RESUMEN
The multipotent stromal cells (MSCs) exhibit a broad differentiation potential. MSCs might participate in neovascularization through their ability to migrate and generate capillary-like structures. These processes were shown to be modulated by tumor angiogenic factors, such as Vascular Endothelial Growth Factor (VEGF). The aim of our study was to define the way the MCF-7 cell line (MCF-7s) influenced the MSCs' recruitment for the tumor-induced angiogenesis, and to assess the role of VEGF in this process. We tested the chemotactic potential of plasma or VEGF, but also of MCF-7s or their conditioned medium (CM) in the MSCs' transmigration. We compared the migratory potential of MSCs, MSCEs (MSCs cultured in endothelial cell growth medium) and HUVECs. Recombinant VEGF has been shown to chemoattract MSCs, although to a lesser degree than plasma or serum containing medium alone. Moreover, it changed the MSCs' morphology, stimulating the appearance of longer and thinner prolongations as compared to plasma. MCF-7s or their CM both directly induced migration of MSCs. Surprisingly, CM augmented with MCF-7s attracted less cells than the control medium itself, but CM augmented or not with MCF-7s changed the morphology of MSCs in a manner similar to VEGF. The migratory behavior of the MSCEs was comparable to that of HUVECs, while their morphology could be considered intermediate between MSCs and HUVECs, as they developed shorter prolongations than MSCs, but much longer than HUVECs in the corresponding wells. In conclusion, both tumor cells and VEGF alter the migration behavior of MSCs in a transmigration model, indicating a role of tumor cell-derived VEGF to modulate the recruitment of MSCs into sites of angiogenesis.
Asunto(s)
Técnicas de Cocultivo/métodos , Células Madre Multipotentes/citología , Neoplasias/irrigación sanguínea , Neovascularización Patológica/patología , Movimiento Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Células Madre Multipotentes/efectos de los fármacos , Neoplasias/patología , Células del Estroma/citología , Células del Estroma/efectos de los fármacosRESUMEN
BACKGROUND: A murine model (C3H mice) of squamous cell carcinoma (SCCVII) has been used to investigate the role of arachidonic acid (AA) metabolites in head and neck cancer. Inhibition of tumor growth by cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors of AA metabolism has been associated with changes in levels of AA metabolites in tumor tissues and inflammatory cell infiltrates. To characterize this model further, the effects of exogenous AA metabolites on tumor growth in vitro and in vivo were investigated. METHODS: Following subcutaneous inoculation with SCCVII tumor cells, control (16 mice) and treatment (24 mice) groups were injected with peritumoral vehicle or AA metabolite. Peritumoral injections of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and 12-hydroxyeicosatetraenoic acid (12-HETE) were performed for 16-21 days, and final excised tumor weights were measured. In vitro production of PGE2 and LTB4 was assayed in 2-5 day cultures of SCCVII. Exogenous PGE2 effects on tumor cell growth was assessed with the MTT assay in vitro. RESULTS: Tumor growth was significantly inhibited (p =.03) following peritumoral injection of PGE2. Final tumor weights were not affected by LTB4 or 12-HETE. Tumor inhibition by PGE2 was associated with increased tumor tissue levels of LTB4 (p =.04). In vitro, SCCVII produced minimal amounts of PGE2 and LTB4, and PGE2 had minimal effect on growth. CONCLUSIONS: In this model, tumor inhibition by exogenous PGE2 is primarily mediated by affecting host-tumor interactions, although there may be some direct effect on tumor cells. Changes in tumor tissue levels of LTB4 following peritumoral PGE2 administration may be attributable to negative feedback inhibition of the COX pathway with shunting into the LOX pathway. SCCVII cells are probably not a significant source of prostaglandins and leukotrienes in vivo. These data provide insight into the mechanism of action of inhibitors of AA metabolism on tumor growth.
Asunto(s)
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/administración & dosificación , Ácidos Araquidónicos/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Dinoprostona/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Leucotrieno B4/administración & dosificación , Animales , Carcinoma de Células Escamosas/metabolismo , División Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Inyecciones Intralesiones , Ratones , Ratones Endogámicos C3H , Valores de ReferenciaRESUMEN
PURPOSE: A murine model of squamous cell carcinoma (SCC) was used to determine the role of arachidonic acid (AA) metabolites in the growth of SCC of the head and neck. MATERIALS AND METHODS: C3H/HeJ mice bearing SCC (SCC VII) were treated with cyclooxygenase inhibitors (piroxicam and nabumetone) or a 5-lipoxygenase inhibitor (ketoconazole). Growth curves were established, and final tumor weights were measured. Following sacrifice, tumor tissue homogenates were assayed for prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE) by enzyme-linked immunosorbent assay (ELISA), and leukotriene B4 (LTB4) by radioimmunoassay (RIA). Inflammatory cell infiltrate was assessed histologically. RESULTS: A significant inhibition of tumor growth (P = .001) and final tumor weight (P = .002) was noted in mice treated with piroxicam and nabumetone. Inhibition of tumor growth was associated with increased tumor tissue levels of PGE2 (P = .04) and lymphocytic infiltration (P = .07). Significant inhibition of tumor growth (P = .002) and final tumor weight (P = .05) was also noted in mice treated with ketoconazole. CONCLUSION: These data suggest that both cyclooxygenase and lipoxygenase metabolites of AA affect tumor growth in this model and that inhibition of tumor growth by inhibitors of AA metabolism may be caused by an enhanced inflammatory cell response at the tumor site.