Abstract
The receptor for the urokinase plasminogen activator (uPAR) is up-regulated in malignant tumors. Historically the function of uPAR in cancer cell invasion is strictly related to its property to promote uPA-dependent proteolysis of extracellular matrix and to open a path to malignant cells. These features are typical of mesenchymal motility. Here we show that the full-length form of uPAR is required when prostate and melanoma cancer cells convert their migration style from the "path generating" mesenchymal to the "path finding" amoeboid one, thus conferring a plasticity to tumor cell invasiveness across three-dimensional matrices. Indeed, in response to a protease inhibitors-rich milieu, prostate and melanoma cells activated an amoeboid invasion program connoted by retraction of cell protrusions, RhoA-mediated rounding of the cell body, formation of a cortical ring of actin and a reduction of Rac-1 activation. While the mesenchymal movement was reduced upon silencing of uPAR expression, the amoeboid one was almost completely abolished, in parallel with a deregulation of small Rho-GTPases activity. In melanoma and prostate cancer cells we have shown uPAR colocalization with β1/β3 integrins and actin cytoskeleton, as well integrins-actin co-localization under both mesenchymal and amoeboid conditions. Such co-localizations were lost upon treatment of cells with a peptide that inhibits uPAR-integrin interactions. Similarly to uPAR silencing, the peptide reduced mesenchymal invasion and almost abolished the amoeboid one. These results indicate that full-length uPAR bridges the mesenchymal and amoeboid style of movement by an inward-oriented activity based on its property to promote integrin-actin interactions and the following cytoskeleton assembly.
Highlights
Cancer cells move within tissues collectively or as single cells
Function of urokinase plasminogen activator (uPAR) in mesenchymal invasion of tumor cells uPAR is expressed by cells that move in a mesenchymal fashion. uPAR-bound urokinase plasminogen activator (uPA) promotes plasminogen activation to plasmin and subsequent proMMPs activation-dependent extracellular matrix (ECM) degradation
A ten years analysis of the prospective multicentre Chemo-N0 trial has identified the uPA/ uPAR system as the only level-of-evidence-1 cancer biomarker system for prognosis and/or prediction in nodenegative breast cancer [31]. uPAR contributes to multiple features of the malignant character, including high metastatic potential [32], angiogenesis [33], epithelialto-mesenchymal-transition (EMT) [34] and cancer cell stemness [35]
Summary
Cancer cells move within tissues collectively or as single cells. In collective invasion inter-cellular cohesion in form of strands, sheets, amorphous masses or more or less regularly shaped tubes is required during the invasion process [1]. The mesenchymal migration requires the activity of extracellular matrix (ECM) degrading proteases, while amoeboid motility is an opportunistic movement, which allows cells to glide through, rather than degrade, www.impactjournals.com/oncotarget. The mesenchymal movement depends on Rac-driven actin cytoskeleton contractility, while the amoeboid one relies on Rho-ROCK-dependent regulation of cortical actin to generate cortical tension, stiffness and the maintenance of roundish cell morphology [3]. Single “default” migration styles are preferentially employed by a particular cell, such as the amoeboid for leukocytes, the mesenchymal for stromal cells, the collective for epithelial cell sheets [2]. An interesting paper has highlighted the role of matrix-bound plasminogen inhibitor type-1 (PAI-1) in supporting amoeboid movement and cell blebbing of human colorectal cancer cells via RhoA/ROCK1 signaling [8]
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