RESUMEN
Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.
Asunto(s)
Humanos , Paxillin/metabolismo , Proteína-Lisina 6-Oxidasa/metabolismo , Carcinoma de Células Escamosas/patología , Transición Epitelial-Mesenquimal , Integrina alfa2beta1/metabolismo , Neoplasias de la Boca/patología , Colágeno/metabolismo , Fibroblastos , Vesículas Extracelulares/metabolismo , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Effect of two calcium channel blockers (CCBs) nifedipine and amlodipine, was studied on normal and steroid depressed wound healing in albino rats, using the dead space wound model. The drugs enhanced normal healing as evidenced by increase in tensile strength of 10 days old granulation tissue. There was neither a significant change in the hydroxyproline level (or collagen) nor a change in the glycosaminoglycan content in granulation tissue. However, lysyloxidase level was increased significantly. The increase in tensile strength could thus be attributed to better cross-linking and maturation of collagen rather than collagen synthesis per se. The drugs were also able to overcome steroid depressed wound healing. It is likely that the prohealing effects may be related to the improved antioxidant status too, since superoxide dismutase levels were observed to be higher in the CCB- treated animals.
Asunto(s)
Amlodipino/farmacología , Animales , Antioxidantes/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Glicosaminoglicanos/metabolismo , Hexosaminas/metabolismo , Ácidos Hexurónicos/metabolismo , Hidroxiprolina/metabolismo , Masculino , Nifedipino/farmacología , Proteína-Lisina 6-Oxidasa/metabolismo , Ratas , Ratas Wistar , Esteroides/metabolismo , Superóxido Dismutasa/metabolismo , Resistencia a la Tracción , Vasodilatadores/farmacología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Treatment of full-thickness wounds with A. vera, on rats resulted in increased biosynthesis of collagen and its degradation. A corresponding increase in the urinary excretion of hydroxyproline was also observed. Elevated levels of lysyl oxidase also indicated increased crosslinking of newly synthesised collagen. The results suggest that A. vera influences the wound healing process by enhancing collagen turnover in the wound tissue.