Preliminary assessment of the possibility of using urokinase uPA and urokinase receptor uPAR as universal diagnostic criteria in patients with colorectal and gastric adenocarcinoma

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Abstract

Background. Lack of universal diagnostic parameters that can accurately and reliably diagnose presence of a malignant neoplasm, anticancer drug effectiveness or metastasis development including dormant ones and also to detect the progression or relapse of the disease at an early stage put on the first place studies related to the identification of such markers. Increased secretion and activity of the urokinase type plasminogen activator (uPA), its receptor (uPAR) accompany many types of malignant neoplasms, contributing their progression and metastasis, as well as the emergence of chemoresistance. So today these proteins are promising diagnostic targets in oncology.

Aim. To evaluate the diagnostic significance of the expression levels of uPA and uPAR in blood serum of patients with colorectal and gastric adenocarcinoma and uPA/uPAR distribution in samples obtained from the primary tumor node, to assess the possibility of their use as universal diagnostic indicators in cancer patients at the stage of primary treatment.

Materials and methods. The study included patients with colorectal and gastric adenocarcinoma in the amount of 50 people and 25 healthy volunteers. The content of uPA and uPAR in blood serum was assessed by enzyme-linked immunosorbent assay, the level of expression of the studied proteins in tumor tissue was assessed using immunohistochemical staining with antibodies to uPA and uPAR.

Results. It was found that in comparison with healthy donors uPA serum concentration was significantly higher in all patients with adenocarcinoma, regardless of gender, and the uPAR content in the blood serum was significantly higher in women. Immunohistochemical staining data showed that the expression of these two proteins in tumor tissue significantly exceeds their expression in normal tissue.

Conclusion. Based on the obtained data the possibility of using uPA in blood serum as a universal diagnostic criterion in patients with colorectal and gastric adenocarcinoma regardless of gender was shown and uPAR in female patients.

About the authors

Polina S. Klimovich

Lomonosov Moscow State University

Email: lex2050@mail.ru
ORCID iD: 0000-0002-8260-5542

Cand. Sci. (Biol.)

Russian Federation, Moscow

Ksenia A. Rubina

Lomonosov Moscow State University

Email: rkseniya@mail.ru
ORCID iD: 0000-0002-7166-7406

D. Sci. (Biol.)

Russian Federation, Moscow

Nikita A. Mironov

Lomonosov Moscow State University

Email: nikimir29@mail.ru
ORCID iD: 0000-0001-6729-4371

Clinical Resident

Russian Federation, Moscow

Viktor V. Kakotkin

Lomonosov Moscow State University

Email: axtroz4894@gmail.com
ORCID iD: 0000-0003-0352-2317

surgeon

Russian Federation, Moscow

Nina A. Oleynikova

Lomonosov Moscow State University

Email: ale_x_05@mail.ru
ORCID iD: 0000-0001-8564-8874

Cand. Sci. (Med.)

Russian Federation, Moscow

Pavel G. Mal`kov

Lomonosov Moscow State University

Email: malkovp@gmail.com
ORCID iD: 0000-0001-5074-3513

D. Sci. (Med.)

Russian Federation, Moscow

Valery A. Kubyshkin

Lomonosov Moscow State University

Email: Vkubyshkin@mc.msu.ru
ORCID iD: 0000-0003-2631-7631

D. Sci. (Med.), Acad. RAS

Russian Federation, Moscow

Eduard A. Galliamov

Sechenov First Moscow State Medical University (Sechenov University)

Email: svgalliamova@gmail.com
ORCID iD: 0000-0002-6359-0998

D. Sci. (Med.), Prof.

Russian Federation, Moscow

Mikhail A. Agapov

Lomonosov Moscow State University

Email: getinfo911@mail.ru
ORCID iD: 0000-0002-6569-7078

D. Sci. (Med.)

Russian Federation, Moscow

Ekaterina V. Semina

Lomonosov Moscow State University

Author for correspondence.
Email: e-semina@yandex.ru
ORCID iD: 0000-0002-3927-9286

Cand. Sci. (Biol.)

