The Role of Stromal Proteolytic Systems in Cancer Progression (Review)

Oncological diseases belong to life-threatening pathologies being the second most frequent cause of morbidity and mortality after cardiovascular diseases. Clarification of carcinogenesis mechanisms makes it possible to expand the stock of tools available for prevention of critical illness accompanying this pathological condition.
Nowadays, proteolytic systems of tumor microenvironment (ТМЕ) are regarded as key regulators of a tumor progression including tumor growth, invasion and metastazing. The review discusses ТМЕ structure and role in cancer progression.
Recent data decipher the role of proteolytic systems in the interaction stromal cells with tumor cells in different types of cancer in humans. The most known proteolytic systems contributed to cancer progression are matrix metalloproteinase system (MMP), urokinase-type plasminogen activator system (uPA-system), various cathepsins, granzymes, and elastase. Inhibition of extracellular proteolysis in the course of an oncological process is considered an effective approach to cancer therapy.

1. Bussard K.M., Mutkus L., Stumpf K., Gomez-Manzano C., Marini F.C. Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 2016; 18 (1): 84. DOI: 10.1186/s13058-016-0740-2. PMID: 27515302

2. Bougnaud S., Golebiewska A., Oudin A., Keunen O., Harter P.N., Mäder L., Azuaje F., Fritah S., Stieber D., Kaoma T., Vallar L., Brons N.H., Daubon T., Miletic H., Sundstrøm T., Herold-Mende C., Mittelbronn M., Bjerkvig R., Niclou S.P. Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget. 2016; 7 (22): 31955–31971. DOI: 10.18632/oncotarget.7454. PMID: 27049916

3. Nilendu P., Sarode S.C., Jahagirdar D., Tandon I., Patil S., Sarode G.S., Pal J.K., Sharma N.K. Mutual concessions and compromises between stromal cells and cancer cells: driving tumor development and drug resistance. Cell Oncol (Dordr). 2018; 41 (4): 353–367. DOI: 10.1007/s13402-018-0388-2. PMID: 30027403

4. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011; 144 (5): 646–674. DOI: 10.1016/j.cell.2011.02.013. PMID: 21376230

5. Bhome R., Al Saihatia H.A., Goh R.W., Bullock M.D., Primrose J.N., Thomas G.J., Sayan A.E., Mirnezami A.H. Translational aspects in targeting the stromal tumor microenvironment: From bench to bedside. New Horiz. Transl. Med. 2016; 3 (1): 9–21. DOI: 10.1016/j.nhtm.2016.03.001. PMID: 27275004

6. Amend S. R., Pienta K. J. Ecology meets cancer biology: the cancer swamp promotes the lethal cancer phenotype. Oncotarget. 2015; 6 (12): 9669–9678. DOI: 10.18632/oncotarget.3430. PMID: 25895024

7. Amend S. R., Roy S., Brown J. S., Pienta, K. J. Ecological paradigms to understand the dynamics of metastasis. Cancer Lett. 2016; 380 (1): 237–242. DOI: 10.1016/j.canlet.2015.10.005. PMID: 26458994

8. Camacho D. F., Pienta K. J. Disrupting the networks of cancer. Clin. Cancer Res. 2012; 18 (10): 2801–2808. DOI: 10.1158/1078-0432.CCR-12-0366. PMID: 22442061

9. de Groot A. E., Roy S., Brown J. S., Pienta K. J., Amend S. R. Revisiting seed and soil: examining the primary tumor and cancer cell foraging in metastasis. Mol. Cancer Res. 2017; 15 (4): 361–370. DOI: 10.1158/1541-7786.MCR-16-0436. PMID: 28209759

10. Maley C. C., Aktipis A., Graham T.A., Sottoriva A., Boddy A.M., Janiszewska M., Silva A.S., Gerlinger M., Yuan Y., Pienta K.J., Anderson K.S., Gatenby R., Swanton C., Posada D., Wu C.I., Schiffman J.D., Hwang E.S., Polyak K., Anderson A.R.A., Brown J.S., Greaves M., Shibata D. Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 2017; 17 (10): 605–619. DOI: 10.1038/nrc.2017.69. PMID: 28912577

11. Valkenburg K.C., Amber E. de Groot, Kenneth J. Pienta. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018; 15 (6): 366–381. DOI: 10.1038/s41571-018-0007-1. PMID: 29651130

12. Najafi M., Goradel N.H., Farhood B., Salehi E., Solhjoo S., Toolee H., Kharazinejad E., Mortezaee K. Tumor microenvironment: Interactions and therapy. J Cell Physiol. 2019; 234 (5): 5700–5721. DOI: 10.1002/jcp.27425. PMID: 30378106

13. Breznik B., Motaln H., Lah Turnšek T. Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours. Biol. Chem. 2017; 398 (7): 709–719. DOI: 10.1515/hsz-2016-0283. PMID: 28002021

14. Bourboulia D., Stetler-Stevenson W.G. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol. 2010; 20 (3): 161–168. DOI: 10.1016/j.semcancer.2010.05.002. PMID: 20470890

15. Cun X., Li M., Wang S., Wang Y., Wang J., Lu Z., Yang R., Tang X., Zhang Z., He Q. A size switchable nanoplatform for targeting the tumor microenvironment and deep tumor penetration. Nanoscale. 2018; 10 (21): 9935–9948. DOI: 10.1039/c8nr00640g. PMID: 29770822

