RESUMEN
Neuroblastoma is a highly metastatic tumor that emerges from neural crest cell progenitors. Focal Adhesion Kinase (FAK) is a regulator of cell migration that binds to the receptor Neogenin-1 and is upregulated in neuroblastoma. Here, we show that Netrin-1 ligand binding to Neogenin-1 leads to FAK autophosphorylation and integrin ß1 activation in a FAK dependent manner, thus promoting neuroblastoma cell migration. Moreover, Neogenin-1, which was detected in all tumor stages and was required for neuroblastoma cell migration, was found in a complex with integrin ß1, FAK, and Netrin-1. Importantly, Neogenin-1 promoted neuroblastoma metastases in an immunodeficient mouse model. Taken together, these data show that Neogenin-1 is a metastasis-promoting protein that associates with FAK, activates integrin ß1 and promotes neuroblastoma cell migration.
Asunto(s)
Integrina beta1 , Neuroblastoma , Animales , Adhesión Celular , Movimiento Celular , Quinasa 1 de Adhesión Focal/genética , Proteína-Tirosina Quinasas de Adhesión Focal , Proteínas de la Membrana , Ratones , Netrina-1RESUMEN
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. It arises during development of the sympathetic nervous system. Netrin-4 (NTN4), a laminin-related protein, has been proposed as a key factor to target NB metastasis, although there is controversy about its function. Here, we show that NTN4 is broadly expressed in tumor, stroma and blood vessels of NB patient samples. Furthermore, NTN4 was shown to act as a cell adhesion molecule required for the migration induced by Neogenin-1 (NEO1) in SK-N-SH neuroblastoma cells. Therefore, we propose that NTN4, by forming a ternary complex with Laminin γ1 (LMγ1) and NEO1, acts as an essential extracellular matrix component, which induces the migration of SK-N-SH cells.
Asunto(s)
Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Laminina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Netrinas/metabolismo , Neuroblastoma/patología , Receptores de Superficie Celular/metabolismo , Adhesión Celular , Femenino , Humanos , Lactante , Masculino , Neuroblastoma/metabolismo , Células Tumorales CultivadasRESUMEN
Over the last decade, genetic and cell biology studies have indicated that tumour growth is not only determined by malignant cancer cells themselves, but also by the tumour microenvironment. Cells present in the tumour microenvironment include fibroblasts, vascular, smooth muscle, adipocytes, immune cells and mesenchymal stem cells (MSC). The nature of the relationship between MSC and tumour cells appears dual and whether MSC are pro- or anti-tumorigenic is a subject of controversial reports. This review is focused on the role of MSC and bone marrow (BM) niches in cancer.