. Nakamura T, Nekarda H, Hoelscher AH, et al. Prognostic value of DNA ploidy and c-erbB-2 oncoprotein overexpression in adenocarcinoma of Barrett’s esophagus. Cancer 1994; 73:1785–94

    PubMed  CAS  Google Scholar 

  57. Tew WP, Kelsen DP, Ilson DH. Targeted therapies for esophageal cancer. Oncologist 2005; 10:590–601

    PubMed  CAS  Google Scholar 

  58. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673–84

    PubMed  CAS  Google Scholar 

  59. Safran H, Iannitti D, Ramanathan R, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 2004; 22:706–12

    PubMed  CAS  Google Scholar 

  60. Lam KY, Law SY, So MK, et al. Prognostic implication of proliferative markers MIB-1 and PC10 in esophageal squamous cell carcinoma. Cancer 1996; 77:7–13

    PubMed  CAS  Google Scholar 

  61. Youssef EM, Matsuda T, Takada N, et al. Prognostic significance of the MIB-1 proliferation index for patients with squamous cell carcinoma of the esophagus. Cancer 1995; 76:358–66

    PubMed  CAS  Google Scholar 

  62. Heeren PA, Kloppenberg FW, Hollema H, et al. Predictive effect of p53 and p21 alteration on chemotherapy response and survival in locally advanced adenocarcinoma of the esophagus. Anticancer Res 2004; 24:2579–83

    PubMed  Google Scholar 

  63. Wijnhoven BP, Tilanus HW, Dinjens WN. Molecular biology of Barrett’s adenocarcinoma. Ann Surg 2001; 233:322–37

    PubMed  CAS  Google Scholar 

  64. Hardie LJ, Darnton SJ, Wallis YL, et al. p16 expression in Barrett’s esophagus and esophageal adenocarcinoma: association with genetic and epigenetic alterations. Cancer Lett 2005; 217:221–30

    PubMed  CAS  Google Scholar 

  65. Schulmann K, Sterian A, Berki A, et al. Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett’s-associated neoplastic progression and predicts progression risk. Oncogene 2005; 24:4138–48

    PubMed  CAS  Google Scholar 

  66. Brock MV, Gou M, Akiyama Y, et al. Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin Cancer Res 2003; 9:2912–9

    PubMed  CAS  Google Scholar 

  67. Heeren PA, Kloppenberg FW, Hollema H, et al. Predictive effect of p53 and p21 alteration on chemotherapy response and survival in locally advanced adenocarcinoma of the esophagus. Anticancer Res 2004; 24:2579–83

    PubMed  Google Scholar 

  68. Powell SM, Papadopoulos N, Kinzler KW, et al. APC gene mutations in the mutation cluster region are rare in esophageal cancers. Gastroenterology 1994; 107:1759–63

    PubMed  CAS  Google Scholar 

  69. Boynton RF, Blount PL, Yin J, et al. Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proc Natl Acad Sci USA 1992; 89:3385–8

    PubMed  CAS  Google Scholar 

  70. Kawakami K, Brabender J, Lord RV, et al. Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J Natl Cancer Inst 2000; 92:1805–11

    PubMed  CAS  Google Scholar 

  71. Fukuchi M, Miyazaki T, Fukai Y, et al. Plasma level of transforming growth factor beta1 measured from the azygos vein predicts prognosis in patients with esophageal cancer. Clin Cancer Res 2004; 10:2738–41

    PubMed  CAS  Google Scholar 

  72. Saad RS, El-Gohary Y, Memari E, et al. Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in esophageal adenocarcinoma. Hum Pathol 2005; 36:955–61

    PubMed  CAS  Google Scholar 

  73. Koliopanos A, Friess H, di Mola FF, et al. Connective tissue growth factor gene expression alters tumor progression in esophageal cancer. World J Surg 2002; 26:420–7

