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Clinicopathologic and prognostic significance of matrix metalloproteinases in rectal cancer

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Abstract

Background and aims

The aim of this study was to determine the prognostic role of matrix metalloproteinases in rectal cancer.

Materials and methods

Formalin-fixed and paraffin-embedded tissue sections of 94 rectal carcinomas were used for the immunohistochemical analysis of matrix metalloproteinases (MMP)-2, MMP-7, MT1-MMP, and tissue inhibitor of metalloproteinases (TIMP)-2. Inclusion criteria were sporadic rectal adenocarcinoma resected curatively (including total mesorectal excision), adjuvant radiochemotherapy in UICC stages II and III, and complete intra-institutional follow-up. Results of immunohistochemistry were correlated with clinical and histopathologic data from the prospective rectal cancer registry and prognosis. End points of the prognostic analysis were tumor progression caused by local and/or distant recurrence and 5-year survival (disease-free and overall). To assess prognostic significance, statistics included univariate and multivariate analysis (p<0.05 statistically significant).

Results

Of the 94 rectal carcinomas, 35% (33/94) showed an epithelial MMP-2 expression, 77% (72/94) were MMP-2 positive in the stroma. Fifty-four percent (51/94) were MMP-7 positive, and 47% (46/94) were positive for both MT1-MMP and TIMP-2. The stromal MMP-2 staining pattern was correlated with the depth of invasion (pT status, p=0.006) with MMP-7 (p=0.016) and TIMP-2 expression (p=0.036). Positive expression of MMP-2 in tumor epithelium was correlated with MMP-7 (p=0.027), MT1-MMP (p=0.036), and TIMP-2 expression (p<0.0001). A positive staining pattern of MMP-7 was significantly correlated with depth of invasion and TIMP-2 (p<0.01). The positive staining pattern of MT1-MMP was correlated with epithelial MMP-2 (p=0.036), MMP-7 (p=0.004), and TIMP-2 expression (p=0.002). TIMP-2 immunoreactivity correlated with depth of invasion (p=0.013), epithelial MMP-2 (p<0.001), stromal MMP-2 (p=0.036), MMP-7 (p<0.001), and MT1-MMP (p=0.002). Neither pattern correlated with age, gender, tumor stage (UICC), grading, preoperative serum carcinoembryonic antigen (CEA) level, or nodal status (p>0.05). Within a mean follow-up of 46 months, tumor progression, caused by either local recurrence or distant metastasis, occurred in 14 patients (15.4%). There was no significant association between the MMP expression and the incidence of local and/or distant recurrence. In terms of survival, preoperative CEA level (disease-free 5-year survival 46% with increased CEA vs 70% with normal CEA, p=0.01; overall 5-year survival 43 vs 74%, p<0.01) and UICC stage were the only factors to be significantly related to 5-year survival by univariate analysis, whereas the metalloproteinases failed to show a significant association. In multivariate analysis, CEA and UICC stage were not identified as independent factors predictive of survival.

Conclusion

MMP-2, MMP-7, MT1-MMP, and TIMP-2 do not appear to be significant predictors of prognosis in a homogenous collective of curatively resected rectal adenocarcinomas.

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References

  1. Basset P, Okada A, Chenard M-P, Kannan R, Stoll I, Anglard P, Bellocq J-P, Rio M-C (1997) Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutical implications. Matrix Biol 15:535–541

    Article  PubMed  CAS  Google Scholar 

  2. Westermarck J, Kahari VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13:781–792

    PubMed  CAS  Google Scholar 

  3. Bruch HP, Schwandner O, Keller R, Farke S, Schiedeck THK (2003) Surgical therapy for rectal cancer. Chirurg 74:905–914

    Article  PubMed  Google Scholar 

  4. Bruch HP, Schwandner O, Schiedeck THK, Roblick UJ (1999) Actual standards and controversies on operative technique and lymph-node dissection in colorectal cancer. Langenbecks Arch Surg 384:167–175

    Article  PubMed  CAS  Google Scholar 

  5. Bruch HP, Schwandner O (2002) Totale mesorektale Exzision beim Rektumkarzinom: Das Dissektionsprinzip ohne kontrollierte Daten. Viszeralchirurgie 37:6–11

    Article  Google Scholar 

  6. Wexner SD, Rotholtz NA (2000) Surgeon-influenced variables in resectional rectal cancer surgery. Dis Colon Rectum 43:1606–1627

    Article  PubMed  CAS  Google Scholar 

  7. Hermanek P (1999) Impact of surgeon’s technique on outcome after treatment of rectal carcinoma. Dis Colon Rectum 42:559–562

