Melanoma cell therapy: Endothelial progenitor cells as shuttle of the MMP12 uPAR-degrading enzyme
نویسندگان
چکیده
The receptor for the urokinase-type plasminogen activator (uPAR) accounts for many features of cancer progression, and is therefore considered a target for anti-tumoral therapy. Only full length uPAR mediates tumor progression. Matrix-metallo-proteinase-12 (MMP12)-dependent uPAR cleavage results into the loss of invasion properties and angiogenesis. MMP12 can be employed in the field of "targeted therapies" as a biological drug to be delivered directly in patient's tumor mass. Endothelial Progenitor Cells (EPCs) are selectively recruited within the tumor and could be used as cellular vehicles for delivering anti-cancer molecules. The aim of our study is to inhibit cancer progression by engeneering ECFCs, a subset of EPC, with a lentivirus encoding the anti-tumor uPAR-degrading enzyme MMP12. Ex vivo manipulated ECFCs lost the capacity to perform capillary morphogenesis and acquired the anti-tumor and anti-angiogenetic activity. In vivo MMP12-engineered ECFCs cleaved uPAR within the tumor mass and strongly inhibited tumor growth, tumor angiogenesis and development of lung metastasis. The possibility to exploit tumor homing and activity of autologous MMP12-engineered ECFCs represents a novel way to combat melanoma by a "personalized therapy", without rejection risk. The i.v. injection of radiolabelled MMP12-ECFCs can thus provide a new theranostic approach to control melanoma progression and metastasis.
منابع مشابه
Endothelial progenitor cell-dependent angiogenesis requires localization of the full-length form of uPAR in caveolae.
Endothelial urokinase-type plasminogen activator receptor (uPAR) is thought to provide a regulatory mechanism in angiogenesis. Here we studied the proangiogenic role of uPAR in endothelial colony-forming cells (ECFCs), a cell population identified in human umbilical blood that embodies all of the properties of an endothelial progenitor cell matched with a high proliferative rate. By using caveo...
متن کاملColony Forming Unit Endothelial Cells Do not Exhibit Telomerase Alternative Splicing Variants and Activity
Introduction: Endothelial progenitor colony forming unit-endothelial cells (CFU-EC) were first believed to be the progenitors of endothelial cells, named endothelial progenitor cells. Further studies revealed that they are monocytes regulating vasculogenesis. The main hindrance of these cells for therapeutic purposes is their low frequency and limited replicative potentials. This study was unde...
متن کاملSpecification of Hemato-Endothelial-Like Structures and Generation of Hematopoietic Progenitor Cells from Human Pluripotent Stem Cells
Background and purpose: Human pluripotent stem cells (hPSCs) with the ability to differentiate into adult cells have provided a new perspective for treatment of some diseases. But, the efficiency of differentiation methods to generate hematopoietic progenitor cells (HPCs) is faced with multiple challenges. In the present study, we investigated the formation of hemato-endothelial-like structure...
متن کاملEndothelial Progenitor Cell Dysfunction in Polycystic Ovary Syndrome: Implications for The Genesis of Cardiovascular Diseases
متن کامل
Chronic Exposure of Human Endothelial Progenitor Cells to Diabetic Condition Abolished the Regulated Kinetics Activity of Exosomes
By virtue of lifestyle change, incidence of type 2 diabetes is increasingly being raised with different up-surging pathologies. This condition found to disqualify endothelial progenitor cells during neo-vascularization. Besides to an aborted differentiation property, malfunctioned paracrine activities exacerbate vascular abnormalities. It is found nano-scaled exosomes play essential roles on re...
متن کامل