Advances in Clinical and Experimental Medicine

Adv Clin Exp Med
Impact Factor (IF) – 1.227
Index Copernicus (ICV 2018) – 157.72
MNiSW – 40
Average rejection rate – 84.38%
ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download PDF

Advances in Clinical and Experimental Medicine

2014, vol. 23, nr 6, November-December, p. 959–967

Publication type: original article

Language: English

Soluble Urokinase-Type Plasminogen Activator Receptor and Ferritin Concentration in Patients with Advanced Alimentary Tract Carcinoma. Relationship to Localization, Surgical Treatment and the Stage of the Disease – Preliminary Report

Lidia Usnarska-Zubkiewicz1,A,C,D, Marta Strutyńska-Karpińska2,A,B,F, Agnieszka Zubkiewicz-Kucharska3,B,C, Paweł Zarębski2,C,D, Krzysztof Grabowski2,E

1 Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Poland

2 Department of Gastrointestinal and General Surgery, Wroclaw Medical University, Poland

3 Department of Endocrinology and Diabetology for Children and Adolescents, Wroclaw Medical University, Poland


Background. . The urokinase plasminogen activation system is associated with metastatic potential of cancer in several tumors. Its specific membrane receptor (uPAR) is released from cancer cells and can be detected as the soluble fraction of the plasminogen activator receptor (suPAR). Ferritin (FRT) is a poor prognostic factor in various neoplasms.
Objectives. We analyzed the serum concentrations of suPAR and FRT in patients with gastrointestinal cancer. Tumor localization, stage of the disease, possibility of surgery and histopathological diagnosis were considered.
Material and Methods. The analysis involved 48 patients (8 females/40 males) treated in the Department of Gastrointestinal and General Surgery, Wroclaw Medical University. Thirty two patients had esophageal, 7–gastric, 9-colorectal cancer. Fifteen patients underwent resection surgery, 33 palliative therapy. The control comprised 10 healthy donors. The serum concentration of suPAR was determined by enzyme-linked immunosorbent assay (ELISA), expressed in pg/mL. Concentration of the serum FRT was detected using immunonephelometry method, expressed in µg/L.
Results. Serum concentration of suPAR ranged from 1789 –7320, x = 3676.2, SD = 1042 and was significantly higher (p = 0.0002) than in the control group. In patients who underwent palliative therapy, the concentration of suPAR was significantly higher (p = 0.05) than in those after resection, also in patients with esophageal cancer compared to those with colorectal one (p = 0.02). Serum concentration of FRT in patients with gastrointestinal cancer was significantly higher than in control group. Serum FRT concentration was higher in patients with esophageal cancer compared to patients with gastric cancer (p = 0.05), in persons with IV compared to patients with I–III stage of the disease, patients who underwent palliative compared to surgical therapy.
Conclusion. In patients with gastrointestinal cancer the level of suPAR is high, with highest values in advances disease with remote metastases. The FRT concentration is sensitive indicator of the disease process: its level is highest in pts with IV stage who underwent palliative therapy.

Key words

colorectal cancer, esophageal cancer, gastric cancer, suPAR concentration, FRT concentration.

References (54)

