Meningioma is the most frequent primary tumor of the central nervous system. The greatest percentage of meningiomas is benign tumors (WHO grade I). However, although surgical and radiotherapy techniques have significantly improved over the years, some meningiomas, independently from the grading, are refractory to multimodality therapies, and recur and/or undergo malignant transformation, representing an unsolved therapeutic challenge. Therefore, beside histopathologic benign appearance, biologically aggressive meningiomas need to be molecularly characterized, to identify novel therapeutic targets. In malignant tumors, recurrence is mainly ascribed to the presence of cancer stem cells (CSCs) which are expression of tumor cell heterogeneity, and sustain tumorigenesis, metastasization and drug resistance. CSCs are characterized by stem cell marker expression, self-renewal, and ability to differentiate into tumor-specific cell types. Recently, CSCs and their functional role have been also studied in benign tumors, including meningioma. A range of genes and proteins have been proposed to identify meningioma stem-like cells, among them CD105, a transmembrane glycoprotein, involved in angiogenesis and in the progression of a variety of tumors. Stemness, as well as cancer cell aggressive behavior, is a cell property strictly linked to tumor microenvironment: reciprocal interactions between growth factors, cytokines and chemokines released by both CSCs and other cell types forming the niche, modulate each other to sustain tumor growth. Chemokine signaling, and the CXCL11/CXCL12-CXCR4/CXCR7 system in particular, drives cell proliferation and migration in several solid tumors. On these premises, this study is focused on the isolation and characterization of stem-like cells from post-surgical samples of human meningiomas, delving deeply into the role of this subpopulation in meningioma aggressive behavior. Moreover, we analyzed the contribution of CXCR4-7 receptors in the regulation of their biological properties. Twenty-eight primary cell cultures have been obtained from 35 meningiomas, and maintained in stem cell-permissive culture conditions to enrich in CSCs. Putative meningioma stem cells rapidly grow, form meningospheres and express stem markers, such as Sox2, NANOG, CD133 and Oct-4. Conversely, CD105 was not differentially expressed between stem-like cells and their “non-stem” counterpart, cells grown in serum-containing medium. Moreover, stem-like cells displayed high migratory capacity and in vitro angiogenic activity, supporting their malignant phenotype. Meningioma stem-like cells displayed a distinct chemokinereceptor profile from “non-stem” cell population, and selectively respond to in vitro CXCL11 and CXCL12 stimulation enhancing proliferation, migration and vascular mimicry. Pharmacological inhibition of individual CXCR4 or CXCR7 significantly impaired CXCL12- and CXCL11-induced proliferation, chemotaxis and vessel-like structure formation, therefore suggesting that these activities are mediated by both receptors. We speculated that these receptors act as heterodimers, formed upon ligand activation and that the blockade of one of them results in a complete inhibition of biological effects. Overall our results, collected from a large number of meningioma cell cultures derived from different patients, allow the identification of a tumor subpopulation endowed with comm on stem cell-like features, and suggest that both CXCR4 and CXCR7 signaling sustains meningioma stem cell phenotype. Prospectively, the isolation and culture of stem-like cells directly from the meningioma tissues will allow to test new therapeutic compounds to block meningioma growth and invasiveness, in particular for those tumors showing an unpredictable aggressive behavior. In this context, we propose that the CXCR4-7 chemokinergic system might represent a relevant pharmacological target.
|Titolo della tesi:||CXCR4/CXCR7-CXCL11/CXCL12 AXIS PROMOTES MALIGNANT PHENOTYPE IN PUTATIVE STEM CELLS FROM HUMAN MENINGIOMAS|
|Data di discussione:||27-mag-2019|
|Appare nelle tipologie:||Tesi di dottorato|