The urokinase-type plasminogen activator system and its role in tumor progression

Abstract

In the multistage process of carcinogenesis, the key link in the growth and progression of the tumor is the invasion of malignant cells into normal tissue and their distribution and the degree of destruction of tissues. The most important role in the development of these processes is played by the system of urokinase-type plasminogen activator (uPA system), which consists of several components: serine proteinase – uPA, its receptor – uPAR and its two endogenous inhibitors – PAI-1 and PAI-2. The components of the uPA system are expressed by cancer cells to a greater extent than normal tissue cells. uPA converts plasminogen into broad spectrum, polyfunctional protease plasmin, which, in addition to the regulation of fibrinolysis, can hydrolyze a number of components of the connective tissue matrix (СTM), as well as activate the zymogens of secreted matrix metalloproteinases (MMР) – pro-MMР. MMРs together can hydrolyze all the main components of the СTM, and thus play a key role in the development of invasive processes, as well as to perform regulatory functions by activating and releasing from STM a number of biologically active molecules that are involved in the regulation of the main processes of carcinogenesis. The uPA system promotes tumor progression not only through the proteolytic cascade, but also through uPAR, PAI-1 and PAI-2, which are involved in both the regulation of uPA/uPAR activity and are involved in proliferation, apoptosis, chemotaxis, adhesion, migration and activation of epithelial-mesenchymal transition pathways. All of the above processes are aimed at regulating invasion, metastasis and angiogenesis. The components of the uPA system are used as prognostic and diagnostic markers of many cancers, as well as serve as targets for anticancer therapy.

Prognostic significance of uPA and uPAR expression in patients with cervical cancer undergoing radiotherapy

“…The main functions of uPAR involve the regulation of extracellular proteolysis and cell-extracellular matrix interactions (11). Upregulation of the expression of uPAR and uPA enhances tumor progression as well as the aggressiveness of numerous cancer cell types such as lung, breast and stomach cancer (12). Furthermore, uPAs serve as biomarkers and targets for treatment of human malignancies such as breast and pancreatic cancer (13).…”

Inhibition of TMPRSS4 mediated epithelial‐mesenchymal transition is critically involved in antimetastatic effect of melatonin in colorectal cancers

“…Cell cycle proteins are involved in cell growth and metastasis (Kar, 2016) by regulation of the G 1 ‐S transition by p27 Kip1 , Cyclin E, and Cyclin A and p21 in the cells (Gartel & Radhakrishnan, 2005). In addition, pro‐uPA (Kugaevskaya, Gureeva, Timoshenko, & Solovyeva, 2018), p‐STAT3 (C. Kim et al, 2014; K. J. Kim et al, 2017), and p‐FAK(Wu, Hao, & Yeo, 2020) are involved in cell cycle and metastasis. The uPA is a well‐known serine protease involved in invasion and metastasis (Andreasen et al, 1997) and TMPRSS4 is critically associated with uPA expression in human lung and prostate cancer metastasis (Min et al, 2014).…”

“…In addition, pro-uPA (Kugaevskaya, Gureeva, Timoshenko, & Solovyeva, 2018), p-STAT3 (C. Kim et al, 2014;K. J. Kim et al, 2017), and p-FAK (Wu, Hao, & Yeo, 2020) are involved in cell cycle and metastasis.…”

Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

“…Increased uPA expression and activity promote tumour cell invasion into surrounding tissues by stimulating the breakdown of BM and ECM (Andreasen et al 1997;Didiasova et al 2014;Magill et al 1999). Dysregulated activity of the uPAS is also implicated in tumour cell proliferation, migration and metastasis (Kugaevskaya et al 2018;Mahmood et al 2018;Zhang et al 2018) and contributes to poor prognosis (Su et al 2016) and progression in various cancers including melanoma (Cho et al 2019), hepatocellular carcinoma (HCC) (Wei et al 2019), lung adenocarcinoma (Zhu et al 2020), neuroendocrine (Özdirik et al 2020), oral (Wyganowska-Świątkowska & Jankun 2015), gastric (Brungs et al 2017;Kaneko et al 2003), ovarian (van der Burg et al 1996), breast (Tang & Han 2013;Xing & Rabbani 1996), prostate (Kimura et al 2020), colorectal (Yang et al 2000) and bladder cancers (Hasui & Osada 1997;Iwata et al 2019). In breast cancer, the uPAS has been identified as the most reliable independent prognostic marker of poor prognosis (Banys-Paluchowski et al 2019;Bouchet et al 1994;Duffy et al 1988;Foekens et al 2000;Harbeck et al 2002).…”