  1. Dano K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS, Skriver L: Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 1985, 44, 139–266.
  2. Egeblad M, Werb Z: New function for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002, 2, 163–176.
  3. Yu HR, Schultz RM: Relationship between secreted urokinase plasminogen activator activity and metastatic potential in murine B16 cells transfected with human urokinase sense and antisense genes. Cancer Res 1990, 50, 7623–7633.
  4. Shapiro RL, Duquette JG, Roses DF, Nunes I, Harris MN, Kamino H, Wilson EL, Rifkin DB: Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res 1996, 56, 3597–3604.
  5. Fisher JL, Mackie PS, Howard ML, Zhou H, Choong PF: The expression of urokinase plasminogen activator system in metastatic murine osteosarcoma: an in vivo mouse model. Clin Cancer Res 2001, 7, 1654–1660.
  6. Shpitz B, Gochberg S, Neufeld D, Grankin M, Buklan G, Klein E, Bernheim J: Angiogenic switch in earliest stages of human colonic tumorigenesis. Anticancer Res 2003, 23, 5153–5157.
  7. Pang RW, Poon RT: Clinical implications of angiogenesis in cancers. Vasc Health Risk Manag 2006, 2, 97–108.
  8. Rajaganeshan R, Prasad R, Guillou PJ, Chlmers CR, Scott N, Sarkar R, Poston G, Jayne DG: The influence of invasive growth pattern and microvessel density on prognosis in colorectal cancer and colorectal liver metastases. Br J Cancer 2007, 96, 1112–1117.
  9. Dkhissi F, Lu H, Soria C, Opolon P, Griscell F, Liu H, Khattar P, Mishal Z, Pericaudet M, Li H: Endostatin exhibits a direct antitumor effect in addition to its antiagiogenic activity in colon cancer cells. Hum Gene Ther 2003, 14, 997–1008.
  10. Przybyłowska K, Szemraj J. Kulig A, Dziki A, Ulanska J, Blasiak J: Antigen levels of urokinaze type plasminogen activator receptor and its gen polymorphism relate to microvassel density in colorectal cancer. Acta Bioch Pol 2008, 2, 357–363.
  11. Ji F, Chen YL, Jin RY, Wang WL, Yang ZL, Li YM: Relationship between matrix metalloproteinase-2 mRNA expression and clinicopathological and urokinase-type plasminogen activator system parameters and prognosis in human gastric cancer. World J Gastroenterol 2005, 11, 3222–3226.
  12. Memarzadeh S, Kozak KR, Chang L, Natorajan S, Shintaku P, Reddy ST, Farias-Eisner R: Urokinase plasminogen activator receptor: Prognostic biomarker for endometrial cancer. Proc Natl Acad Sci USA 2002, 99, 10647– –10652.
  13. Stillfried GE, Saunders DN, Ranson M: Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res 2007, 9.
  14. Pappot H, Høyer-Hansen G, Rønne E, Hansen HH, Brünner N, Danø K, Grøndahl-Hansen J: Elevated plasma levels of urokinase plasminogen activator receptor in non-small lung cancer patients. Eur J Cancer 1997, 33, 867–872.
  15. Riisbro R, Christensen IJ, Piiroren T, Greenall M, Larsen B, Stephens RW, Han C, Heyer-Hansen G, Smith K, Brünner N, Harris AL: Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin Cancer Res 2002, 8, 1132–1141.
  16. Sier CF, Stephens R, Bizik J, Mariani A, Bassan M, Pedersen N, Frigerio L, Ferrari A, Dano K, Brünner N, Blasi F: The level of urokinase – type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res 1998, 58, 1843–1849.
  17. Riisbro R, Christensen IJ, Nielsen HJ, Brünner N, Nilbert M, Fernebro E: Preoperative plasma soluble urokinase plasminogen activator receptor as prognostic marker in rectal cancer patients. An EORTC-Receptor and Biomarker Group collaboration. Int J Biol Markers 2005, 20, 93–102.
  18. Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius-Ussing O, Sorensen S, Dano K, Brünner N: Plasma urokinase receptor levels in patients with colorectal cancer: Relationship to prognosis. J Nat Cancer 1999, 10, 869–874.
  19. Fernebro E, Madsen RR, Fernö M, Brünner N, Bendahl P, Christensen IJ, Johnson A, Nilbert M: Prognostic importance of the soluble plasminogen activator receptor, suPAR, in plasma from rectal cancer patients. Eur J Cancer 2001, 37, 486–491.
  20. Nelson RL, Davis FG, Sutter E, Sobin LH, Kikkendal JW, Bowen P: Body iron stores and risk of colonic neoplasia. J Natl Cancer Inst 1994, 86, 455–460.
  21. Nelson RL: Iron and colorectal cancer risk: Human studies: Nutr Rev 2001, 59, 140–148.
  22. Strasser-Weippl K, Ludwig H: Ferritin as prognostic marker in multiple myeloma in patient undergoing autologous transplantation. Leukemia Lymphoma 2014, in press.
  23. Kalousová M, Krechler T, Jáchymová M, Kuběna AA, Zák A, Zima T: Ferritin as an independent mortality predictor in patients with pancreas cancer. Results of a pilot study. Tumor Biol 2012, 33, 1685–1700, 1695–177.
  24. Alkhateeb AA, Han B, Connor JR: Ferritin stimulates breast cancer cells through an iron independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res Treat 2013, 137, 733–744.
  25. Kikuchi S, Kobune M, Iyama S, Sato T, Murase K, Kawano Y, Takada K, Ono K, Hayashi T, Miyanishi K, Sato Y, Takimoto R, Kato J: Prognostic significance of serum ferritin level at diagnosis in myelodysplastic syndrome. Int J Hematol 2012, 95, 527–534.
  26. Dizdaroglu M, Jaruga P: Mechanisms of free radical-induced demage to DNA. Free Radic Res 2012, 26, 382–419.