16. Cammarota F., Laukkanen M.O. Mesenchymal Stem/Stromal Cells in Stromal Evolution and Cancer Progression. Stem Cells Int. 2016; 2016: 4824573. DOI: 10.1155/2016/4824573. PMID: 26798356

17. Kulikov V.A., Belyaeva L.E. Metabolic reprogramming of cancer cells. Vest. VGMU 2013; 12 (2): 6–18. [In Russ.]

18. Boroughs L. K., DeBerardinis R. J. Metabolic pathways promoting cancer cell survival and growth. Nature Cell Biology. 2015; 17 (4): 351–359. DOI: 10.1038/ncb3124. PMID: 25774832

19. Muppalla J.N., Muddana K., Dorankula S.P., Thokala M.R., Pasupula A.P. Microenvironment-a role in tumour progression and prognosis. J Clin Diagn Res. 2013; 7 (9): 2096–2099. DOI: 10.7860/JCDR/2013/6619.3419. PMID: 24179956

20. Antonio M.J., Le A. Different Tumor Microenvironments Lead to Different Metabolic Phenotypes. Adv Exp Med Biol. 2018; 1063: 119–129. DOI: 10.1007/978-3-319-77736-8_9. PMID: 29946782

21. Kidd S., Spaeth E., Watson K., Burks J., Lu H., Klopp A., Andreeff M., Marini F.C. Origins of the tumor microenvironment: quantitative assessment of adiposederived and bone marrow-derived stroma. PLoS One. 2012; 7 (2): e30563. DOI: 10.1371/journal.pone.0030563. PMID: 22363446

22. Xiong Y., McDonald L.T., Russell D.L., Kelly R.R., Wilson K.R., Mehrotra M., Soloff A.C., LaRue A.C. Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment. World J Stem Cells. 2015; 7 (2): 253–265. DOI: 10.4252/wjsc.v7.i2.253. PMID: 25815113

23. Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986; 315: 1650–1659. DOI: 10.1056/NEJM198612253152606. PMID: 3537791

24. Kojima Y., Acar A., Eaton E.N., Mellody K.T., Scheel C., Ben-Porath I., Onder T.T., Wang Z.C., Richardson A.L., Weinberg R.A., Orimo A. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumorpromoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A. 2010; 107 (46): 20009–20014. DOI: 10.1073/pnas.1013805107. PMID: 21041659

25. Spaeth E.L., Dembinski J.L., Sasser A.K., Watson K., Klopp A., Hall B., Andreeff M., Marini F. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One. 2009; 4: e4992. DOI: 10.1371/journal.pone.0004992. PMID: 19352430

26. Medrek C., Ponten F., Jirstrom K., Leandersersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012; 12: 306. DOI: 10.1186/1471-2407-12-306. PMID: 22824040

27. Smith H.A., Kang Y. The metastasis-promoting roles of tumor-associated immune cells. J Mol Med. 2013; 91 (4): 411–429. DOI: 10.1007/s00109-013-1021-5. PMID: 23515621

28. Brown J. M. Vasculogenesis: a crucial player in the resistance of solid tumours to radiotherapy. Br. J. Radiol. 2014; 87 (1035): 20130686. DOI: 10.1259/bjr.20130686. PMID: 24338942

29. Hida K., Akiyama K., Ohga N., Maishi N., Hida Y. Tumour endothelial cells acquire drug resistance in a tumour microenvironment. J. Biochem. 2013; 153 (3): 243–249. DOI: 10.1093/jb/mvs152. PMID: 23293323

30. Kibria G., Hatakeyama H., Harashima H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch. Pharm. Res. 2014; 37 (1): 4–15. DOI: 10.1007/s12272-013-0276-2. PMID: 24272889

31. Ruffell B., Coussens L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015; 27 (4): 462–472. DOI: 10.1016/j.ccell.2015.02.015. PMID: 25858805

32. van Beijnum J. R., Nowak-Sliwinska P., Huijbers E. J., Thijssen V. L., Griffioen A. W. The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol. Rev. 2015; 67 (2): 441–461. DOI: 10.1124/pr.114.010215. PMID: 25769965

33. Choi J., Cha Y. J., Koo J. S. Adipocyte biology in breast cancer: from silent bystander to active facilitator. Prog. Lipid Res. 2017; 69: 11–20. DOI: 10.1016/j.plipres.2017.11.002. PMID: 29175445

34. Kozin S. V., Kamoun W.S., Huang Y., Dawson M.R., Jain R.K., Duda D.G. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res. 2010; 70 (14): 5679–5685. DOI: 10.1158/0008-5472.CAN-09-4446. PMID: 20631066

35. Ribas A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 2015; 5 (9): 915–919. DOI: 10.1158/2159-8290.CD-15-0563. PMID: 26272491

36. Roca H., Hernandez J., Weidner S., McEachin R.C., Fuller D., Sud S., Schumann T., Wilkinson J.E., Zaslavsky A., Li H., Maher C.A., Daignault-Newton S., Healy P.N., Pienta K.J. Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS ONE. 2013; 8 (10): e76773. DOI: 10.1371/journal.pone.0076773. PMID: 24124593

