ORIGINAL ARTICLE
Immunohistochemical expression analysis of MMP-1, TIMP-2 and p53 in Barrett’s esophagus, dysplasia and esophageal adenocarcinoma
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1
Department of Pathology, Hospital El Bierzo, Ponferrada, Spain
2
Department of Pathology, Hospital Universitario Central de Asturias, Oviedo, Spain
3
Department of Dermatology, Hospital Universitario Central de Asturias, Oviedo, Spain
Submission date: 2020-11-17
Final revision date: 2021-02-08
Acceptance date: 2021-03-14
Publication date: 2021-05-31
Pol J Pathol 2021;72(1):48-56
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ABSTRACT
Barrett’s esophagus (BE) is the most important risk factor for the development of esophageal adenocarcinoma. It develops through a progressive sequence of histologic and molecular events that begin with metaplasia and then progresses through various stages of dysplasia. Matrix metalloproteinases are involved in the degradation of the extracellular matrix and play an important role in tumor progression.
The immunohistochemical expression of MMP-1, TIMP-2 and p53 in 111 samples from 45 patients diagnosed with BE with and without dysplasia and adenocarcinoma of the esophagus was retrospectively studied, and statistical analysis was conducted to measure the association between their expression and the degree of dysplasia present.
MMP-1 was expressed in 33.3% of the samples studied, mainly in the adenocarcinoma subgroup with up to 40% positive cases (p = 0.494). In contrast, TIMP-2 was expressed in 25.2% of the samples, and no positive cases were identified in the adenocarcinoma subgroup (p = 0.037). Aberrant p53 expression was observed in 81.4% of the samples diagnosed with some degree of dysplasia (p < 0.001).
MMP-1 showed no statistically significant differences between diagnostic entities. A statistically significant loss of TIMP-2 expression was observed in distal esophageal adenocarcinoma samples, which contrasts with the aberrant expression of p53 in dysplastic cases.
REFERENCES (35)
1.
Naini BV, Souza RF, Odze RD. Barrett’s Esophagus: A Comprehensive and Contemporary Review for Pathologists. Am.
2.
J Surg Pathol 2016; 40: e45-66.
3.
Shaheen NJ, Falk GW, Iyer PG, et al. American College of Gastroenterology. ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus. Am J Gastroenterol 2016; 111: 30-50.
4.
Fitzgerald RC, di Pietro M, Ragunath K, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut 2014; 63: 7-42.
6.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70: 7-30.
7.
Iyer PG, Kaul V. Barrett Esophagus. Mayo Clin Proc 2019; 94: 1888-1901.
8.
Folgueras AR, Pendás AM, Sánchez LM, et al. Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 2004; 48: 411-424.
9.
Laronha H, Caldeira J. Structure and function of human matrix metalloproteinases. Cells 2020; 9: 1076.
10.
Vilalta A, Sahuquillo Barris J, Poca MA. Matrix metaloproteinases in neurological brain lesions: a new therapeutic target? Rev Neurol 2010; 51: 95-107.
11.
Brinckerhoff CE, Rutter JL, Benbow U. Interstitial collagenases as markers of tumor progression. Clin Cancer Res 2000; 6: 4823-4830.
12.
Peeney D, Jensen SM, Castro NP, et al. TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer. Carcinogenesis 2020; 41: 313-325.
13.
Rüschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 2010; 457: 299-307.
14.
Kastelein F, Biermann K, Steyerberg EW, et al. Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett’s oesophagus. Gut 2013; 62: 1676-1683.
15.
Wani S, Falk G, Hall M, et al. Patients with nondysplastic Barrett’s esophagus have low risks for developing dysplasia or esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2011; 9: 220-227.
16.
O’Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett’s esophagus: report on the Cleveland Clinic Barrett’s Esophagus Registry. Am J Gastroenterol 1999; 94: 2037-2042.
17.
Salmela MT, Karjalainen-Lindsberg ML, Puolakkainen P, et al. Upregulation and differential expression of matrilysin.