  27. Stevens RG, Jones DY, Miccozzi MS, Taylor PR: Body iron stores and the risk of cancer. N Engl J Med 1988, 319, 1047–1052.
  28. Elmberg M, Hultcrantz R, Ekbom A, Brandt L, Olsson S, Olsson R, Lindgren S, Lööf L, Stål P, Wallerstedt S, Almer S, Sandberg-Gertzén H, Askling J: Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 2003, 125, 1733–1741.
  29. Edgren G, Reilly M, Hjalgrim H, Tran TN, Rostgaard K, Adami J, Titlestad K, Shanwell A, Melbye M, Nyrén O: Donation frequency, iron loss, and risk of cancer among blood donors. J Natl Cancer Inst 2008, 100, 572–579.
  30. Lambert R: Overview of the epidemiology and prevention of digestive cancer. World Gastroenterology News 2003, 82, 21–25.
  31. Brenner H, Rothenbacher D, Arndt V: Epidemiology of stomach cancer. Methods Mol Biol 2009, 472, 467–477.
  32. Crew KD, Neugut AI: Epidemiology of gastric cancer. World J Gastroenterol 2006, 12, 354–362.
  33. Eslick GD: Epidemiology of esophageal cancer. Gastroenterol Clin North Am 2009, 38, 17–25.
  34. Lerut T, Coosemans W, Decketr G, De Leyn P, Moons J, Nafteux P, Van Raemdonck D: Extended surgery for cancer of the esophagus and gastroesophageal junction. J Surg Res 2004, 117, 58–63.
  35. Khosravi Shahi P, Diaz Munoz de la Espada VM, Garcia Alfonso P, Encina Garcia S, Izarzugaza Peron Y, Arranz Cozar JL, Hernandez Maria B, Perez Manga G: Management of gastric adenocarcinoma. Clin Transl Oncol 2007, 9, 438–442.
  36. Wilkinson N, Scott-Conner CE: Surgical therapy for colorectal adenocarcinoma. Gastroenterol Clin North Am 2008, 37, 253–267.
  37. Romer J, Nielsen BS, Ploug M: The urokinase receptor as a potential target in cancer therapy. Curr Pharm Des 2004, 10, 2359–2376.
  38. Illemann M, Hansen U, Nielsen HJ, Andreasen PA, Høyer-Hansen G, Lund LR, Danø K, Nielsen BS: Leadingedge myelofibroblast in human colon cancer express plasminogen activator inhibitor 1. Am J Clin Pathol 2004, 122, 256–265.
  39. Beyer BC, Heiss MM, Simon EH, Gruetzner KU, Babic R, Jauch KW, Schildberg FW, Allgayer M: Urokinase System expression in gastric carcinoma. Prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimes. Cancer 2006, 106, 1026–1035.
  40. Seetoo DQ, Crowe PJ, Russell PJ, Yang JL: Quantitative expression of protein markers of plasminogen activation system in prognosis in colorectal cancer. J Surg Oncol 2003, 82, 184–193.
  41. Shiomi H, Eguchi Y, Tani T, Kodama M, Hattori T: Cellular distribution and clinical value of urokinase-type plasminogen activator, its receptor and plasminogen activator inhibitor-2 in esophageal squamous cell carcinoma. Am J Pathol 2000, 156, 567–575.
  42. Heiss MM, Allgayer H, Gruetzner KU, Babic R, Jauch KW, Schildberg FW: Clinical value of an extended biological staging by bone marrow micrometastases and tumor associated proteases in gastric cancer. Ann Surg 1997, 226, 726–745, 736–744, discussion 744–745.
  43. Mulcahy HE, Duffy MJ, Gibbons D, McCarthy P, Parfrey NA, O’Donoghue DP, Sheahan K: Urokinase type plasminogen activator and outcome in Dukes’B colorectal cancer. Lancet 1994, 344, 583–684, 583–584.
  44. Zhang L, Zhao ZS, Ru GQ, Ma J: Correlative studies on uPA mRNA, uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer. World J Gastroenterol 2006, 12, 3970–3976.
  45. Hogdall CK, Christensen IJ, Stephens RW, Sorensen S, Norgaard-Petersen B, Nielsen HJ: Serum tetranectin is an independent prognostic marker in colorectal cancer and weakly correlated with plasma suPAR, plasma PAI-1 and serum CEA. APMIS 2002, 110, 630–638.
  46. Heiss MM, Allgayer H, Gruetzner KU, Funke I, Babic R, Jauch KW, Schildberg FW: Individual development and uPA receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nat Med 1995, 1, 1035–1039.
  47. Usnarska-Zubkiewicz L, Strutyńska-Karpińska M, Podolak-Dawidziak M, Nienartowicz M, Grabowski K, Prajs I, Kuliczkowski K: Epithelial bone marrow cells in patients with advanced esophageal squamous cell carcinoma. Neoplasma 2009, 56, 245–251.
  48. Linkesch W, Ludwig H: Serum ferritin and beta-2-microglobulin in patients with multiple myeloma. Cancer Detect Prev 1983, 6, 297–301.
  49. Cozzi A, Corsi B, Levi S, Santambrogio P, Biasiotto G, Arosio P: Analysis of the biologic functions of H and L ferritin in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin. Blood 2004, 103, 2377–2383.
  50. Cozzi A, Levi S, Corsi B, Santambrogio P, Campanella A, Gerardi G, Arosio P: Role of iron and ferritin in TNF alpha induced apoptosis in HeLa cells. FEBS lett 2003, 537, 187–192.
  51. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, Beaumont C, Torti FM, Torti SV, Franzoso G: Ferritin heavy chain upregulation by NF-kappa B inhibits TNF alpha-induced apoptosis by suppressing reactive oxygen species. Cell 2004, 119, 529–542.
  52. Dass K, Ahmed A, Azmi AS, Sarkar SH, Sarkar FH: Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 2008, 34, 122–136.
  53. Fazioli F, Blasi F: Urokinase-type plasminogen activator and its receptor: new targets for anti-metastatic therapy? Trends Pharmac Sci 1994, 15, 25–29.
  54. Pillay V, Dass CR, Choong PF: The urokinase plasminogen activator receptor as a gene therapy target for cancer. Trends Biotechnol 2007, 25, 33–39.