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Urokinase-type plasminogen activator and its inhibitor in thyroid neoplasms: a cytosol study

Urokinase-Typ Plasminogen Aktivator und sein Inhibitor in Neoplasmen der Schilddrüse: Eine Cytosol-Studie

Zusammenfassung

ZIEL DER STUDIE: Erhöhte Konzentrationen des Urokinase-Typ Plasminogen-Aktivators (uPA) und seines Inhibitors (PAI 1) sind bei einer Reihe von malignen Erkrankungen mit einer schlechten Prognose verbunden. Entsprechend immunhistochemischer Messungen werden uPA und PAI 1 von den meisten Schilddrüsenkarzinomen exprimiert. Es konnte allerdings kein Zusammenhang zwischen der Expression dieser Substanzen und klinisch-pathologischen Parametern gefunden werden. Das Ziel der vorliegenden Studie war es, die klinische Relevanz der Expression von uPA und PAI 1 bei Patienten mit Schilddrüsenkarzinom zu untersuchen. PATIENTEN UND METHODEN: Die Konzentrationen von uPA und PAI 1 wurden in gepaarten Cytosol-Proben von Tumoren und normalen Gewebe der Schilddrüse mittels ELISA gemessen und mit den bekannten prognostischen Faktoren korreliert. ERGEBNISSE: Sowohl die uPA als auch die PAI 1 Konzentrationen waren in malignen Schilddrüsentumoren (uPA: 1,342 ± 2,944; PAI 1: 17,615 ± 31,933 ng/mg Protein) signifikant höher als im normalen Schilddrüsengewebe (uPA: 0.002 + 0,009 p = 0,011; PAI 1: 2,333 + 0,338 ng/mg Protein, p = 0,001). Es bestand eine positive Korrelation zwischen beiden Proteinen. Die Konzentrationen dieser Proteine waren in benignen Tumoren im Vergleich zu den Konzentrationen im Normalgewebe nicht unterschiedlich. Bei den verschiedenen histologischen Stadien gab es für die Konzentrationen beider Proteine signifikante Unterschiede (uPA: p = 0,024 und PAI 1: p = 0,017) im Sinne von höheren Werten bei höheren Tumorstadien (Grad 1: uPA: 0,116 + 0,247 und PAI 1: 4,802 + 1,151 ng/mg Protein). Die niedrigsten Werte wurden in Adenomen (uPA: 0,013 + 0,025 und PAI 1: 2,785 + 1.069 ng/mg Protein) – die höchsten Werte in anaplastischen Karzinomen (uPA: 8,45 ± 2,192 und PAI-1: 94,65 ± 59,468 ng/mg Protein) gemessen. uPA und PAI 1 waren bei den anaplastischen Karzinomen im Vergleich zu den gut differenzierten Karzinomen signifikant höher (uPA p = 0,014 und PAI-1 p = 0,026). Weiters wurden in Abhängigkeit von folgenden Faktoren signifikante Unterschiede beobachtet: extrathyreoidale Invasion (uPA p = 0,019 und PAI-1 p = 0,009), entfernte Metastasen (uPA p = 0,006 und PAI-1 p = 0,003), Tumorgröße mehr als 1 cm (uPA: p = 0,009 und PAI-1 p = 0,035). Der Vergleich von multizentrischen Tumoren mit solitären Tumoren (p = 0,012) ergab ebenso wie der Vergleich von Patienten mit und ohne Lymphknotenmetastasen (p = 0,042) nur für PAI-1 signifikant höhere Werte. Keine signifikanten Unterschiede wurden in Abhängigkeit vom Alter (unter/über 40 Jahre) beobachtet. Die Analyse der Überlebensrate ergab eine signifikante Bedeutung beider Proteine in Bezug auf das progressionsfreie Überleben (38,84 vs. 3.67 Monate für Patienten mit jeweils hohen bzw. niedrigen uPA Konzentrationen p < 0.001; 38.2 vs. 12 Monate für Patienten mit jeweils hohen bzw. niedrigen PAI 1 Konzentrationen; p = 0,012). SCHLUSSFOLGERUNGEN: Die Korrelation von hohen uPA und PAI 1 Konzentrationen mit den bekannten Prognosefaktoren für einen schlechteren Verlauf und für ein progressionsfreies Überleben bei Patienten mit Schilddrüsenkrebs zeigen, dass diese Proteine ein nützlicher zusätzlicher prognostischer Parameter bei dieser Erkrankung sein könnten.