    Article  PubMed  CAS  Google Scholar 

  8. Köckerling F, Reymond MA, Altendorf-Hofmann A, Dworak O, Hohenberger W (1998) Influence of surgery on metachronous distant metastases and survival in rectal cancer. J Clin Oncol 16:324–329

    PubMed  Google Scholar 

  9. Talvensaari-Mattila A, Paakko P, Hoyhtya M, Blanco-Sequeiros G, Turpeenniemi-Hujanen T (1998) Matrix metalloproteinase-2 immunoreactive protein: a marker of aggressiveness in breast carcinoma. Cancer 83:1153–1162

    Article  PubMed  CAS  Google Scholar 

  10. Westerlund A, Apaja-Sarkkinen M, Hoyhtya M, Puistola U, Turpeenniemi-Hujanen T (1999) Gelatinase A-immunoreactive protein in ovarian lesions—prognostic value in epithelial ovarian cancer. Gynecol Oncol 75:91–98

    Article  PubMed  CAS  Google Scholar 

  11. Grigioni WF, D’Errico A, Fortunato C, Fiorentino M, Mancini AM, Stetler-Stevenson WG et al (1994) Prognosis of gastric carcinoma revealed by interactions between tumor cells and basement membrane. Mod Pathol 7:220–225

    PubMed  CAS  Google Scholar 

  12. Miyajima Y, Nakano R, Morimatsu M (1995) Analysis of expression of matrix metalloproteinases-2 and -9 in hypopharyngeal squamous cell carcinoma by in situ hybridization. Ann Otol Rhinol Laryngol 104:678–684

    PubMed  CAS  Google Scholar 

  13. Walther MM, Kleiner DE, Lubensky IA, Pozzatti R, Nyguen T, Gnarra JR et al (1997) Progelatinase A mRNA expression in cell lines derived from tumors in patients with metastatic renal cell carcinoma correlates inversely with survival. Urology 50:295–301

    Article  PubMed  CAS  Google Scholar 

  14. D’Errico A, Garbisa S, Liotta LA et al (1991) Augmentation of type IV collagenase, laminin receptor, and Ki-67 proliferation antigen associated with human colon, gastric and breast carcinoma progression. Mod Pathol 4:239–246

    PubMed  CAS  Google Scholar 

  15. Tomita T, Iwata K (1996) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in colonic adenomas-adenocarcinomas. Dis Colon Rectum 39:1255–1264

    Article  PubMed  CAS  Google Scholar 

  16. Kikuchi R, Noguchi T, Takeno S, Kubo N, Uchida Y (2000) Immunohistochemical detection of membrane-type-1-matrixmetalloproteinase in colorectal carcinoma. Br J Cancer 83:215–218

    Article  PubMed  CAS  Google Scholar 

  17. Masaki T, Sugiyama M, Matsuoka H, Abe N, Izumisato Y, Sakamoto A, Atomi Y (2003) Matrix metalloproteinases may contribute compensationally to tumor invasion in T1 colorectal carcinomas. Anticancer Res 23:4169–4173

    PubMed  CAS  Google Scholar 

  18. Sato H, Seiki M (1996) Membrane-type matrix metalloproteinases (MT-MMPs) in tumor metastasis. J Biochem 119:209–215

    PubMed  CAS  Google Scholar 

  19. Ring P, Johansson K, Hoyhtya M, Rubin K, Lindmark G (1997) Expression of tissue inhibitor of metalloproteinase TIMP-2 in human colorectal cancer—a predictor of tumour stage. Br J Cancer 76:805–811

    PubMed  CAS  Google Scholar 

  20. Sis B, Sagol O, Kupelioglu A, Sokmen S, Terzi C, Fuzun M, Ozer E, Bishop P (2004) Prognostic significance of matrix metalloproteinase-2, cathepsin D, and tenascin-C expression in colorectal carcinoma. Pathol Res Pract 200:379–387

    Article  PubMed  CAS  Google Scholar 

  21. Malhotra S, Newman E, Eisenberg D, Scholes J, Wieczorek R, Mignatti P, Shamamian P (2002) Increased membrane type 1 matrix metalloproteinase expression from adenoma to colon cancer: a possible mechanism of neoplastic progression. Dis Colon Rectum 45:537–4322

    Article  PubMed  Google Scholar 

  22. Bendardaf R, Lamlum H, Vihinen P, Ristamaki R, Laine J, Pyrhonen S (2003) Low collagenase-1 (MMP-1) and MT1-MMP expression levels are favourable survival markers in advanced colorectal carcinoma. Oncology 65:337–346

    Article  PubMed  CAS  Google Scholar 

  23. Joo YE, Seo KS, Kim J, Kim HS, Rew JS, Park CS, Kim SJ (1999) Role of tissue inhibitors of metalloproteinases (TIMPs) in colorectal carcinoma. J Korean Med Sci 14:417–423