37. Jarvelainen H., Sainio A., Koulu M., Wight T.N., Penttinen R. Extracellular matrix molecules: potential targets in pharmacotherapy. Pharmacol. Rev. 2009; 61 (2): 198–223. DOI: 10.1124/pr.109.001289. PMID: 19549927

38. Mammoto T., Ingber D. E. Mechanical control of tissue and organ development. Development. 2010; 137 (9): 1407–1420. DOI: 10.1242/dev.024166. PMID: 20388652

39. Hynes R. O., Naba A. Overview of the matrisome — an inventory of extracellular matrix constituents and functions. Cold Spring Harb. Perspect. Biol. 2012; 4 (1): a004903. DOI: 10.1101/cshperspect.a004903. PMID: 21937732

40. Butcher D.T., Alliston T., Weaver V.M. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009; 9 (2): 108–122. DOI: 10.1038/nrc2544. PMID: 19165226

41. Levental K.R., Yu H., Kass L., Lakins J.N., Egeblad M., Erler J.T., Fong S.F., Csiszar K., Giaccia A., Weninger W., Yamauchi M., Gasser D.L., Weaver V.M. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009; 139 (5): 891–906. DOI: 10.1016/j.cell.2009.10.027. PMID: 19931152

42. Mouw J. K., Yui Y., Damiano L., Bainer R.O., Lakins J.N., Acerbi I., Ou G., Wijekoon A.C., Levental K.R., Gilbert P.M., Hwang E.S., Chen Y.Y., Weaver V.M. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 2014; 20 (4): 360-367. DOI: 10.1038/nm.3497. PMID: 24633304

43. Kaukonen R., Mai A., Georgiadou M., Saari M., De Franceschi N., Betz T., Sihto H., Ventelä S., Elo L., Jokitalo E., Westermarck J., Kellokumpu-Lehtinen P.L., Joensuu H., Grenman R., Ivaska J. Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription. Nat. Commun. 2016; 7: 12237. DOI: 10.1038/ncomms12237. PMID: 27488962

44. Olumi A.F., Grossfeld G.D., Hayward S.W., Carroll P.R., Tlsty T.D., Cunha G.R. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999; 59 (19): 5002–5011. PMID: 10519415

45. Turk B., Turk D., Salvesen G.S. Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators. Curr Pharm Des. 2002; 8 (18): 1623–1637. PMID: 12132995

46. Hedrich J., Lottaz D., Meyer K., Yiallouros I., Jahnen-Dechent W., Stöcker W., Becker-Pauly C. Fetuin-A and Cystatin C Are Endogenous Inhibitors of Human Meprin Metalloproteases. Biochemistry. 2010; 49 (39): 8599-8607. DOI: 10.1021/bi1004238. PMID: 20806899

47. Wyganowska-Świątkowska M., Tarnowski M., Murtagh D., Skrzypczak-Jankun E., Jankun J. Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically. Int J Mol Med. 2019; 43 (1): 15–25. DOI: 10.3892/ijmm.2018.3983. PMID: 30431071

48. Pulz L.H., Strefezzi R.F. Proteases as prognostic markers in human and canine cancers. Vet Comp Oncol. 2017; 15 (3): 669–683. DOI: 10.1111/vco.12223. PMID: 27136601

49. Verollet C., Charrière G.M., Labrousse A., Cougoule C., Le Cabec V., Maridonneau-Parini I. Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough. Eur J Immunol. 2011; 41: 2805–2813. DOI: 10.1002/eji.201141538. PMID: 21953638

50. Roycik M.D., Fang X., Sang Q.X. A fresh prospect of extracellular matrix hydrolytic enzymes and their substrates. Curr Pharm Des. 2009; 15 (12): 1295–1308. PMID: 19355969

51. Christiaens V., Lijnen H.R. Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue. Arch Physiol Biochem. 2006; 112 (4–5): 254–259. DOI: 10.1080/13813450601093567. PMID: 17178599

52. Riddick A.C., Shukla C.J., Pennington C.J., Bass R., Nuttall R.K., Hogan A., Sethia K.K., Ellis V., Collins A.T., Maitland N.J., Ball R.Y., Edwards D.R. Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues. Br J Cancer. 2005; 92 (12): 2171–2180. DOI: 10.1038/sj.bjc.6602630. PMID: 15928670

53. Eatemadi A., Aiyelabegan H.T., Negahdari B., Mazlomi M.A., Daraee H., Daraee N., Eatemadi R., Sadroddiny E. Role of protease and protease inhibitors in cancer pathogenesis and treatment. Biomed Pharmacother. 2017; 86: 221–231. DOI: 10.1016/j.biopha.2016.12.021. PMID: 28006747

54. Liu W.L., Liu D., Cheng K., Liu Y.J., Xing S., Chi P.D., Liu X.H., Xue N., Lai Y.Z., Guo L., Zhang G. Evaluating the diagnostic and prognostic value of circulating cathepsin S in gastric cancer. Oncotarget. 2016; 7 (19): 28124–28138. DOI: 10.18632/oncotarget.8582. PMID: 27058412

55. Pišlar A., Perišić Nanut M., Kos J. Lysosomal cysteine peptidases-Molecules signaling tumor cell death and survival. Semin Cancer Biol. 2015; 35: 168–179. DOI: 10.1016/j.semcancer.2015.08.001. PMID: 26255843