    PubMed  Google Scholar 

  74. Iyer S, Wang ZG, Akhtari M, et al. Targeting TGFbeta signaling for cancer therapy. Cancer Biol Ther 2005; 4:261–6

    Article  PubMed  CAS  Google Scholar 

  75. Natsugoe S, Xiangming C, Matsumoto M, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res 2002; 8:1838–42

    PubMed  CAS  Google Scholar 

  76. Kim YH, Lee HS, Lee HJ, et al. Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. Ann Oncol 2004; 15:574–80

    PubMed  CAS  Google Scholar 

  77. Kim MA, Lee HS, Yang HK, et al. Clinicopathologic and protein expression differences between cardia carcinoma and noncardia carcinoma of the stomach. Cancer 2005; 103:1439–46

    PubMed  Google Scholar 

  78. Casson AG, Tammemagi M, Eskandarian S, et al. p53 alterations in oesophageal cancer: association with clinicopathological features, risk factors, and survival. Mol Pathol 1998; 51:71–9

    Article  PubMed  CAS  Google Scholar 

  79. Ribeiro U, Jr., Finkelstein SD, Safatle-Ribeiro AV, et al. p53 sequence analysis predicts treatment response and outcome of patients with esophageal carcinoma. Cancer 1998; 83:7–18

    PubMed  CAS  Google Scholar 

  80. Ireland AP, Shibata DK, Chandrasoma P, et al. Clinical significance of p53 mutations in adenocarcinoma of the esophagus and cardia. Ann Surg 2000; 231:179–87

    PubMed  CAS  Google Scholar 

  81. Schneider PM, Stoeltzing O, Roth JA, et al. P53 mutational status improves estimation of prognosis in patients with curatively resected adenocarcinoma in Barrett’s esophagus. Clin Cancer Res 2000; 6:3153–8

    PubMed  CAS  Google Scholar 

  82. Raouf AA, Evoy DA, Carton E, et al. Loss of Bcl-2 expression in Barrett’s dysplasia and adenocarcinoma is associated with tumor progression and worse survival but not with response to neoadjuvant chemoradiation. Dis Esophagus 2003; 16:17–23

    PubMed  CAS  Google Scholar 

  83. Garber K. Targeting mitochondria emerges as therapeutic strategy. J Natl Cancer Inst 2005; 97:1800–1

    Article  PubMed  Google Scholar 

  84. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998; 396:580–4

    PubMed  CAS  Google Scholar 

  85. Beardsmore DM, Verbeke CS, Davies CL, et al. Apoptotic and proliferative indexes in esophageal cancer: predictors of response to neoadjuvant therapy [corrected]. J Gastrointest Surg 2003; 7:77–86

    PubMed  Google Scholar 

  86. bdel-Latif MM, O’Riordan J, Windle HJ, et al. NF-kappaB activation in esophageal adenocarcinoma: relationship to Barrett’s metaplasia, survival, and response to neoadjuvant chemoradiotherapy. Ann Surg 2004; 239:491–500

    Google Scholar 

  87. Buskens CJ, van Rees BP, Sivula A, et al. Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology 2002; 122:1800–7

    PubMed  CAS  Google Scholar 

  88. Buskens CJ, Sivula A, van Rees BP, et al. Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus. Gut 2003; 52(12):1678–83

    PubMed  CAS  Google Scholar 

  89. Buskens CJ, Ristimaki A, Offerhaus GJ, et al. Role of cyclooxygenase-2 in the development and treatment of oesophageal adenocarcinoma. Scand J Gastroenterol Suppl 2003; 239:87–93

    PubMed  Google Scholar 

  90. Usselmann B, Newbold M, Morris AG, et al. Telomerase activity and patient survival after surgery for gastric and oesophageal cancer. Eur J Gastroenterol Hepatol 2001; 13:903–8

    PubMed  CAS  Google Scholar 

  91. Shammas MA, Koley H, Beer DG, et al. Growth arrest, apoptosis, and telomere shortening of Barrett’s-associated adenocarcinoma cells by a telomerase inhibitor. Gastroenterology 2004; 126:1337–46

    PubMed  CAS  Google Scholar 

  92. Kelland LR. Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics–current status and future prospects. Eur J Cancer 2005; 41:971–9

    PubMed  CAS  Google Scholar 

  93. Kleespies A, Guba M, Jauch KW, et al. Vascular endothelial growth factor in esophageal cancer. J Surg Oncol 2004; 87:95–104