Russian Federation, Moscow

References

  1. Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14(2):89-103. doi: 10.5114/pg.2018.81072
  2. Machlowska J, Baj J, Sitarz M, et al. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci. 2020;21(11). PMID: 32512697
  3. Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Current Pharmaceutical Design. 2004;10(1):39-49. PMID: 147544044
  4. Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front Оncol. 2018;8:24. doi: 10.3389/fonc.2018.00024
  5. Zubkova ES, Men'shikov MY, Plekhanova OS, et al. Urokinase stimulates production of matrix metalloproteinase-9 in fibroblasts with involvement of reactive oxygen species. Bull Exp Biol Med. 2014;157(1):18-21. PMID: 24906961
  6. Leduc D, Beaufort N, de Bentzmann S, et al. The Pseudomonas aeruginosa LasB metalloproteinase regulates the human urokinase-type plasminogen activator receptor through domain-specific endoproteolysis. Infect Immun. 2007;75(8):3848-58. PMID: 17517866
  7. Mustjoki S, Sidenius N, Sier CF, et al. Soluble urokinase receptor levels correlate with number of circulating tumor cells in acute myeloid leukemia and decrease rapidly during chemotherapy. Cancer Res. 2000;60(24):7126-32. PMID: 11156421
  8. Su SC, Lin CW, Yang WE, et al. The urokinase-type plasminogen activator (uPA) system as a biomarker and therapeutic target in human malignancies. Expert Opin Ther Targets. 2016;20(5):551-66. PMID: 6667094
  9. Rubina KA, Semina EV, Tkachuk VA. Guidance molecules and chemokines in angiogenesis and vascular remodeling. J Evol Biochem Physiol. 2017;53(5):349-67.
  10. Huebschman ML, Lane NL, Liu H, et al. Molecular heterogeneity in adjacent cells in triple-negative breast cancer. Breast Cancer (Dove Med Press). 2015;7:231-7. PMID: 26316815
  11. Duffy MJ. Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clin Chem. 2002;48(8):1194-7. PMID: 12142372
  12. Dariusz S, Agnieszka M, Elzbieta R, et al. A potency of plasminogen activation system in long-term prognosis of endometrial cancer: a pilot study. Eur J Obstet Gynecol Reprod Biol. 2012;163(2):193-9. doi: 10.1016/j.ejogrb.2012.03.031
  13. Chandran VI, Eppenberger-Castori S, Venkatesh T, et al. HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer. Oncoscience. 2015;2(3):207-24. doi: 10.18632/oncoscience.146
  14. Baker EA, Leaper DJ, Hayter JP, et al. Plasminogen activator system in oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 2007;45(8):623-7. PMID: 17590247
  15. Yang JL, Seetoo DQ, Wang Y, et al. Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. Int J Cancer. 2000;89(5):431-9. doi: 10.1002/1097-0215(20000920)89:5<431::AID-IJC6>3.0.CO;2-V
  16. Asuthkar S, Stepanova V, Lebedeva T, et al. Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer. Mol Biol Cell. 2013;24(17):2620-32. doi: 10.1091/mbc.e12-04-0306
  17. Ding Y, Zhang H, Zhong M, et al. Clinical significance of the uPA system in gastric cancer with peritoneal metastasis. Eur J Med Res. 2013;18:28. PMID: 23985164
  18. Kaneko T, Konno H, Baba M, et al. Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci. 2003;94(1):43-9. doi: 10.1111/j.1349-7006.2003.tb01350.x
  19. Semina EV, Rubina KA, Shmakova AA, et al. Downregulation of uPAR promotes urokinase translocation into the nucleus and epithelial to mesenchymal transition in neuroblastoma. J Cell Physiol. 2020;235(9):6268-86. PMID: 31990070
  20. Kim SE, Paik HY, Yoon H, et al. Sex- and gender-specific disparities in colorectal cancer risk. World J Gastroenterol. 2015;21(17):5167-75. doi: 10.3748/wjg.v21.i17.5167
  21. Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol. 2010;11(1):23-36. doi: 10.1038/nrm2821
  22. Al-Janabi O, Taubert H, Lohse-Fischer A, et al. Association of tissue mRNA and serum antigen levels of members of the urokinase-type plasminogen activator system with clinical and prognostic parameters in prostate cancer. Biomed Res Int. 2014;2014:972587. doi: 10.1155/2014/972587

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2. Fig. 1. uPAR serum concentrations of healthy volunteers and of patients with adenocarcinoma of the gastrointestinal tract.

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3. Fig. 2. uPAR serum concentrations of healthy volunteers and of cancer men and women.

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4. Fig. 3. Immunohistochemical staining with urokinase antibodies of the intact mucous membrane layer of the stomach (a) and of the sigmoid colon (b) and gastric adenocarcinoma (c) and sigmoid colon adenocarcinoma (d); ×400.

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5. Fig. 4. Immunohistochemical staining with antibodies to the urokinase receptor of the intact mucous membrane layer of the sigmoid colon (a) and the stomach (b) and sigmoid colon adenocarcinoma (c) and gastric adenocarcinoma (d); ×400.

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