56. Wallin H., Abrahamson M., Ekstrom U. Cystatin C properties crucial for uptake and inhibition of intracellular target enzymes. J Biol Chem. 2013; 288 (23): 17019–17029. DOI: 10.1074/jbc.M113.453449. PMID: 23629651

57. Mason S.D., Joyce J.A. Proteolytic networks in cancer. Trends Cell Biol. 2011; 21 (4): 228–237. DOI: 10.1016/j.tcb.2010.12.002. PMID: 25086747

58. Jaiswal R.K., Varshney A. K., Yadava P.K. Diversity and functional evolution of the plasminogen activator system. Biomed Pharmacother. 2018; 98: 886–898. DOI: 10.1016/j.biopha.2018.01.029. PMID: 29571259

59. Kugaevskaya E.V., Gureeva T.A., Timoshenko O.S., Solovyeva N.I. Urokinase-Type Plasminogen Activator System in Norm and in Life-Threatening Processes (Review).Obschaya reaninatologiya= General Reanimatology. 2018; 14 (6): 61–79. [In Russ.] DOI: 0.15360/1813-9779-2018-6-61-79

60. Mahmood N., Mihalcioiu C., Rabbani S.A. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front Oncol. 2018; 8: 24. DOI: 10.3389/fonc.2018.00024. PMID: 29484286

61. Binder B.R. Physiology and Pathophysiology of the Fibrinolytic System. Fibrinolysis. 1995; 9 (1): 3–8. DOI: 10.1016/S0268-9499 (05)80002-5.

62. Behrendt N., Ronne E., Dano K. The structure and function of the urokinase receptor, a membrane protein governing plasminogen activation on the cell surface. Biol Chem Hoppe Seyler. 1995; 376 (5): 269–279. PMID: 7662169

63. Skrzydlewska E., Sulkowska M., Koda M., Sulkowski S. Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. World J Gastroenterol. 2005; 11 (9): 1251–1266. DOI: 10.3748/wjg.v11.i9.1251. PMID: 15761961

64. Sotiropoulou G., Pampalakis G., Diamandis E.P. Functional roles of human kallikrein-related peptidases. J Biol Chem. 2009; 284 (48): 32989–32994. DOI: 10.1074/jbc.R109.027946. PMID: 19819870

65. Dass K., Ahmad A., Azmi A.S., Sarkar S.H., Sarkar F.H. Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev. 2008; 34 (2): 122–136. DOI: 10.1016/j.ctrv.2007.10.005. PMID: 18162327

66. Harris N.L.E., Vennin C., Conway J.R.W., Vine K.L., Pinese M., Cowley M.J.,Shearer R.F., Lucas M.C., Herrmann D., Allam A.H., Pajic M., Morton J.P.; Australian Pancreatic Cancer Genome Initiative, Biankin A.V., Ranson M.,Timpson P., Saunders D.N. SerpinB2 regulates stromal remodelling andlocal invasion in pancreatic cancer. Oncogene. 2017; 36 (30): 4288–4298. DOI: 10.1038/onc.2017.63. PMID: 28346421

67. Sato M., Kawana K., Adachi K., Fujimoto A., Yoshida M., Nakamura H., Nishida H., Inoue T., Taguchi A., Takahashi J., Kojima S., Yamashita A., Tomio K., Nagamatsu T., Wada-Hiraike O., Oda K., Osuga Y., Fujii T. Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells. Int. J. Oncol. 2016; 48 (2): 829–835. DOI: 10.3892/ijo.2015.3283. PMID: 26676222

68. Ellis V. In: Handbook of Proteolytic Enzymes, vol. 3 (Rawlings N.D., Salvesen G., eds.), Academic Press, 2013: 2938–2945.

69. Noh H., Hong S., Huang S. Role of urokinase receptor in tumor progression and development. Theranostics.2013; 3 (7): 487–495. DOI: 10.7150/thno.4218. PMID: 23843896.

70. Gonias S.L., Hu J. Urokinase receptor and resistance to targeted anticancer agents. Front. Pharmacol. 2015; 6: 154. DOI: 10.3389/fphar.2015.00154. PMID: 26283964

71. Santibanez J.F., Obradović H., Kukolj T., Krstić J. Transforming growth factor-β, matrix metalloproteinases, and urokinase-type plasminogen activator interaction in the cancer epithelial to mesenchymal transition. Dev. Dyn. 2018; 247 (3): 382–395. DOI: 10.1002/dvdy.24554. PMID: 28722327

72. Ulisse S., Baldini E., Sorrenti S., D’Armiento M. The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr. Cancer Drug Targets. 2009; 9 (1): 32–71. DOI: 10.2174/156800909787314002. PMID: 19200050

73. Jo M., Lester R.D., Montel V., Eastman B., Takimoto S., Gonias S.L. Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling. J. Biol. Chem. 2009; 284 (34): 22825–22833. DOI: 10.1074/jbc.M109.023960. PMID: 19546228

74. Gilder A.S., Natali L., Van Dyk D.M., Zalfa C., Banki M.A., Pizzo D.P., Wang H., Klemke R.L., Mantuano E., Gonias S.L. The Urokinase Receptor Induces a Mesenchymal Gene Expression Signature in Glioblastoma Cells and Promotes Tumor Cell Survival in Neurosphere. Sci. Rep. 2018; 8 (1): 2982. DOI: 10.1038/s41598-018-21358-1. PMID: 29445239

75. Vandooren J., Opdenakker G., Loadman P.M., Edwards D.R. Proteases in cancer drug delivery. Adv. Drug. Deliv. Rev. 2016; 97: 144–155. DOI: 10.1016/j.addr.2015.12.020. PMID: 26756735

76. Mekkawy A.H., Pourgholami M.H., Morris D.L. Involvement of urokinasetype plasminogen activator system in cancer: an overview. Med. Res. Rev. 2014; 34 (5): 918–956. DOI: 10.1002/med.21308. PMID: 24549574.