    PubMed  CAS  Google Scholar 

  24. Li BH, Zhao P, Liu SZ, Yu YM, Han M, Wen JK (2005) Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in colorectal carcinoma invasion and metastasis. World J Gastroenterol 11:3046–3050

    PubMed  CAS  Google Scholar 

  25. Murashige M, Miyahara M, Shiraishi N, Saito T, Kohno K, Kobayashi M (1996) Enhanced expression of tissue inhibitors of metalloproteinases in human colorectal tumors. Jpn J Clin Oncol 26:303–309

    PubMed  CAS  Google Scholar 

  26. Adachi Y, Yamamoto H, Itoh F, Arimura Y, Nishi M, Endo T, Imai K (2001)Clinicopathologic and prognostic significance of matrilysin expression at the invasive front in human colorectal cancers. Int J Cancer 20:290–294

    Article  Google Scholar 

  27. Adachi Y, Yamamoto H, Itoh F, Hinoda Y, Okada Y, Imai K (1999) Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers. Gut 45:252–258

    Article  PubMed  CAS  Google Scholar 

  28. Masaki T, Matsuoka H, Sugiyama M, Abe N, Goto A, Sakamoto A, Atomi Y (2001) Matrilysin (MMP-7) as a significant determinant of malignant potential of early invasive colorectal carcinomas. Br J Cancer 84:1317–1321

    Article  PubMed  CAS  Google Scholar 

  29. Luo HZ, Zhou ZG, Yang L, Yu YY, Tian C, Zhou B, Zheng XL, Xia QJ, Li Y, Wang R (2005) Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol 35:739–744

    Article  PubMed  Google Scholar 

  30. Roeb E, Arndt M, Jansen B, Schumpelick V, Matern S (2004) Simultaneous determination of matrix metalloproteinases (MMP)-7, MMP-1, -3, and -13 gene expression by multiplex PCR in colorectal carcinomas. Int J Colorectal Dis 19:518–524

    Article  PubMed  Google Scholar 

  31. Kurokawa S, Arimura Y, Yamamoto H, Adachi Y, Endo T, Sato T, Suga T, Hosokawa M, Shinomura Y, Imai K (2005) Tumour matrilysin expression predicts metastatic potential of stage I (pT1) colon and rectal cancers. Gut 54:1751–1758

    Article  PubMed  CAS  Google Scholar 

  32. Malhotra S, Newman E, Eisenberg D, Scholes J, Wieczorek R, Mignatti P, Shamamian P (2002) Increased membrane type 1 matrix metalloproteinase expression from adenoma to colon cancer: a possible mechanism of neoplastic progression. Dis Colon Rectum 45:537–543

    Article  PubMed  Google Scholar 

  33. Pesta M, Holubec L Jr, Topolcan O, Cerna M, Rupert K, Holubec LS, Treska V, Kormunda S, Elgrova L, Finek J, Cerny R (2005) Quantitative estimation of matrix metalloproteinases 2 and 7 (MMP-2, MMP-7) and tissue inhibitors of matrix metalloproteinases 1 and 2 (TIMP-1, TIMP-2) in colorectal cancer carcinoma tissue samples. Anticancer Res 25:3387–3391

    PubMed  CAS  Google Scholar 

  34. Langenskiold M, Holmdahl L, Falk P, Ivarsson ML (2005) Increased plasma MMP-2 protein expression in lymph node-positive patients with colorectal cancer. Int J Colorectal Dis 20:245–2552

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank Prof. Dr. A.C. Feller, Director of the Institute of Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, for providing tissue blocks. We also thank Mrs. G. Grosser-Pape for technical assistance in the Surgical Research Laboratory, Mrs. C. Killaitis, Department of Surgery, for processing the computerized registry database of rectal cancer, and Dr. H. Paul, Institute of Statistics and Mathematic Economy Research, University of Augsburg, Germany, for independent data analysis and statistical evaluation.

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Authors and Affiliations

  1. Department of Surgery, University Hospital, Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538, Luebeck, Germany

    A. Schlamp, R. Broll & H. P. Bruch

  2. Department of Surgery, Caritas-Krankenhaus St. Josef, Landshuter Strasse 65, 93053, Regensburg, Germany

    O. Schwandner

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  1. O. Schwandner
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Correspondence to O. Schwandner.

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Schwandner, O., Schlamp, A., Broll, R. et al. Clinicopathologic and prognostic significance of matrix metalloproteinases in rectal cancer. Int J Colorectal Dis 22, 127–136 (2007). https://doi.org/10.1007/s00384-006-0173-y

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