18.
(MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett’s oesophageal adenocarcinoma. Br J Cancer 2001; 85: 383-392.
19.
Murray GI, Duncan ME, O’Neil P, et al. Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer. J Pathol 1998; 185: 256-261.
20.
Grimm M, Lazariotou M, Kircher S, et al. MMP-1 is a (pre-)invasive factor in Barrett-associated esophageal adenocarcinomas and is associated with positive lymph node status. J Transl Med 2010; 8: 99.
21.
Garalla HM, Lertkowit N, Tiszlavicz L, et al. Matrix metalloproteinase (MMP)-7 in Barrett’s esophagus and esophageal adenocarcinoma: expression, metabolism, and functional significance. Physiol Rep 2018; 6: e13683.
22.
Davelaar AL, Straub D, Buttar NS, et al. Active matrix metalloproteases are expressed early on and are high during the Barrett’s esophagus malignancy sequence. Scand J Gastroenterol 2015; 50: 321-332.
23.
Sharma R, Chattopadhyay TK, Mathur M, et al. Prognostic significance of stromelysin-3 and tissue inhibitor of matrix metalloproteinase-2 in esophageal cancer. Oncology 2004; 67: 300-309.
24.
Plum PS, Warnecke-Eberz U, Dhaouadi O, et al. Molecular markers predicting lymph node metastasis in early esophageal cancer. Histol Histopathol 2015; 30: 1193-1202.
25.
Groblewska M, Mroczko B, Kozlowski M, et al. Serum matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in esophageal cancer patients. Folia Histochem Cytobiol 2012; 50: 590-598.
26.
Lu X, Duan L, Xie H, et al. Evaluation of MMP-9 and MMP-2 and their suppressor TIMP-1 and TIMP-2 in adenocarcinoma of esophagogastric junction. Onco Targets Ther 2016; 9: 4343-4349.
27.
Alakus H, Grass G, Hennecken JK, et al. Clinicopathological significance of MMP-2 and its specific inhibitor TIMP-2 in gastric cancer. Histol Histopathol 2008; 23: 917-923.
28.
Joo YE, Seo KS, Kim HS, et al. Expression of Tissue Inhibitors of Metalloproteinases (TIMPs) in Gastric Cancer. Digestive Diseases and Sciences 2000; 45: 114-121.
29.
Ring P, Johansson K, Höyhtyä M, et al. Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer – a predictor of tumour stage. Br J Cancer 1997; 76: 805-811.
30.
Wang W, Li D, Xiang L, et al. TIMP-2 inhibits metastasis and predicts prognosis of colorectal cancer via regulating MMP-9. Cell Adh Migr 2019; 13: 273-284.
31.
Kaye PV, Ilyas M, Soomro I, et al. Dysplasia in Barrett’s oesophagus: p53 immunostaining is more reproducible than haematoxylin and eosin diagnosis and improves overall reliability, while grading is poorly reproducible. Histopathology 2016; 69: 431-440.
32.
Skacel M, Petras RE, Rybicki LA, et al. p53 expression in low grade dysplasia in Barrett’s esophagus: correlation with interobserver agreement and disease progression. Am J Gastroenterol 2002; 97: 2508-2513.
33.
van der Wel MJ, Duits LC, Pouw RE, et al. Improved diagnostic stratification of digitized Barrett´s oesophagus biopsies by p53 immunohistochemical staining. Histopathology 2018; 72: 1015-1023.
34.
Snyder P, Dunbar K, Cipher DJ, et al. Aberrant p53 immunostaining in Barrett’s esophagus predicts neoplastic progression: systematic review and meta-analyses. Dig Dis Sci 2019; 64: 1089-1097.
35.
Srivastava A, Appelman H, Goldsmith JD, et al. The use of ancillary stains in the diagnosis of Barrett esophagus and Barrett esophagus-associated dysplasia. Am J Surg Pathol 2017; 41: e8-e21.