77. Alizadeh H., Ma D., Berman M., Bellingham D., Comerford S.A., Gething M.J.H., Sambrook J.F., Niederkorn J.Y. Tissue-type plasminogen activator-induced invasion and metastasis of murine melanomas. Curr Eye Res. 1995; 14 (6): 449–458. PMID: 7671626

78. Ma D., Gerard R.D., Li X-Y., Alizadeh H., Nierderkorn J.Y. Inhibition of metastasis of intraocular melanomas by adenovirus-mediated gene transfer of plasminogen activator inhibitor type-1 in an athymic mouse model. Blood. 1997; 90 (7): 2738–2746. PMID: 9326241

79. Liu G., Shuman M.A., Cohen R.L. Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer 1995; 60 (4): 501–506. PMID: 7829264

80. Duffy M.J. 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): 1194–1197. PMID: 12142372

81. Croucher D.R., Saunders D.N., Lobov S., Ranson M. Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat. Rev. Cancer. 2008; 8 (7): 535–545. DOI: 10.1038/nrc2400. PMID: 18548086.

82. Unkeless J., Dano K., Kellerman G.M., Reich E. Fibrinolysis associated with oncogenic transformation. Partial purification and characterization of the cell factor, a plasminogen activator J. Biol. Chem. 1974; 249 (13): 4295-4305. PMID: 4368727.

83. Danø K., Reich E. Serine enzymes released by cultured neoplastic cells J. Exp. Med. 1978; 147 (3): 745–757. DOI: 10.1084/jem.147.3.745. PMID: 632749

84. Skriver L., L.I. Larsson, V. Kielberg, L.S. Nielsen, P.B. Andresen, P. Kristensen, K. Danø Immunocytochemical localization of urokinase-type plasminogen activator in Lewis lung carcinoma. J. Cell Biol. 1984; 99 (2): 753–757. DOI: 10.1083/jcb.99.2.753. PMID: 6378927

85. Pyke C., Kristensen P., Ralfkiaer E., Grøndahl-Hansen J., Eriksen J., Blasi F., Danø K. Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas Am. J. Pathol. 1991; 138 (5): 1059–1067. PMID: 1850957

86. Grøndahl-Hansen J., Ralfkiaer E., Kirkeby L.T., Kristensen P., Lund L.R., Danø K. Localization of urokinase-type plasminogen activator in stromal cells in adenocarcinomas of the colon in humans. Am. J. Pathol. 1991; 138 (1): 111–117. PMID: 1702928

87. Usher P.A., Thomsen O.F., Iversen P., Johnsen M., Brünner N., Høyer-Hansen G., Andreasen P., Danø K., Nielsen B.S. Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue. Int. J. Cancer. 2005; 113 (6): 870–880. DOI: 10.1002/ijc.20665. PMID: 15515049

88. Nielsen B.S., Sehested M., Timshel S., Pyke C., Danø K. Messenger RNA for urokinase plasminogen activator is expressed in myofibroblasts adjacent to cancer cells in human breast cancer Lab. Investig. J. Tech. Methods Pathol. 1996; 74 (1): 168-177. PMID: 8569179

89. Nielsen B.S., Sehested M., Duun S., Rank F., Timshel S., Rygaard J., Johnsen M., Danø K. Urokinase plasminogen activator is localized in stromal cells in ductal breast cancer. Lab. Investig. J. Tech. Methods Pathol. 2001; 81 (11): 1485–1501. PMID: 11706057

90. Pyke C., Graem N., Ralfkiaer E., Rønne E., Høyer-Hansen G., Brünner N., Danø K. Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma Cancer Res. 1993; 53 (8): 1911–1915. PMID: 8385573

91. Rømer J., Lund L.R., Eriksen J., Ralfkiaer E., Zeheb R., Gelehrter T.D., Danø K., Kristensen P. Differential expression of urokinase-type plasminogen activator and its type-1 inhibitor during healing of mouse skin wounds. J. Invest. Dermatol. 1991; 97 (5): 803–811. DOI: 10.1111/1523-1747.ep12486833. PMID: 1919045

92. Rømer J., Pyke C., Lund L.R., Ralfkiaer E., Danø K. Cancer cell expression of urokinase-type plasminogen activator receptor mRNA in squamous cell carcinomas of the skin J. Invest. Dermatol. 2001; 116 (3): 353–358. DOI: 10.1046/j.1523-1747.2001.01241.x. PMID: 11231307

93. Ciavarella S., Laurenzana A., De Summa S., Pilato B., Chillà A., Lacalamita R., Minoia C., Margheri F., Iacobazzi A., Rana A., Merchionne F., Fibbi G., Del Rosso M., Guarini A., Tommasi S., Serratì S. u-PAR expression in cancer associated fibroblast: new acquisitions in multiple myeloma progression. BMC Cancer. 2017; 17 (1): 215. DOI: 10.1186/s12885-017-3183-y. PMID: 28340565

