RESUMEN
The cytoskeleton is a central factor contributing to various hallmarks of cancer. In recent years, there has been increasing evidence demonstrating the involvement of actin regulatory proteins in malignancy, and their dysregulation was shown to predict poor clinical prognosis. Although enhanced cytoskeletal activity is often associated with cancer progression, the expression of several inducers of actin polymerization is remarkably reduced in certain malignancies, and it is not completely clear how these changes promote tumorigenesis and metastases. The complexities involved in cytoskeletal induction of cancer progression therefore pose considerable difficulties for therapeutic intervention; it is not always clear which cytoskeletal regulator should be targeted in order to impede cancer progression, and whether this targeting may inadvertently enhance alternative invasive pathways which can aggravate tumor growth. The entire constellation of cytoskeletal machineries in eukaryotic cells are numerous and complex; the system is comprised of and regulated by hundreds of proteins, which could not be covered in a single review. Therefore, we will focus here on the actin cytoskeleton, which encompasses the biological machinery behind most of the key cellular functions altered in cancer, with specific emphasis on actin nucleating factors and nucleation-promoting factors. Finally, we discuss current therapeutic strategies for cancer which aim to target the cytoskeleton.
Asunto(s)
Citoesqueleto de Actina/inmunología , Actinas/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias/inmunología , Transducción de Señal/inmunología , Citoesqueleto de Actina/patología , Animales , Progresión de la Enfermedad , Humanos , Metástasis de la Neoplasia , Neoplasias/patologíaRESUMEN
Overactivation of Wnt-ß-catenin signaling, including ß-catenin-TCF target gene expression, is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin family of cell-adhesion receptors member L1 as a ß-catenin-TCF target gene preferentially expressed at the invasive edge of human CRC tissue. L1 can confer enhanced motility and liver metastasis when expressed in CRC cells. This ability of L1-mediated metastasis is exerted by a mechanism involving ezrin and the activation of NF-κB target genes. In this study, we identified the secreted modular calcium-binding matricellular protein-2 (SMOC-2) as a gene activated by L1-ezrin-NF-κB signaling. SMOC-2 is also known as an intestinal stem cell signature gene in mice expressing Lgr5 in cells at the bottom of intestinal crypts. The induction of SMOC-2 expression in L1-expressing CRC cells was necessary for the increase in cell motility, proliferation under stress and liver metastasis conferred by L1. SMOC-2 expression induced a more mesenchymal like phenotype in CRC cells, a decrease in E-cadherin and an increase in Snail by signaling that involves integrin-linked kinase (ILK). SMOC-2 was localized at the bottom of normal human colonic crypts and at increased levels in CRC tissue with preferential expression in invasive areas of the tumor. We found an increase in Lgr5 levels in CRC cells overexpressing L1, p65 or SMOC-2, suggesting that L1-mediated CRC progression involves the acquisition of a stem cell-like phenotype, and that SMOC-2 elevation is necessary for L1-mediated induction of more aggressive/invasive CRC properties.
Asunto(s)
Proteínas de Unión al Calcio/genética , Neoplasias del Colon/genética , Mucosa Intestinal/metabolismo , Células Madre/metabolismo , Animales , Proteínas de Unión al Calcio/biosíntesis , Proteínas de Unión al Calcio/metabolismo , Procesos de Crecimiento Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Progresión de la Enfermedad , Xenoinjertos , Humanos , Intestinos/patología , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Células Madre/patología , Activación Transcripcional , Vía de Señalización WntRESUMEN
L1, a neuronal cell adhesion receptor of the immunoglobulin-like protein family is expressed in invading colorectal cancer (CRC) cells as a target gene of Wnt/ß-catenin signaling. Overexpression of L1 in CRC cells enhances cell motility and proliferation, and confers liver metastasis. We recently identified ezrin and the IκB-NF-κB pathway as essential for the biological properties conferred by L1 in CRC cells. Here, we studied the underlying molecular mechanisms and found that L1 enhances ezrin phosphorylation, via Rho-associated protein kinase (ROCK), and is required for L1-ezrin co-localization at the juxtamembrane domain and for enhancing cell motility. Global transcriptomes from L1-expressing CRC cells were compared with transcriptomes from the same cells expressing small hairpin RNA (shRNA) to ezrin. Among the genes whose expression was elevated by L1 and ezrin we identified insulin-like growth factor-binding protein 2 (IGFBP-2) and showed that its increased expression is mediated by an NF-κB-mediated transactivation of the IGFBP-2 gene promoter. Expression of a constitutively activated mutant ezrin (Ezrin567D) could also increase IGFBP-2 levels in CRC cells. Overexpression of IGFBP-2 in CRC cells lacking L1-enhanced cell proliferation (in the absence of serum), cell motility, tumorigenesis and induced liver metastasis, similar to L1 overexpression. Suppression of endogenous IGFBP-2 in L1-transfected cells inhibited these properties conferred by L1. We detected IGFBP-2 in a unique organization at the bottom of human colonic crypts in normal mucosa and at increased levels throughout human CRC tissue samples co-localizing with the phosphorylated p65 subunit of NF-κB. Finally, we found that IGFBP-2 and L1 can form a molecular complex suggesting that L1-mediated signaling by the L1-ezrin-NF-κB pathway, that induces IGFBP-2 expression, has an important role in CRC progression.