    PubMed  CAS  Google Scholar 

  94. Mobius C, Stein HJ, Spiess C, et al. COX2 expression, angiogenesis, proliferation and survival in Barrett’s cancer. Eur J Surg Oncol 2005; 31:755–9

    PubMed  CAS  Google Scholar 

  95. von Rahden BH, Stein HJ, Puhringer F, et al. Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma. Cancer Res 2005; 65:5038–44

    Google Scholar 

  96. Mobius C, Stein HJ, Becker I, et al. Vascular endothelial growth factor expression and neovascularization in Barrett’s carcinoma. World J Surg 2004; 28:675–9

    PubMed  Google Scholar 

  97. Kleespies A, Bruns CJ, Jauch KW. Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies. Onkologie 2005; 28:281–8

    PubMed  CAS  Google Scholar 

  98. Nair KS, Naidoo R, Chetty R. Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value. J Clin Pathol 2005; 58:343–51

    PubMed  CAS  Google Scholar 

  99. Krishnadath KK, Tilanus HW, van BM, et al. Reduced expression of the cadherin-catenin complex in oesophageal adenocarcinoma correlates with poor prognosis. J Pathol 1997; 182:331–8

    PubMed  CAS  Google Scholar 

  100. Bottger TC, Youssef V, Dutkowski P, et al. Beta 1 integrin expression in adenocarcinoma of Barrett’s esophagus. Hepatogastroenterology 1999; 46:938–43

    PubMed  CAS  Google Scholar 

  101. Bottger TC, Youssef V, Dutkowski P, et al. Expression of CD44 variant proteins in adenocarcinoma of Barrett’s esophagus and its relation to prognosis. Cancer 1998; 83:1074–80

    PubMed  CAS  Google Scholar 

  102. Nekarda H, Schlegel P, Schmitt M, et al. Strong prognostic impact of tumor-associated urokinase-type plasminogen activator in completely resected adenocarcinoma of the esophagus. Clin Cancer Res 1998; 4:1755–63

    PubMed  CAS  Google Scholar 

  103. Murray GI, Duncan ME, O’Neil P, et al. Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer. J Pathol 1998; 185:256–61

    PubMed  CAS  Google Scholar 

  104. Tanioka Y, Yoshida T, Yagawa T, et al. Matrix metalloproteinase-7 and matrix metalloproteinase-9 are associated with unfavourable prognosis in superficial oesophageal cancer. Br J Cancer 2003; 89:2116–21

    PubMed  CAS  Google Scholar 

  105. Salmela MT, Karjalainen-Lindsberg ML, Puolakkainen P, et al. Upregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett’s oesophageal adenocarcinoma. Br J Cancer 2001; 85:383–92

    PubMed  CAS  Google Scholar 

  106. Porte H, Triboulet JP, Kotelevets L, et al. Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis. Clin Cancer Res 1998; 4:1375–82

    PubMed  CAS  Google Scholar 

  107. Bramhall SR, Hallissey MT, Whiting J, et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer 2002; 86:1864–70

    PubMed  CAS  Google Scholar 

  108. Darnton SJ, Hardie LJ, Muc RS, et al. Tissue inhibitor of metalloproteinase-3 (TIMP-3) gene is methylated in the development of esophageal adenocarcinoma: loss of expression correlates with poor prognosis. Int J Cancer 2005; 115:351–8

    PubMed  CAS  Google Scholar 

  109. Menke-Pluymers MB, Hop WC, Mulder AH, et al. DNA ploidy as a prognostic factor for patients with an adenocarcinoma in Barrett’s esophagus. Hepatogastroenterology 1995; 42:786–8

    PubMed  CAS  Google Scholar 

  110. Nakamura T, Nekarda H, Hoelscher AH, et al. Prognostic value of DNA ploidy and c-erbB-2 oncoprotein overexpression in adenocarcinoma of Barrett’s esophagus. Cancer 1994; 73:1785–94

    PubMed  CAS  Google Scholar 

  111. Bottger T, Dutkowski P, Kirkpatrick CJ, et al. Prognostic significance of tumor ploidy and histomorphological parameters in adenocarcinoma of Barrett’s esophagus. Dig Surg 1999; 16:180–5