94. Wang L., Madigan M.C., Chen H., Liu F., Patterson K.I., Beretov J., O’Brien P.M., Li Y. Expression of urokinase plasminogen activator and its receptor in advanced epithelial ovarian cancer patients. Gynecol. Oncol. 2009; 114 (2): 265–272. DOI: 10.1016/j.ygyno.2009.04.031. PMID: 19450871

95. Hildenbrand R., Schaaf A. The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion. Int. J. Oncol. 2009; 34 (1): 15–23. DOI: 10.3892/ijo_00000124. PMID: 19082473

96. Nielsen B.S., Rank F., Illemann M., Lund L.R., Danø K. Stromal cells associated with early invasive foci in human mammary ductal carcinoma in situ coexpress urokinase and urokinase receptor. Int. J. Cancer. 2007; 120 (10): 2086–2095. DOI: 10.1002/ijc.22340. PMID: 17290405

97. Grøndahl-Hansen J., Christensen I.J., Rosenquist C., Brünner N., Mouridsen H.T., Danø K., Blichert-Toft M. High levels of urokinasetype plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res. 1993; 53 (11): 2513–2521. DOI: PMID: 8388317

98. Grøndahl-Hansen J., Peters H.A., van Putten W.L., Look M.P., Pappot H., Rønne E., Dano K., Klijn J.G., Brünner N., Foekens J.A. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res. 1995; 1 (10): 1079–1087. PMID: 9 815897

99. Sameni M., Cavallo-Medved D., Franco O.E., Chalasani A., Ji K., Aggarwal N., Anbalagan A., Chen X., Mattingly R.R., Hayward S.W., Sloane B.F. Pathomimetic avatars reveal divergent roles of microenvironment in invasive transition of ductal carcinoma in situ. Breast Cancer Res. 2017; 19 (1): 56. DOI: 10.1186/s13058-017-0847-0. PMID: 28506312

100. Mohamed M.M., Cavallo-Medved D., Rudy D., Anbalagan A., Moin K., Sloane B.F. Interleukin-6 increases expression and secretion of cathepsin B by breast tumor-associated monocytes. Cell. Physiol. Biochem. 2010; 25 (2-3): 315–324. DOI: 10.1159/000276564. PMID: 20110692

101. Daubriac J., Han S., Grahovac J., Smith E., Hosein A., Buchanan M.., Basik M., Boucher Y. The crosstalk between breast carcinoma-associated fibroblasts and cancer cells promotes RhoA-dependent invasion via IGF-1 and PAI-1. Oncotarget. 2018; 9 (12): 10375–10387. DOI: 10.18632/oncotarget.23735. PMID: 29535813

102. Mazar A.P., Ahn R.W., O’Halloran T.V. Development of novel therapeutics targeting the urokinase plasminogen activator receptor (uPAR) and their translation toward the clinic. Curr. Pharm. Des. 2011; 17 (19): 1970–1978. DOI: 10.2174/138161211796718152. PMID: 21711234

103. Cianfrocca M.E., Kimmel K.A., Gallo J., Cardoso T., Brown M.M., Hudes G., Lewis N., Weiner L., Lam G.N., Brown S.C., Shaw D.E., Mazar A.P., Cohen R.B. Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2), a beta integrin antagonist, in patients with solid tumours. Br. J. Cancer. 2006; 94 (11): 1621. DOI: 10.1038/sj.bjc.6603171. PMID: 16705310

104. Ertongur S., Lang S., Mack B., Wosikowski K., Muehlenweg B., Gires O. Inhibition of the invasion capacity of carcinoma cells by WX-UK1, a novel synthetic inhibitor of the urokinase-type plasminogen activator system. Int. J. Cancer. 2004; 110: 815–824. DOI: 10.1002/ijc.20192. PMID: 15170662

105. Brungs D., Chen J., Aghmesheh M., Vine K.L., Becker T.M., Carolan M.G., Ranson M. The urokinase plasminogen activation system in gastroesophageal cancer: Asystematic review and meta-analysis. Oncotarget. 2017; 8, 23099–23109. DOI: 10.18632/oncotarget.15485. PMID: 28416743

106. Xu X., Cai Y., Wei Y., Donate F., Juarez J., Parry G., Chen L., Meehan E.J., Ahn R.W., Ugolkov A., Dubrovskyi O., O’Halloran T.V., Huang M., Mazar A.P. Identification of a new epitope in uPAR as a target for the cancer therapeutic monoclonal antibody ATN-658, a structural homolog of the uPAR binding integrin CD11b (αM). PLoS One. 2014; 9 (1): e85349. DOI: 10.1371/journal.pone.0085349. PMID: 24465541

107. Jabłońska-Trypuć A., Matejczyk M., Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J. Enzyme Inhib. Med. Chem. 2016; 31 (sup1): 177–183. DOI: 10.3109/14756366.2016.1161620. PMID: 27028474

108. Cui N., Hu M., Khalil R.A. Biochemical and Biological Attributes of Matrix Metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017; 147: 1–73. DOI: 10.1016/bs.pmbts.2017.02.005. PMID: 28413025

