The Urokinase Receptor: A Multifunctional Receptor in Cancer Cell Biology. Therapeutic Implications

Abstract

Proteolysis is a key event in several biological processes; proteolysis must be tightly controlled because its improper activation leads to dramatic consequences. Deregulation of proteolytic activity characterizes many pathological conditions, including cancer. The plasminogen activation (PA) system plays a key role in cancer; it includes the serine-protease urokinase-type plasminogen activator (uPA). uPA binds to a specific cellular receptor (uPAR), which concentrates proteolytic activity at the cell surface, thus supporting cell migration. However, a large body of evidence clearly showed uPAR involvement in the biology of cancer cell independently of the proteolytic activity of its ligand. In this review we will first describe this multifunctional molecule and then we will discuss how uPAR can sustain most of cancer hallmarks, which represent the biological capabilities acquired during the multistep cancer development. Finally, we will illustrate the main data available in the literature on uPAR as a cancer biomarker and a molecular target in anti-cancer therapy.

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

“…Subsequent studies showed that these soluble uPAR fragments were independent prognostic biomarkers in pre- and post-operative plasma samples from patients with colorectal cancer ( Rolff et al, 2019 ). For more detailed information on uPAR expression and cancer dissemination the reader is referred to the following reviews ( Andreasen et al, 2000 ; Romer et al, 2004 ; Allgayer, 2010 ; Kriegbaum et al, 2011 ; Madunic, 2018 ; Li Santi et al, 2021 ).…”

“…Furthermore, the functional implications of several of these putative uPAR-interactors are either circumstantial or at best indirect ( Ferraris et al, 2014 ). For more information on non-canonical uPAR ligands, their possible role(s) in cell migration and signaling, and their targeting, the reader is referred to the following comprehensive reviews ( Blasi and Sidenius, 2010 ; Smith and Marshall, 2010 ; Gonias and Hu, 2015 ; Li Santi et al, 2021 ; Yuan et al, 2021 ). We will instead focus on (i) structure-function relationships in uPAR and (ii) recent developments in targeted imaging of uPAR expression using radionuclide probes for positron emission tomography (PET) scanning or near-infrared (NIR) fluorescent probes for optical imaging to assist precision guided cancer surgery.…”

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

“…Although promising in some preclinical settings, none of them have advanced to the clinics so far. An in-depth overview of the mentioned approaches, along with the existing challenges hampering their clinical translation, is provided by the following comprehensive reviews [ 4 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Development of AE147 Peptide-Conjugated Nanocarriers for Targeting uPAR-Overexpressing Cancer Cells

“…The AE147 peptide, composed of 13 amino acids, is an antagonist of uPAR. 9,16,17 The AE147 binds to uPAR by occupying its central cavity, causing subsequent internalization via receptor-mediated endocytosis. 18,19 Therefore, conjugating AE147 on therapeutic nanoformulations is expected to impart tumor specificity and improve cytotoxic drug delivery.…”