    PubMed  CAS  Google Scholar 

  112. Wu TT, Watanabe T, Heitmiller R, et al. Genetic alterations in Barrett esophagus and adenocarcinomas of the esophagus and esophagogastric junction region. Am J Pathol 1998; 153:287–94

    PubMed  CAS  Google Scholar 

  113. van Sandick JW, Boermeester MA, Gisbertz SS, et al. Lymphocyte subsets and T(h)1/T(h)2 immune responses in patients with adenocarcinoma of the oesophagus or oesophagogastric junction: relation to pTNM stage and clinical outcome. Cancer Immunol Immunother 2003; 52:617–24

    PubMed  Google Scholar 

  114. Romano F, Cesana G, Berselli M, et al. Biological, histological, and clinical impact of preoperative IL-2 administration in radically operable gastric cancer patients. J Surg Oncol 2004; 88:240–7

    PubMed  CAS  Google Scholar 

  115. Guillem P, Triboulet JP. Elevated serum levels of C-reactive protein are indicative of a poor prognosis in patients with esophageal cancer. Dis Esophagus 2005; 18:146–50

    PubMed  CAS  Google Scholar 

  116. Deans C, Wigmore S, Paterson-Brown S, et al. Serum parathyroid hormone-related peptide is associated with systemic inflammation and adverse prognosis in gastroesophageal carcinoma. Cancer 2005; 103:1810–8

    PubMed  CAS  Google Scholar 

  117. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004; 23:7274–82

    PubMed  CAS  Google Scholar 

  118. Rizvi AZ, Hunter JG, Wong MH. Gut-derived stem cells. Surgery 2005; 137:585–90

    PubMed  Google Scholar 

  119. Jonsson M, Dejmek J, Bendahl PO, et al. Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res 2002; 62:409–16

    PubMed  CAS  Google Scholar 

  120. Dejmek J, Dejmek A, Safholm A, et al. Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res 2005; 65:9142–6

    PubMed  CAS  Google Scholar 

  121. Kremenevskaja N, von WR, Rao AS, et al. Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene 2005; 24:2144–54

  122. Watkins DN, Peacock CD. Hedgehog signalling in foregut malignancy. Biochem Pharmacol 2004; 68:1055–60

    PubMed  CAS  Google Scholar 

  123. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003; 425:846–51

    PubMed  CAS  Google Scholar 

  124. Katoh M, Katoh M. Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med 2006; 17:681–5

    PubMed  CAS  Google Scholar 

  125. Reedijk M, Odorcic S, Chang L, et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 2005; 65:8530–7

    PubMed  CAS  Google Scholar 

  126. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 2005; 24:7443–54

    PubMed  CAS  Google Scholar 

  127. Chambers AF, Groom AC, Macdonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 2:563–72

    PubMed  CAS  Google Scholar 

  128. Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004; 118:277–9

    PubMed  CAS  Google Scholar 

  129. van’t Veer L, Dai H, Van de Vijver M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 415:530–6

    CAS  Google Scholar 

  130. Xu Y, Selaru FM, Yin J, et al. Artificial neural networks and gene filtering distinguish between global gene expression profiles of Barrett’s esophagus and esophageal cancer. Cancer Res 2002; 62:3493–7

    PubMed  CAS  Google Scholar 

  131. Kimchi ET, Posner MC, Park JO, et al. Progression of Barrett’s metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation. Cancer Res 2005; 65:3146–54

    PubMed  CAS  Google Scholar 

  132. Brabender J, Marjoram P, Salonga D, et al. A multigene expression panel for the molecular diagnosis of Barrett’s esophagus and Barrett’s adenocarcinoma of the esophagus. Oncogene 2004; 23:4780–8

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Sources of financial support: S. M. Lagarde is supported by a grant (04-77) from the Maag Lever Darm Stichting (Dutch Digestive Diseases Foundation).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S. M. Lagarde.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lagarde, S.M., ten Kate, F.J.W., Richel, D.J. et al. Molecular Prognostic Factors in Adenocarcinoma of the Esophagus and Gastroesophageal Junction. Ann Surg Oncol 14, 977–991 (2007). https://doi.org/10.1245/s10434-006-9262-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-006-9262-y

Keywords

Navigation