109. Liu J., Khalil R.A. Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders. Prog. Mol. Biol. Transl. Sci. 2017; 148: 355–420. DOI: 10.1016/bs.pmbts.2017.04.003. PMID: 28662828

110. Fisher K.E., Fei Q., Laird E.R., Stock J.L., Allen M.R., Sahagan B.G., Strick C.A. Engineering autoactivating forms of matrix metalloproteinase-9 and expression of the active enzyme in cultured cells and transgenic mouse brain. Biochemistry. 2002; 41: 8289–8297. DOI: 10.1021/bi012076t. PMID: 12081477

111. Marchenko G.N., Ratnikov B.I., Rozanov D.V., Godzik A., Deryugina E.I., Strongin A.Y. Characterization of matrix metalloproteinase-26, a novel metalloproteinase widely expressed in cancer cells of epithelial origin. Biochem. J. 2001; 356: 705–718. DOI: 10.1042/bj3560705. PMID: 11389678

112. Merchant N., Nagaraju G.P., Rajitha B., Lammata S., Jella K.K., Buchwald Z.S., Lakka S.S., Ali A.N. Matrix metalloproteinases: Their functional role in lung cancer. Carcinogenesis. 2017; 38: 766–780. DOI: 10.1093/carcin/bgx063. PMID: 28637319

113. Morgunova E., Tuuttila A., Bergmann U., Isupov M., Lindqvist Y., Schneider G., Tryggvason K. Structure of human pro-matrix metalloproteinase-2: Activation mechanism revealed. Science. 1999; 284: 1667–1670. DOI: 10.1126/science.284.5420.1667. PMID: 10356396

114. Yadav L., Puri N., Rastogi V., Satpute P., Ahmad R., Kaur G. Matrix metalloproteinases and cancer - roles in threat and therapy. Asian Pac. J. Cancer Prev. 2014; 15: 1085–1091. DOI: 10.7314/apjcp.2014.15.3.1085. PMID: 24606423

115. Overall C.M., Kleifeld O. Tumour microenvironment – opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer. 2006; 6 (3): 227–239. DOI: 10.1038/nrc1821. PMID: 16498445

116. Ra H.J., Parks W.C. Control of matrix metalloproteinase catalytic activity. Matrix Biol. 2007; 26 (8): 587–596. DOI: 10.1016/j.matbio.2007.07.001. PMID: 17669641

117. Webb A.H., Gao B.T., Goldsmith Z.K., Irvine A.S., Saleh N., Lee R.P., Lendermon J.B., Bheemreddy R., Zhang Q., Brennan R.C., Johnson D., Steinle J.J., Wilson M.W., Morales-Tirado V.M. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer. 2017; 17: 434. DOI: 10.1186/s12885-017-3418-y. PMID: 28633655

118. Eiro N., Fernandez-Gomez J., Sacristan R., Sacristán R., Fernandez-Garcia B., Lobo B., Gonzalez-Suarez J., Quintas A., Escaf S., Vizoso F.J. Stromal factors involved in human prostate cancer development, progression and castration resistance. J. Cancer Res. Clin. Oncol. 2017; 143: 351–359. DOI: 10.1007/s00432-016-2284-3. PMID: 27787597

119. Su S.C., Hsieh M.J., Yang W.E., Chung W.H., Reiter R.J., Yang S.F. Cancer metastasis: Mechanisms of inhibition by melatonin. J. Pineal. Research. 2017; 62 (1). DOI: 10.1111/jpi.12370. PMID: 27706852

120. Solovуeva N.I., Timoshenko O.S., Gureeva T.A., Kugaevskaya E.V. Matrix metalloproteinases and their endogenous regulators in squamous cervical carcinoma (review of the own data). Biochem. Moscow Suppl. Ser. B. 2016; 10 (2): 110–121. DOI: 10.1134/S1990750816020116. PMID: 26716740

121. Gialeli C., Theocharis A.D., Karamanos N.K. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011; 278 (1): 16–27. DOI: 10.1111/j.1742-4658.2010.07919.x. PMID: 21087457

122. Stetler-Stevenson W.G. The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev. 2008; 27 (1): 57–66. DOI: 10.1007/s10555-007-9105-8. PMID: 18058195

123. Birgisson H., Nielsen H.J., Christensen I.J., Glimelius B., Brünner N. Preoperative plasma TIMP-1 is an independent prognostic indicator in patients with primary colorectal cancer: a prospective validation study. Eur J Cancer. 2010; 46 (18): 3323–3331. DOI: 10.1016/j.ejca.2010.06.009. PMID: 20619633

124. Egeblad M., Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002; 2 (3): 161–174. DOI: 10.1038/nrc745. PMID: 11990853

125. Sternlicht M.D., Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17: 463–516. DOI: 10.1146/annurev.cellbio.17.1.463. PMID: 11687497

126. Basset P., Bellocq J.P., Wolf C., Stoll I., Hutin P., Limacher J.M., Podhajcer O.L., Chenard M.P., Rio M.C., Chambon P. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature. 1990; 348 (6303): 699–704. DOI: 10.1038/348699a0. PMID: 1701851

127. Coussens L.M., Werb Z. Matrix metalloproteinases and the development of cancer Chem. Biol. 1996; 3 (11): 895–904. PMID: 8939708

