The Crosstalk between N-Formyl Peptide Receptors and uPAR in Systemic Sclerosis: Molecular Mechanisms, Pathogenetic Role and Therapeutic Opportunities.

Systemic Sclerosis (SSc) is a heterogeneous autoimmune disease characterized by widespread vasculopathy, the presence of autoantibodies and the progressive fibrosis of skin and visceral organs. There are still many questions about its pathogenesis, particularly related to the complex regulation of the fibrotic process, and to the factors that trigger its onset. Our recent studies supported a key role of N-formyl peptide receptors (FPRs) and their crosstalk with uPAR in the fibrotic phase of the disease. Here, we found that dermal fibroblasts acquire a proliferative phenotype after the activation of FPRs and their interaction with uPAR, leading to both Rac1 and ERK activation, c-Myc phosphorylation and Cyclin D1 upregulation which drive cell cycle progression. The comparison between normal and SSc fibroblasts reveals that SSc fibroblasts exhibit a higher proliferative rate than healthy control, suggesting that an altered fibroblast proliferation could contribute to the initiation and progression of the fibrotic process. Finally, a synthetic compound targeting the FPRs/uPAR interaction significantly inhibits SSc fibroblast proliferation, paving the way for the development of new targeted therapies in fibrotic diseases.

The Benefits of Water from Nitrodi's Spring: The In Vitro Studies Leading the Potential Clinical Applications.

Natural products (water, plants, and minerals) have been studied for diverse applications in health and disease. Since there has been a growing interest in the introduction of thermal water as a clinical complementary approach in the treatment of low-grade inflammation and stress-related conditions, this review focuses on the oldest spa in the world: Nitrodi's spring. Substantial studies in the 1960s showed that both the internal and external use of Nitrodi's water yielded several benefits in physiological processes and in treating certain disorders, mainly allergic and autoimmune inflammatory conditions. More recently, a novel interest in Nitrodi's water has prompted researchers to further explore the effects of this water and shed light on the molecular mechanisms sustaining its therapeutic efficacy. In different epithelial cell models, Nitrodi's water had strong promotional effects on proliferation, cell migration, cell viability, and fibroblast to myofibroblast transition, all of which essential for wound healing and tissue remodeling. Moreover, Nitrodi's water exhibited anti-oxidant and anti-inflammatory properties through the inhibition of ROS production and protein S-nitrosylation. Here, we have collected the clinical and basic data on Nitrodi's water and reviewed articles that have discussed its use as a potential treatment for several inflammatory and autoimmune diseases and age-related skin deterioration.

Plasminogen System in the Pathophysiology of Sepsis: Upcoming Biomarkers.

Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning strategy in both the diagnosis and the treatment of sepsis. However, the optimal cutoff value, the timing of the measurements, and their combination with coagulation indicators should be further investigated. The purpose of this review is to summarize all relevant publications regarding the role of the main components of the plasminogen activation system (PAS) in the pathophysiology of sepsis. In addition, the clinical value of PAS-associated biomarkers in the diagnosis and the outcomes of patients with septic syndrome will be explored. In particular, experimental and clinical trials performed in emergency departments highlight the validity of soluble urokinase plasminogen activator receptor (suPAR) as a predictive and prognostic biomarker in patients with sepsis. The measurements of PAI-I may also be useful, as its increase is an early manifestation of sepsis and may precede the development of thrombocytopenia. The upcoming years will undoubtedly see progress in the use of PAS-associated laboratory parameters.

Macrophages and Urokinase Plasminogen Activator Receptor System in Multiple Myeloma: Case Series and Literature Review.

The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes to migration through an extracellular matrix. Here, we first summarized the role of macrophages and the uPAR system in MM pathogenesis, and then we reported the potential therapeutic effects of uPAR inhibitors in a case series of primary MM-derived adherent cells. Our preliminary results showed that after uPAR inhibitor treatments, interleukein-6 (mean ± SD, 8734.95 ± 4169.2 pg/mL vs. 359.26 ± 393.8 pg/mL, pre- vs. post-treatment; p = 0.0012) and DKK-1 levels (mean ± SD, 7005.41 ± 6393.4 pg/mL vs. 61.74 ± 55.2 pg/mL, pre- vs. post-treatment; p = 0.0043) in culture medium were almost completely abolished, supporting further investigation of uPAR blockade as a therapeutic strategy for MM treatment. Therefore, uPAR inhibitors could exert both anti-inflammatory and pro-immunosurveillance activity. However, our preliminary results need further validation in additional in vitro and in vivo studies.