Summary

PURPOSE: Higher levels of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) are linked to the poor prognosis in a variety of malignances. uPA and PAI-1 were expressed in most thyroid carcinomas, as had been measured immunohistochemically. However, no relationship between their expression and clinicopathological parameters were found. Aim of the present study was to investigate the expression and clinical relevance of uPA and PAI-1 in thyroid cancer. PATIENTS AND METHODS: uPA and PAI-1 in paired cytosol samples of thyroid tumor and normal tissue were determined in 23 patients using enzyme-linked immunosorbent assay and correlated to the known prognostic features. RESULTS: Both uPA and PAI-1 concentrations were significantly higher in malignant thyroid tumors (uPA = 1.342 ± 2.944 and PAI-1 = 17.615 ± 31.933 ng/mg protein) than in normal tissue (uPA = 0.002 ± 0.009, P = 0.011 and PAI-1 = 2.333 ± 0.338 ng/mg protein, P = 0.001) with positive correlation of the two proteins in the tumors. There were no differences in proteins' levels between benign tumors and normal tissue. Both proteins' concentrations were significantly different among various histological grades (uPA P = 0.024 and PAI-1 P = 0.017), showing higher values in higher tumor grades (grade I uPA = 0.116 ± 0.247 and PAI-1 = 4.802 ± 4.151 ng/mg protein; grade III uPA = 8.45 ± 2.192 and PAI-1 = 94.65 ± 59.468 ng/mg protein). The uPA and PAI-1 levels showed significant differences among different histological types of thyroid cancer (uPA P = 0.049 and PAI-1 = 0.017). The lowest values were in adenomas (uPA = 0.013 ± 0.025 and PAI-1 = 2.785 ± 1.069 ng/mg protein) and the highest in anaplastic carcinomas (uPA = 8.45 ± 2.192 and PAI-1 = 94.65 ± 59.468 ng/mg protein). uPA and PAI-1 were significantly higher in anaplastic vs. well-differentiated cancers (uPA P = 0.014 and PAI-1 P = 0.026), if extrathyroidal invasion (uPA P = 0.019 and PAI-1 P = 0.009) or distant metastases (uPA P = 0.006 and PAI-1 P = 0.003) had been present, and in tumors whose size exceeded 1 cm in diameter (uPA P = 0.009 and PAI-1 P = 0.035). Only PAI-1, but not uPA was significantly higher in multicentric vs. solitary tumors (P = 0.012) and lymph node positive compared to lymph node negative patients (P = 0.042). The differences of uPA and PAI-1 did not reach the significant level when patients with well-differentiated tumors below and above 40 years of age had been compared. Survival analysis revealed the significant impact of both uPA and PAI-1 on the Progression-Free Survival (PFS) (38.84 vs. 3.67 months for patients with low and high uPA, respectively, P < 0.001; 38.2 vs. 12 months for patients with low and high PAI-1, respectively, P = 0.016). CONCLUSIONS: The correlation of high uPA and PAI-1 with the known prognostic factors of poorer outcome and with lower PFS rate in patients with thyroid cancers proved that these proteins could be an additional prognostic parameter.

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Correspondence to Gordana Horvatić Herceg.

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Horvatić Herceg, G., Herceg, D., Kralik, M. et al. Urokinase-type plasminogen activator and its inhibitor in thyroid neoplasms: a cytosol study. Wien Klin Wochenschr 118, 601–609 (2006). https://doi.org/10.1007/s00508-006-0703-1

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Keywords

  • Urokinase-type plasminogen activator
  • Type 1 plasminogen activator inhibitor
  • Thyroid cancer
  • Prognosis
  • Enzyme-linked immunosorbent assay