128. Qiao Y., Wan J., Zhou L., Ma W., Yang Y., Luo W., Yu Z., Wang H. Stimuliresponsive nanotherapeutics for precision drug delivery and cancer therapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2019; 11 (1): e1527. DOI: 10.1002/wnan.1527. PMID: 29726115

129. Kurschat P., Zigrino P., Nischt R., Breitkopf K., Steurer P., Klein CE, Krieg T., Mauch C.Tissue inhibitor of matrix metalloproteinase-2 regulates matrix metalloproteinase-2 activation by modulation of membranetype 1 matrix metalloproteinase activity in high and low invasive melanoma cell lines. J. Biol. Chem. 1999; 274 (30): 21056–21062. DOI: 10.1074/jbc.274.30.21056. PMID: 10409657

130. Baumann P., Zigrino P., Mauch C., Breitkreutz D., Nischt R. Membrane-type 1 matrix metalloproteinase-mediated progelatinase A activation in non-tumorigenic and tumorigenic human keratinocytes Br. J. Cancer. 2000; 83 (10): 1387–1393. DOI: 10.1054/bjoc.2000.1454. PMID: 11044366

131. Kurschat P., Wickenhauser C., Groth W., Krieg T., Mauch C. Identification of activated matrix metalloproteinase-2 (MMP-2) as the main gelatinolytic enzyme in malignant melanoma by in situ zymography. J. Pathol. 2002; 197 (2): 179–187. DOI: 10.1002/path.108. PMID: 12015741

132. Hofmann U.B., Westphal J.R., Zendman A.J., Becker J.C., D.J. Ruiter D.J., van Muijen G.N. Expression and activation of matrix metalloproteinase-2 (MMP-2) and its co-localization with membrane-type 1 matrix metalloproteinase (MT1-MMP) correlate with melanoma progression. J.Pathol. 2000; 191 (3): 245-256. DOI: 10.1002/1096-9896(2000)9999:9999<::AID-PATH632>3.0.CO;2-# PMID: 10878545

133. Okada A., Bellocq J. P., Rouyer N., Chenard M. P., Rio M.C., Chambon P. and Basset P. Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc. Natl. Acad. Sci. USA. 1995; 92 (7): 2730–2734. DOI: 10.1073/pnas.92.7.2730. PMID: 7708715

134. Airola K., Johansson N., Kariniemi A.L., Kahari V.M., Saarialho-Kere U.K. Human collagenase-3 is expressed in malignant squamous epithelium of the skin J. Invest. Dermatol. 1997; 109 (2): 225–231. PMID: 9242512

135. Takahashi M., Fukami S., Iwata N., Inoue K., Itohara S., Itoh H., Haraoka J., Saido T. In vivo glioma growth requires host-derived matrix metalloproteinase 2 for maintenance of angioarchitecture. Pharmacol. Res. 2002; 46 (2): 155–163. PMID: 12220955

136. Salvatore V., Teti G., Focaroli S., Mazzotti M.C., Mazzotti A., Falconi M. The tumor microenvironment promotes cancer progression and cell migration Oncotarget. 2017; 8 (6): 9608–9616. DOI: 10.18632/oncotarget.14155. PMID: 28030810

137. Littlepage L.E., Sternlicht M.D., Rougier N., Phillips J., Gallo E., Yu Y., Williams K., Brenot A., Gordon J.I., Werb Z. Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res. 2010; 70 (6): 2224–2234. DOI: 10.1158/0008-5472.CAN-09-3515. PMID: 20215503

138. Cid S., Eiro N., Fernández B., Sánchez R., Andicoechea A., Fernández-Muñiz P.I., González L.O., Vizoso F.J. Prognostic Influence of Tumor Stroma on Breast Cancer Subtypes. Clin Breast Cancer. 2018; 18 (1): e123–e133. DOI: 10.1016/j.clbc.2017.08.008. PMID: 28927692

139. Overall C.M., López-Otín C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Reviews Cancer. 2002; 2: 657–672. DOI: 10.1038/nrc884. PMID: 12209155

140. Ito T.K., Ishii G., Chiba H., Ochiai A. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene.2007; 26 (51): 7194–7203. DOI: 10.1038/sj.onc.1210535. PMID: 17525740

141. Bergers G., Brekken R., McMahon G., Vu T.H., Itoh T., Tamaki K., Tanzawa K., Thorpe P., Itohara S., Werb Z., Hanahan D. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol, 2000; 2 (10): 737–744. DOI: 10.1038/35036374. PMID: 11025665

142. Deryugina E.I., L. Soroceanu L., Strongin A.Y. Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. Cancer Res. 2002; 62 (2): 580–588. PMID: 11809713

143. Sounni N.E., Devy L., Hajitou A., Frankenne F., Munaut C., Gilles C., Deroanne C., Thompson E.W., Foidart J.M., Noel A. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J. 2002; 16 (6): 555–564. DOI: 10.1096/fj.01-0790com. PMID: 11919158

144. Hua F, A. DeClerck Y. Targeting the Tumor Microenvironment: From Understanding Pathways to Effective Clinical Trials. Cancer Res. 2013; 73 (16): 4965–4977. DOI: 10.1158/0008-5472.CAN-13-0661. PMID: 23913938

145. Olson O.C., Joyce J.A. Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat. Rev. Cancer. 2015; 15 (12): 712–729. DOI: 10.1038/nrc4027. PMID: 2659752