Water from Nitrodi's Spring Induces Dermal Fibroblast and Keratinocyte Activation, Thus Promoting Wound Repair in the Skin: An In Vitro Study.

The Romans knew of Nitrodi's spring on the island of Ischia more than 2000 years ago. Although the health benefits attributed to Nitrodi's water are numerous, the underlying mechanisms are still not understood. In this study, we aim to analyze the physicochemical properties and biological effects of Nitrodi's water on human dermal fibroblasts to determine whether the water exerts in vitro effects that could be relevant to skin wound healing. The results obtained from the study indicate that Nitrodi's water exerts strong promotional effects on dermal fibroblast viability and a significant stimulatory activity on cell migration. Nitrodi's water induces alpha-SMA expression in dermal fibroblasts, thus promoting their transition to myofibroblast-protein ECM deposition. Furthermore, Nitrodi's water reduces intracellular reactive oxygen species (ROS), which play an important role in human skin aging and dermal damage. Unsurprisingly, Nitrodi's water has significant stimulatory effects on the cell proliferation of epidermal keratinocytes and inhibits the basal ROS production but enhances their response to the oxidative stress caused by external stimuli. Our results will contribute to the development of human clinical trials and further in vitro studies to identify inorganic and/or organic compounds responsible for pharmacological effects.

Role of Plasminogen Activation System in Platelet Pathophysiology: Emerging Concepts for Translational Applications.

Traditionally, platelets have been exclusively considered for their procoagulant and antifibrinolytic effects during normal activation of hemostasis. Effectively, activated platelets secrete coagulation factors, expose phosphatidylserine, and promote thrombin and fibrin production. In addition to procoagulant activities, platelets confer resistance of thrombi to fibrinolysis by inducing clot retraction of the fibrin network and release of huge amounts of plasminogen activator inhibitor-1, which is the major physiologic inhibitor of the fibrinolytic cascade. However, the discovery of multiple relations with the fibrinolytic system, also termed Plasminogen Activation System (PAS), has introduced new perspectives on the platelet role in fibrinolysis. Indeed, the activated membrane surface of platelets provides binding sites on which fibrinolytic enzymes can be activated. This review discusses the evidence of the profibrinolytic properties of platelets through the description of PAS components and related proteins that are contained in or bind to platelets. Our analyses of literature data lead to the conclusion that in the initial phase of the hemostatic process, antifibrinolytic effects prevail over profibrinolytic activity, but at later stages, platelets might enhance fibrinolysis through the engagement of PAS components. A better understanding of spatial and temporal characteristics of platelet-mediated fibrinolysis during normal hemostasis could improve therapeutic options for bleeding and thrombotic disorders.

Soluble Urokinase Receptor as a Promising Marker for Early Prediction of Outcome in COVID-19 Hospitalized Patients.

The Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has rapidly spread to become a global pandemic, putting a strain on health care systems. SARS-CoV-2 infection may be associated with mild symptoms or, in severe cases, lead patients to the intensive care unit (ICU) or death. The critically ill patients suffer from acute respiratory distress syndrome (ARDS), sepsis, thrombotic complications and multiple organ failure. For optimization of hospital resources, several molecular markers and algorithms have been evaluated in order to stratify COVID-19 patients, based on the risk of developing a mild, moderate, or severe disease. Here, we propose the soluble urokinase receptor (suPAR) as a serum biomarker of clinical severity and outcome in patients who are hospitalized with COVID-19. In patients with mild disease course, suPAR levels were increased as compared to healthy controls, but they were dramatically higher in severely ill patients. Since early identification of disease progression may facilitate the individual management of COVID-19 symptomatic patients and the time of admission to the ICU, we suggest paying more clinical attention on patients with high suPAR levels.

The Value of Flow Cytometry Clonality in Large Granular Lymphocyte Leukemia.

Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder of mature T or NK cells frequently associated with autoimmune disorders and other hematological conditions, such as myelodysplastic syndromes. Immunophenotype of LGL cells is similar to that of effector memory CD8+ T cells with T-cell receptor (TCR) clonality defined by molecular and/or flow cytometric analysis. Vß usage by flow cytometry can identify clonal TCR rearrangements at the protein level, and is fast, sensitive, and almost always available in every Hematology Center. Moreover, Vß usage can be associated with immunophenotypic characterization of LGL clone in a multiparametric staining, and clonal kinetics can be easily monitored during treatment and follow-up. Finally, Vß usage by flow cytometry might identify LGL clones silently underlying other hematological conditions, and routine characterization of Vß skewing might identify recurrent TCR rearrangements that might trigger aberrant immune responses during hematological or autoimmune conditions.

Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens.

Cytomegalovirus (CMV) reactivation during chemotherapy or after organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality, and the risk of reactivation increases with patients' age. Bendamustine, an alkylating agent currently used for treatment of indolent and aggressive non-Hodgkin lymphomas, can augment the risk of secondary infections including CMV reactivation. In this real-world study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapsed/refractory indolent and aggressive diseases treated with bendamustine-containing regimens. In particular, patients who received bendamustine plus rituximab and dexamethasone were at higher risk of CMV reactivation, especially when administered as first-line therapy and after the third course of bendamustine. In addition, patients with CMV reactivation showed a significant depression of circulating CD4+ T cell count and anti-CMV IgG levels during active infection, suggesting an impairment of immune system functions which are not able to properly face viral reactivation. Therefore, a close and early monitoring of clinical and laboratory findings might improve clinical management and outcome of non-Hodgkin lymphoma patients by preventing the development of CMV disease in a subgroup of subjects treated with bendamustine more susceptible to viral reactivation.

WT1 Expression Levels Combined with Flow Cytometry Blast Counts for Risk Stratification of Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Wilm's tumor 1 (WT1), a zinc-finger transcription factor and an epigenetic modifier, is frequently overexpressed in several hematologic disorders and solid tumors, and it has been proposed as diagnostic and prognostic marker of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the exact role of WT1 in leukemogenesis and disease progression remains unclear. In this real-world evidence retrospective study, we investigated prognostic role of WT1-mRNA expression levels in AML and MDS patients and correlations with complete blood counts, flow cytometry counts, and molecular features. A total of 71 patients (AML, n = 46; and MDS, n = 25) were included in this study, and WT1 levels were assessed at diagnosis, during treatment and follow-up. We showed that WT1 expression levels were inversely correlated with normal hemopoiesis in both AML and MDS, and positively associated with blast counts. Flow cytometry was more sensitive and specific in distinguishing normal myeloid cells from neoplastic counterpart even just using linear parameters and CD45 expression. Moreover, we showed that a simple integrated approach combining blast counts by flow cytometry, FLT3 mutational status, and WT1 expression levels might be a useful tool for a better prognostic definition in both AML and MDS patients.

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

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.

The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis.

The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. The plasminogen activation (PA) system includes urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), and two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In addition to the regulation of fibrinolysis, the PA system plays an important role in other biological processes, which include degradation of extracellular matrix such as embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and immune response. Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. Different forms of angioedema are linked to uncontrolled activation of coagulation and fibrinolysis systems. Moreover, plasmin itself can induce a potentiation of bradykinin production with consequent swelling episodes. The number of studies investigating the PA system involvement in angioedema has grown in recent years, highlighting its relevance in etiopathogenesis. In this review, we present the components and diverse functions of the PA system in physiology and its importance in angioedema pathogenesis.

New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms.

The urokinase (uPA) receptor (uPAR) plays a key role in cell migration. We previously showed that uPAR-negative HEK-293 cells efficiently migrate toward serum but, after uPAR ectopic expression, migrate only in a uPAR-dependent manner. In fact, migration of uPAR-transfected HEK-293 (uPAR-293) cells is impaired by anti-uPAR antibodies, without recovery of the uPAR-independent migration mechanisms formerly active. Prostate carcinoma PC3 cells, which express high endogenous uPAR levels, migrated only through a uPAR-dependent mechanism; in fact, the silencing of uPAR expression inhibited their migration. We hypothesize a crucial role of the uPAR glycosyl-phosphatidyl-inositol (GPI) tail, which promotes uPAR partitioning to lipid rafts, in uPAR-controlled cell migration. Here, we show that removal of the uPAR GPI-tail, or lipid rafts disruption by methyl-beta-cyclodextrin impairs migration of PC3 cells, incapable of uPAR-independent migration, whereas it restores uPAR-independent migration in uPAR-293 cells. We then show that, in PC3 cells, both uPAR signaling partners, ß1 integrins and receptors for formylated peptides (FPRs), partly associate with lipid rafts. Inhibition of their interaction with uPAR impairs this association and impairs cell migration. Interestingly, blocking uPAR association with FPRs also impairs ß1 integrin partitioning to lipid rafts, whereas blocking its association with ß1 integrins has no effect on FPRs partitioning. On these bases, we propose that uPAR controls cell migration by connecting ß1 integrins and FPRs and, through its GPI tail, by driving them into lipid rafts, thus promoting pro-migratory signals. uPAR-mediated partitioning of integrins to lipid rafts is strictly dependent on uPAR association with FPRs.

Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-ß in Human Skin Fibroblasts from Familial Alzheimer's Disease.

Alzheimer's disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aß), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aß and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted Aß in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the "typical" APP localization in the Golgi apparatus, with consequences on the Aß level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aß levels with implications in Alzheimer's disease.

APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells.

Amyloid precursor protein (APP) is processed along both the nonamyloidogenic pathway preventing amyloid beta peptide (Aß) production and the amyloidogenic pathway, generating Aß, whose accumulation characterizes Alzheimer's disease. Items of evidence report that the intracellular trafficking plays a key role in the generation of Aß and that the 37/67 kDa LR (laminin receptor), acting as a receptor for Aß, may mediate Aß-pathogenicity. Moreover, findings indicating interaction between the receptor and the key enzymes involved in the amyloidogenic pathway suggest a strong link between 37/67 kDa LR and APP processing. We show herein that the specific 37/67 kDa LR inhibitor, NSC48478, is able to reversibly affect the maturation of APP in a pH-dependent manner, resulting in the partial accumulation of the immature APP isoforms (unglycosylated/acetylated forms) in the endoplasmic reticulum (ER) and in transferrin-positive recycling endosomes, indicating alteration of the APP intracellular trafficking. These effects reveal NSC48478 inhibitor as a novel small molecule to be tested in disease conditions, mediated by the 37/67 kDa LR and accompanied by inactivation of ERK1/2 (extracellular signal-regulated kinases) signalling and activation of Akt (serine/threonine protein kinase) with consequent inhibition of GSK3ß.

A novel oncogenic role for urokinase receptor in leukemia cells: molecular sponge for oncosuppressor microRNAs.

Urokinase receptor (uPAR) expression is up-regulated and represents a negative prognostic marker in most cancers. We previously reported that uPAR and CXCR4 can be regulated by common microRNAs in leukemia cells. Transcripts containing response elements for shared microRNAs in their 3'UTR may regulate their availability. We investigated uPAR 3'UTR capability to recruit microRNAs, thus regulating the expression of their targets. uPAR 3'UTR transfection in KG1 leukemia cells up-regulates the expression of endogenous uPAR. Transfection of uPAR 3'UTR, inserted downstream a reporter gene, increases uPAR expression and simultaneously down-regulates the reporter gene expression. Transfection of uPAR 3'UTR also increases CXCR4 expression; accordingly, uPAR silencing induces down-regulation of CXCR4 expression, through a mechanism involving Dicer, the endoribonuclease required for microRNA maturation. Transfection of uPAR 3'UTR also increases the expression of pro-tumoral factors and modulates cell adhesion and migration, consistently with the capability of uPAR3'UTR-recruited microRNAs to target several and different transcripts and, thus, functions. Finally, we found 3'UTR-containing variants of uPAR transcript in U937 leukemia cells, which show higher levels of uPAR expression as compared to KG1 cells, in which these variants are not detected. These results suggest that uPAR mRNA may recruit oncosuppressor microRNAs, allowing the expression of their targets.

N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis, alteration in the microvasculature and immunologic abnormalities. It has been hypothesized that an abnormal redox state could regulate the persistent fibrotic phenotype in SSc patients. N-Formyl peptide receptors (FPRs) are chemotactic receptors overexpressed in fibroblasts derived from SSc patients. In this study, we demonstrated that stimulation of FPRs promotes the generation of reactive oxygen species (ROS) in skin fibroblasts. In fibroblast cells, ROS production was due to FPRs interaction with the urokinase receptor (uPAR) and to ß1 integrin engagement. FPRs cross-talk with uPAR and integrins led to Rac1 and ERKs activation. FPRs stimulation increased gp91phox and p67phox expression as well as the direct interaction between GTP-Rac1 and p67phox, thus promoting assembly and activation of the NADPH oxidase complex. FPRs functions occur through interaction with a specific domain of uPAR (residues 88SRSRY92) that can be exposed on the cell membrane by protease-mediated receptor cleavage. Immunohistochemistry analysis with a specific anti-SRSRY antibody showed increased expression of uPAR in a cleaved form, which exposes the SRSRY sequence at its N-terminus (DIIDIII-uPAR88-92) in skin biopsies from SSc patients. As expected by the increased expression of both FPRs and DII-DIII-uPAR88-92, fibroblasts derived from SSc patients showed a significantly increase in ROS generation both at a basal level than after FPRs stimulation, as compared to fibroblasts from normal subjects. C37, a small molecule blocking the interaction between FPRs and uPAR, and selumetinib, a clinically approved MAPKK/ERK inhibitor, significantly inhibited FPRs-mediated ROS production in fibroblasts derived from SSc patients. Thus, FPRs, through the interaction with the uPA/uPAR system, can induce ROS generation in fibroblasts by activating the NADPH oxidase, playing a role in the alteration of the redox state observed in SSc.

Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors.

The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell membrane receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. Its expression is increased in many human cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and correlates with a poor prognosis and early invasion and metastasis. uPAR is able to control, through a cross-talk with tyrosine kinase receptors, the shift between tumor dormancy and proliferation, that usually precedes metastasis formation. Therefore, we investigated the role of uPAR expression in RAS mutated NSCLC and CRC cells. In this study we provided evidence, for the first time, that RAS mutational condition is functionally correlated to uPAR overexpression in NSCLC and CRC cancer cell lines and patient-derived tissue samples. Moreover, oncogenic features related to uPAR overexpression in RAS mutated NSCLC and CRC, such as adhesion, migration and metastatic process may be targeted, in vitro and in vivo, by new anti-uPAR small molecules, specific inhibitors of uPAR-vitronectin interaction. Therefore, anti-uPAR drugs could represent an effective pharmacological strategy for NSCLC and CRC patients carrying RAS mutations.

Recent Advances in the Function of the 67 kDa Laminin Receptor and its Targeting for Personalized Therapy in Cancer.

The 67 kDa high affinity laminin receptor (67LR) is a non-integrin cell surface receptor for laminin, the major component of basement membranes. Interactions between 67LR and laminin play a major role in mediating cell adhesion, migration, proliferation and survival. 67LR derives from homo- or hetero-dimerization of a 37 kDa cytosolic precursor (37LRP), most probably by fatty acid acylation. Interestingly, 37LRP, also called p40 or OFA/iLR (oncofetal antigen/immature laminin receptor), is a multifunctional protein with a dual activity in the cytoplasm and in the nucleus. In the cytoplasm, 37LRP it is associated with the 40S subunit of ribosome, playing a critical role in protein translation and ribosome biogenesis while in the nucleus it is tightly associated with nuclear structures, and bound to components of the cytoskeleton, such as tubulin and actin. 67LR is mainly localized in the cell membrane, concentrated in lipid rafts. Acting as a receptor for laminin is not the only function of 67LR; indeed, it also acts as a receptor for viruses, bacteria and prions. 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. The primary function of 67LR in cancer is to promote tumor cell adhesion to basement membranes, the first step in the invasion-metastasis cascade. Thus, 67LR is overexpressed in neoplastic cells as compared to their normal counterparts and its overexpression is considered a molecular marker of metastatic aggressiveness in cancer of many tissues, including breast, lung, ovary, prostate, stomach, thyroid and also in leukemia and lymphoma. Thus, inhibiting 67LR binding to laminin could be a feasible approach to block cancer progression. Here, we review the current understanding of the structure and function of this molecule, highlighting its role in cancer invasion and metastasis and reviewing the various therapeutic options targeting this receptor that could have a promising future application.

Urokinase type plasminogen activator receptor (uPAR) as a new therapeutic target in cancer.

The urokinase (uPA)-type plasminogen activator receptor (uPAR) is a GPI-anchored receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. uPAR also regulates cell adhesion, migration and proliferation, protects from apoptosis and contributes to epithelial mesenchymal transition (EMT), independently of uPA enzymatic activity. Indeed, uPAR interacts with beta1, beta2 and beta3 integrins, thus regulating their activities. uPAR cross-talks with receptor tyrosine kinases through integrins and regulates cancer cell dormancy, proliferation and angiogenesis. Moreover, uPAR mediates uPA-dependent cell migration and chemotaxis induced by fMet-Leu-Phe (fMLF), through its association with fMLF-receptors (fMLF-Rs). Further, uPAR is an adhesion receptor because it binds vitronectin (VN), a component of provisional extracellular matrix. High uPAR expression predicts for more aggressive disease in several cancer types for its ability to increase invasion and metastasis. In fact, uPAR has been hypothesized to be the link between tumor cell dormancy and proliferation that usually precedes the onset of metastasis. Thus, inhibiting uPAR could be a feasible approach to affect tumor growth and metastasis. Here, we review the more recent advances in the development of uPAR-targeted anti-cancer therapeutic agents suitable for further optimization or ready for the evaluation in early clinical trials.